Zhiquan Yuan

Upon cytokine treatment, members of the signal transducers and activators of transcription (STAT) family of proteins are phosphorylated on tyrosine and serine sites within the carboxyl-terminal region in cells. We show that in response to cytokine treatment, Stat3 is also acetylated on a single lysine residue, Lys685. Histone acetyltransferase p300-mediated Stat3 acetylation on Lys685 was reversible by type I histone deacetylase (HDAC). Use of a prostate cancer cell line (PC3) that lacks Stat3 and PC3 cells expressing wild-type Stat3 or a Stat3 mutant containing a Lys685-to-Arg substitution revealed that Lys685 acetylation was critical for Stat3 to form stable dimers required for cytokine-stimulated DNA binding and transcriptional regulation, to enhance transcription of cell growth-related genes, and to promote cell cycle progression in response to treatment with oncostatin M.

Sepsis, a leading cause of death worldwide, involves concomitant expression of an overzealous inflammatory response and inefficient bacterial clearance. Macrophage function is pivotal to the development of these two aspects during sepsis; however, the mechanisms underlying these changes remain unclear. Here we report that the PD-1:PD-L pathway appears to be a determining factor of the outcome of sepsis, regulating the delicate balance between effectiveness and damage by the antimicrobial immune response. To this end we observed that PD-1(-/-) mice were markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response. To the extent that this is a macrophage-specific aspect of the effects of PD-1, we found the following: first, peritoneal macrophages expressed significantly higher levels of PD-1 during sepsis, which was associated with their development of cellular dysfunction; second, when peritoneal macrophages were depleted (using clodronate liposomes) from PD-1(-/-) mice, the animals' bactericidal capacity was lowered, their inflammatory cytokine levels were elevated, and protection from septic lethality was diminished; and third, blood monocytes from both septic mice and patients with septic shock shared markedly increased PD-1 levels. Together, these data suggest that PD-1 may not only be a dysfunctional marker/effector of macrophages/monocytes, but may also be a potential therapeutic target for designing measures to modulate the innate immune response, thereby preventing the detrimental effects of sepsis.

STAT3 inhibits glucose production by suppressing the expression of key gluconeogenic genes. In a novel nutrient sensing pathway, the fasting activated longevity protein SirT11 promotes gluconeogenesis by suppressing this inhibitory effect of STAT3. The fasting-activated longevity protein sirtuin 1 (SirT1, ref. 1) promotes gluconeogenesis in part, by increasing transcription of the key gluconeogenic genes pepck1 and g6pase2,3, through deacetylating PGC-1α and FOXO1 (ref. 4). In contrast, signal transducer and activator of transcription 3 (STAT3) inhibits glucose production by suppressing expression of these genes5,6. It is not known whether the inhibition of gluconeogenesis by STAT3 is controlled by metabolic regulation. Here we show that STAT3 phosphorylation and function in the liver were tightly regulated by the nutritional status of an animal, through SirT1-mediated deacetylation of key STAT3 lysine sites. The importance of the SirT1–STAT3 pathway in the regulation of gluconeogenesis was verified in STAT3-deficient mice in which the dynamic regulation of gluconeogenic genes by nutritional status was disrupted. Our results reveal a new nutrient sensing pathway through which SirT1 suppresses the inhibitory effect of STAT3, while activating the stimulatory effect of PGC-1α and FOXO1 on gluconeogenesis, thus ensuring maximal activation of gluconeogenic gene transcription. The connection between acetylation and phosphorylation of STAT3 implies that STAT3 may have an important role in other cellular processes that involve SirT1.

Exceptional points (EPs) are special spectral degeneracies of non-Hermitian Hamiltonians governing the dynamics of open systems. At the EP two or more eigenvalues and the corresponding eigenstates coalesce. Recently, it has been proposed that EPs can enhance the sensitivity of optical gyroscopes. Here we report measurement of rotation sensitivity boost by over 4X resulting from operation of a chip-based stimulated Brillouin gyroscope near an exceptional point. A second-order EP is identified in the gyroscope and originates from the dissipative coupling between the clockwise and counterclockwise lasing modes. The modes experience opposing Sagnac shifts under application of a rotation, but near the exceptional point new modal admixtures dramatically increase the Sagnac shift. Modeling confirms the measured enhancement. Besides the ability to operate an optical gyroscope with enhanced sensitivity, this result provides a new platform for study of non-Hermitian physics and nonlinear optics with precise control.

Abstract 2D layered materials have emerged in recent years as a new platform to host novel electronic, optical, or excitonic physics and develop unprecedented nanoelectronic and energy applications. By definition, these materials are strongly anisotropic between the basal plane and cross the plane. The structural and property anisotropies inside their basal plane, however, are much less investigated. Black phosphorus, for example, is a 2D material that has such in‐plane anisotropy. Here, a rare chemical form of arsenic, called black‐arsenic (b‐As), is reported as a cousin of black phosphorus, as an extremely anisotropic layered semiconductor. Systematic characterization of the structural, electronic, thermal, and electrical properties of b‐As single crystals is performed, with particular focus on its anisotropies along two in‐plane principle axes, armchair (AC) and zigzag (ZZ). The analysis shows that b‐As exhibits higher or comparable electronic, thermal, and electric transport anisotropies between the AC and ZZ directions than any other known 2D crystals. Such extreme in‐plane anisotropies can potentially implement novel ideas for scientific research and device applications.

Representation Learning is a significant and challenging task in multimodal learning. Effective modality representations should contain two parts of characteristics: the consistency and the difference. Due to the unified multimodal annota- tion, existing methods are restricted in capturing differenti- ated information. However, additional unimodal annotations are high time- and labor-cost. In this paper, we design a la- bel generation module based on the self-supervised learning strategy to acquire independent unimodal supervisions. Then, joint training the multimodal and uni-modal tasks to learn the consistency and difference, respectively. Moreover, dur- ing the training stage, we design a weight-adjustment strat- egy to balance the learning progress among different sub- tasks. That is to guide the subtasks to focus on samples with the larger difference between modality supervisions. Last, we conduct extensive experiments on three public multimodal baseline datasets. The experimental results validate the re- liability and stability of auto-generated unimodal supervi- sions. On MOSI and MOSEI datasets, our method surpasses the current state-of-the-art methods. On the SIMS dataset, our method achieves comparable performance than human- annotated unimodal labels. The full codes are available at https://github.com/thuiar/Self-MM.

Non-Hermitian Hamiltonians describing open systems can feature singularities called exceptional points (EPs). Resonant frequencies become strongly dependent on externally applied perturbations near an EP which has given rise to the concept of EP-enhanced sensing in photonics. However, while increased sensor responsivity has been demonstrated, it is not known if this class of sensor results in improved signal-to-noise performance. Here, enhanced responsivity of a laser gyroscope caused by operation near an EP is shown to be exactly compensated by increasing sensor noise in the form of linewidth broadening. The noise, of fundamental origin, increases according to the Petermann factor, because the mode spectrum loses the oft-assumed property of orthogonality. This occurs as system eigenvectors coalesce near the EP and a biorthogonal analysis confirms experimental observations. Besides its importance to the physics of microcavities and non-Hermitian photonics, this is the first time that fundamental sensitivity limits have been quantified in an EP sensor.

Abstract Integrated photonics has profoundly affected a wide range of technologies underpinning modern society 1–4 . The ability to fabricate a complete optical system on a chip offers unrivalled scalability, weight, cost and power efficiency 5,6 . Over the last decade, the progression from pure III–V materials platforms to silicon photonics has significantly broadened the scope of integrated photonics, by combining integrated lasers with the high-volume, advanced fabrication capabilities of the commercial electronics industry 7,8 . Yet, despite remarkable manufacturing advantages, reliance on silicon-based waveguides currently limits the spectral window available to photonic integrated circuits (PICs). Here, we present a new generation of integrated photonics by directly uniting III–V materials with silicon nitride waveguides on Si wafers. Using this technology, we present a fully integrated PIC at photon energies greater than the bandgap of silicon, demonstrating essential photonic building blocks, including lasers, amplifiers, photodetectors, modulators and passives, all operating at submicrometre wavelengths. Using this platform, we achieve unprecedented coherence and tunability in an integrated laser at short wavelength. Furthermore, by making use of this higher photon energy, we demonstrate superb high-temperature performance and kHz-level fundamental linewidths at elevated temperatures. Given the many potential applications at short wavelengths, the success of this integration strategy unlocks a broad range of new integrated photonics applications.

Chemically disordered face centered cubic (fcc) FePt nanoparticles (NPs) show the controlled release of Fe in low pH solution. The released Fe catalyzes H2O2 decomposition into reactive oxygen species within cells, causing fast oxidation and deterioration of cellular membranes. Functionalized with luteinizing hormone-releasing hormone (LHRH) peptide via phospholipid, the fcc-FePt NPs can bind preferentially to the human ovarian cancer cell line (A2780) that overexpresses LHRH receptors and exhibit high toxicity to these tumor cells. In contrast, the fcc-FePt NPs pre-etched in the low pH (4.8) buffer solution show nonappreciable cytotoxicity. The work demonstrates that fcc-FePt NPs may function as a new type of agent for controlled cancer therapy.

Cytokine-activated receptors initiate intracellular signaling by recruiting protein kinases that phosphorylate the receptors on tyrosine residues, thus enabling docking of SH2 domain-bearing activating factors. Here we report that in response to type 1 interferon (IFNalpha), IFNalpha receptors recruit cytoplasmic CREB-binding protein (CBP). By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9). IRF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. All three components are acetylated by CBP. Remarkably, acetylation within the DNA-binding domain (DBD) of both IRF9 and STAT2 is critical for the ISGF3 complex activation and its associated antiviral gene regulation. These results have significant implications concerning the central role of acetylation in cytokine receptor signal transduction.

A rapid and efficient method for the separation and purification of fucoxanthin from edible brown algae by microwave‐assisted extraction coupled with high‐speed countercurrent chromatography was developed. The algae were first extracted using microwave‐assisted extraction, then the dried extract was dissolved and directly introduced into the high‐speed countercurrent chromatography system with a two‐phase solvent system consisting of hexane‐ethyl acetate‐ethanol‐water (5:5:6:4, v/v/v/v). The isolation was done in less than 75 min, and a total of 0.83 mg, 1.09 mg, and 0.20 mg fucoxanthin were obtained from 25.0 g fresh L aminaria japonica A resch, 1.5 g dry U ndaria pinnatifida ( H arv) S ur, and 15.0 g dry S argassum fusiforme ( H arv) S etch, respectively. The purity of fucoxanthin determined by HPLC was over 90% and its structure was further identified by LC‐ESI‐MS and 1 H‐NMR .

Flexible actuators responsive to multiple stimuli are much desired in wearable electronics. However, general designs containing organic materials are usually subject to slow response and limited lifetime, or high triggering threshold. In this study, we develop flexible, all-inorganic actuators based on bimorph structures composed of vanadium dioxide (VO2) and carbon nanotube (CNT) thin films. The drastic, reversible phase transition of VO2 drives the actuators to deliver giant amplitude, fast response up to ∼100 Hz, and long lifetime more than 1 000 000 actuation cycles. The excellent electrical conductivity and light absorption of CNT thin films enable the actuators to be highly responsive to multiple stimuli including light, electric, and heat. The power consumption of the actuators can be much reduced by doping VO2 to lower its phase transition temperature. These flexible bimorph actuators find applications in biomimetic inspect wings, millimeter-scale fingers, and physiological-temperature driven switches.

Biaxial deformation of suspended membranes widely exists and is used in nanoindentation to probe elastic properties of structurally isotropic two-dimensional (2D) materials. However, the elastic properties and, in particular, the fracture behaviors of anisotropic 2D materials remain largely unclarified in the case of biaxial deformation. MoTe2 is a polymorphic 2D material with both isotropic (2H) and anisotropic (1T' and Td) phases and, therefore, an ideal system of single-stoichiometric materials with which to study these critical issues. Here, we report the elastic properties and fracture behaviors of biaxially deformed, polymorphic MoTe2 by combining temperature-variant nanoindentation and first-principles calculations. It is found that due to similar atomic bonding, the effective moduli of the three phases deviate by less than 15%. However, the breaking strengths of distorted 1T' and Td phases are only half the value of 2H phase due to their uneven distribution of bonding strengths. Fractures of both isotropic 2H and anisotropic 1T' phases obey the theorem of minimum energy, forming triangular and linear fracture patterns, respectively, along the orientations parallel to Mo-Mo zigzag chains. Our findings not only provide a reference database for the elastic behaviors of versatile MoTe2 phases but also illuminate a general strategy for the mechanical investigation of any isotropic and anisotropic 2D materials.

We self-injection-lock a diode laser to a 1.41 m long, ultra-high Q integrated resonator. The hybrid integrated laser reaches a frequency noise floor of 0.006Hz2/Hz at 4 MHz offset, corresponding to a Lorentzian linewidth below 40 mHz-a record among semiconductor lasers. It also exhibits exceptional stability at low-offset frequencies, with frequency noise of 200Hz2/Hz at 100 Hz offset. Such performance, realized in a system comprised entirely of integrated photonic chips, marks a milestone in the development of integrated photonics; and, for the first time, to the best of our knowledge, exceeds the frequency noise performance of commercially available, high-performance fiber lasers.

Abstract Dual-comb spectroscopy (DCS) offers high sensitivity and wide spectral coverage without the need for bulky spectrometers or mechanical moving parts. And DCS in the mid-infrared (mid-IR) is of keen interest because of inherently strong molecular spectroscopic signatures in these bands. We report GHz-resolution mid-IR DCS of methane and ethane that is derived from counter-propagating (CP) soliton microcombs in combination with interleaved difference frequency generation. Because all four combs required to generate the two mid-IR combs rely upon stability derived from a single high-Q microcavity, the system architecture is both simplified and does not require external frequency locking. Methane and ethane spectra are measured over intervals as short as 0.5 ms, a time scale that can be further reduced using a different CP soliton arrangement. Also, tuning of spectral resolution on demand is demonstrated. Although at an early phase of development, the results are a step towards mid-IR gas sensors with chip-based architectures for chemical threat detection, breath analysis, combustion studies, and outdoor observation of trace gases.

Abstract High‐coherence visible and near‐visible laser sources are centrally important to the operation of advanced position/navigation/timing systems as well as classical/quantum sensing systems. However, the complexity and size of these bench‐top lasers are an impediment to their transition beyond the laboratory. Here, a system‐on‐chip that emits high‐coherence near‐visible lightwaves is demonstrated. The devices rely upon a new approach wherein wavelength conversion and coherence increase by self‐injection locking are combined within a single nonlinear resonator. This simplified approach is demonstrated in a hybridly‐integrated device and provides a short‐term linewidth of around 4.7 kHz (10 kHz before filtering). On‐chip converted optical power over 2 mW is also obtained. Moreover, measurements show that heterogeneous integration can result in a conversion efficiency higher than 25% with an output power over 11 mW. Because the approach uses mature III–V pump lasers in combination with thin‐film lithium niobate, it can be scaled for low‐cost manufacturing of high‐coherence visible emitters. Also, the coherence generation process can be transferred to other frequency conversion processes, including optical parametric oscillation, sum/difference frequency generation, and third‐harmonic generation.

Normal group velocity dispersion (GVD) microcombs offer high comb line power and high pumping efficiency compared to bright pulse microcombs. The recent demonstration of normal GVD microcombs using CMOS foundry-produced microresonators is an important step toward scalable production. However, the chromatic dispersion of CMOS devices is large and impairs the generation of broadband microcombs. Here, we report the development of a microresonator in which GVD is reduced due to a coupled-ring resonator configuration. Operating in the turnkey self-injection locking mode, the resonator is integrated in a hybrid manner with a semiconductor laser pump to produce high-power efficiency combs spanning a bandwidth of 9.9 nm (1.22 THz) centered at 1560 nm, corresponding to 62 comb lines. Fast, linear optical sampling of the comb waveform is used to observe the rich set of near-zero GVD comb behaviors, including soliton molecules, switching waves (platicons), and their hybrids. Tuning of the 20 GHz repetition rate by electrical actuation enables servo locking to a microwave reference, which simultaneously stabilizes the comb repetition rate, offset frequency, and temporal waveform. This integrated hybrid system could be used in coherent communications or for ultrastable microwave signal generation by two-point optical frequency division.

The receptor tyrosine kinases (RTKs) RET, MET, and RON all carry the Met(p+1loop)-->Thr point mutation (i.e., 2B mutation), leading to the formation of tumors with high metastatic potential. Utilizing a novel antibody array, we identified constitutive phosphorylation of STAT3 in cells expressing the 2B mutation but not wild-type RET. MET or RON with the 2B mutation also constitutively phosphorylated STAT3. Members of the EPH, the only group of wild-type RTK that carry Thr(p+1loop) residue, are often expressed unexpectedly in different types of cancers. Ectopic expression of wild-type but not Thr(p+1loop)-->Met substituted EPH family members constitutively phosphorylated STAT3. In both RTK(Metp+1loop) with 2B mutation and wild-type EPH members the Thr(p+1loop) residue is required for constitutive kinase autophosphorylation and STAT3 recruitment. In multiple endocrine neoplasia 2B (MEN-2B) patients expressing RET(M918T), nuclear enrichment of STAT3 and elevated expression of CXCR4 was detected in metastatic thyroid C-cell carcinoma in the liver. In breast adenocarcinoma cell lines expressing multiple EPH members, STAT3 constitutively bound to the promoters of MUC1, MUC4, and MUC5B genes. Inhibiting STAT3 expression resulted in reduced expression of these metastasis-related genes and inhibited mobility. These findings provide insight into Thr(p+1loop) residue in RTK autophosphorylation and constitutive activation of STAT3 in metastatic cancer cells.

Abstract Compact, low-noise microwave sources are required throughout a wide range of application areas including frequency metrology, wireless-communications and airborne radar systems. And the photonic generation of microwaves using soliton microcombs offers a path towards integrated, low noise microwave signal sources. In these devices, a so called quiet-point of operation has been shown to reduce microwave frequency noise. Such operation decouples pump frequency noise from the soliton’s motion by balancing the Raman self-frequency shift with dispersive-wave recoil. Here, we explore the limit of this noise suppression approach and reveal a fundamental noise mechanism associated with fluctuations of the dispersive wave frequency. At the same time, pump noise reduction by as much as 36 dB is demonstrated. This fundamental noise mechanism is expected to impact microwave noise (and pulse timing jitter) whenever solitons radiate into dispersive waves belonging to different spatial mode families.

Improving robustness against data missing has become one of the core challenges in Multimodal Sentiment Analysis (MSA), which aims to judge speaker sentiments from the language, visual, and acoustic signals. In the current research, translation-based methods and tensor regularization methods are proposed for MSA with incomplete modality features. However, both of them fail to cope with random modality feature missing in non-aligned sequences. In this paper, a transformer-based feature reconstruction network (TFR-Net) is proposed to improve the robustness of models for the random missing in non-aligned modality sequences. First, intra-modal and inter-modal attention-based extractors are adopted to learn robust representations for each element in modality sequences. Then, a reconstruction module is proposed to generate the missing modality features. With the supervision of SmoothL1Loss between generated and complete sequences, TFR-Net is expected to learn semantic-level features corresponding to missing features. Extensive experiments on two public benchmark datasets show that our model achieves good results against data missing across various missing modality combinations and various missing degrees.

Coherently-pumped (Kerr) solitons in an ideal optical microcavity are expected to undergo random quantum motion that determines fundamental performance limits in applications of soliton microcombs. Here, this diffusive motion and its impact on Kerr soliton timing jitter is studied experimentally. Typically hidden below technical noise contributions, the quantum limit is discerned by measuring counter-propagating solitons. Their relative motion features only weak interactions and also presents excellent common mode suppression of technical noise. This is in strong contrast to co-propagating solitons which are found to have relative timing jitter well below the quantum limit of a single soliton on account of strong mutual motion correlation. Good agreement is found between theory and experiment. The results establish the fundamental limits to timing jitter in soliton microcombs and provide new insights on multi-soliton physics

Chemokines play important roles in leukocyte trafficking as well as function regulation. In this study, we described the identification and characterization of a novel CXC chemokine from a human dendritic cell (DC) cDNA library, the full-length cDNA of which contains an open reading frame encoding 111 aa with a putative signal peptide of 34 aa. This CXC chemokine shares greatest homology with macrophage inflammatory protein (MIP)-2alphabeta, hence is designated as MIP-2gamma. Mouse MIP-2gamma was identified by electrocloning and is highly homologous to human MIP-2gamma. Northern blotting revealed that MIP-2gamma was constitutively and widely expressed in most normal tissues with the greatest expression in kidney, but undetectable in most tumor cell lines except THP-1 cells. In situ hybridization analysis demonstrated that MIP-2gamma was mainly expressed by the epithelium of tubules in the kidney and hepatocytes in the liver. Although no detectable expression was observed in freshly isolated or PMA-treated monocytes, RT-PCR analysis revealed MIP-2gamma expression by monocyte-derived DC. Recombinant MIP-2gamma from 293 cells is about 9.5 kDa in size and specifically detectable by its polyclonal Ab developed by the immunization with its 6His-tagged fusion protein. The eukaryotically expressed MIP-2gamma is a potent chemoattractant for neutrophils, and weaker for DC, but inactive to monocytes, NK cells, and T and B lymphocytes. Receptor binding assays showed that MIP-2gamma does not bind to CXCR2. This implies that DC might contribute to the innate immunity through the production of neutrophil-attracting chemokines and extends the knowledge about the regulation of DC migration.

A rapid method of microwave-assisted extraction coupled with high-speed counter current chromatography and UV detector was established for the preparation of phytosterols from edible marine algae. Extraction conditions, namely microwave power, liquid/solid ratio, irradiation time and extraction temperature were optimized using orthogonal array design. The microwave-assisted extraction of Undaria pinnatifida and Sargassum fusiforme were separated and purified with a non-aqueous two-phase solvent system composed of n-hexane–acetonitrile–methanol (5:5:3, v/v/v). The isolation was done in less than 220 min, and a total of 13.0 mg fucosterol, 1.5 mg 24-methylenecholesterol and 10.7 mg phytol were obtained from 15.0 g U. pinnatifida; 4.6 mg fucosterol, 0.3 mg 24-methylenecholesterol and 3.5 mg phytol were obtained from 15.0 g S. fusiforme. The purities of all products were over 97% determined by high performance liquid chromatography. The results demonstrate that microwave-assisted extraction coupled with high-speed counter-current chromatography is a feasible, economical and efficient technique for rapid extraction, separation and purification of effective compounds from natural products.

Identifying relevant mediators responsible for the pathogenesis during sepsis may lead to finding novel diagnostic and therapeutic targets. Recent studies indicate programmed cell death receptor (PD)-1 plays a significant role in the development of immune suppression associated with sepsis. In this study, we determine whether B7-H1, the primary ligand of PD-1, contributes to the pathogenesis of sepsis. We report that B7-H1 is upregulated extensively on various immune cells during sepsis and B7-H1 gene deficiency protects mice from the lethality of sepsis. In terms of the histological development of multiple organ damage and inflammatory cytokine levels in circulation or at infectious site, B7-H1-deficient mice showed a remarkable reduction in these indices when compared with wild-type mice. However, B7-H1 gene-deficient mice did not exhibit a lower bacterial burden when compared with wild-type mice, although they recruited more macrophages and neutrophils into infectious site. In addition, we found that, during sepsis, whereas there were no marked differences affecting ex vivo macrophage cytokine productive capacity between PD-1 and B7-H1 gene-deficient mice, preservation of ex vivo macrophage phagocytic function was only seen in septic PD-1 knockout mouse cells. Finally, higher percentage B7-H1(+) neutrophils in peripheral blood correlated not only with higher levels of pro- and anti-inflammatory cytokines/chemokines (CCL2, IL-6, CXCL2, KC, TNF-α, and IL-10), but with lethal outcome as well. Together, these results indicate B7-H1 contributes to septic morbidity in fashion distinct from PD-1 and suggest B7-H1 expression on neutrophils could be used as a biomarker of septic severity.

In this paper we study the spatial and temporal distribution of the wind and hydro resources, together with electricity demand and prices, with the objective to gain insights on the trade-offs of developing wind power in different parts of the country. It is particularly important to understand the impacts of a high penetration level of wind power on an electricity market that is already highly influenced by seasonal hydro power availability. The correlation between the seasonal patterns of wind, hydro, demand and prices has received little attention in the literature. In our approach, we separate daily deviations from the expected seasonal value, and show that for some locations it is the anomalies that have a more significant correlation with electricity prices than the seasonal patterns themselves. This indicates that the correlation results for anomalies from different wind sites can give valuable information on wind resource availability in critical periods of the year, such as dry seasons, and thereby enables identifying sites that can most optimally balance price volatility during these periods while potentially also maximising profits to investors. Even though the numerical results pertain to New Zealand, our methodology is applicable to any electricity system that utilises wind and hydro resources such as Chile, Colombia and several North American and Northern European jurisdictions.

Atrial fibrillation (AF) is one of the most common complications of acute coronary syndrome (ACS) patients. Possible risk factors related to new-onset AF (NOAF) in ACS patients have been reported in some studies, and several prediction models have been established. However, the predictive power of these models was modest and lacked independent validation. The aim of this study is to define risk factors of NOAF in patients with ACS during hospitalization and to develop a prediction model and nomogram for individual risk prediction.Retrospective cohort studies were conducted. A total of 1535 eligible ACS patients from one hospital were recruited for model development. External validation was performed using an external cohort of 1635 ACS patients from another hospital. The prediction model was created using multivariable logistic regression and validated in an external cohort. The discrimination, calibration, and clinical utility of the model were evaluated, and a nomogram was constructed. A subgroup analysis was performed for unstable angina (UA) patients.During hospitalization, the incidence of NOAF was 8.21% and 6.12% in the training and validation cohorts, respectively. Age, admission heart rate, left atrial diameter, right atrial diameter, heart failure, brain natriuretic peptide (BNP) level, less statin use, and no percutaneous coronary intervention (PCI) were independent predictors of NOAF. The AUC was 0.891 (95% CI: 0.863-0.920) and 0.839 (95% CI: 0.796-0.883) for the training and validation cohort, respectively, and the model passed the calibration test (P > 0.05). The clinical utility evaluation shows that the model has a clinical net benefit within a certain range of the threshold probability.A model with strong predictive power was constructed for predicting the risk of NOAF in patients with ACS during hospitalization. It might help with the identification of ACS patients at risk and early intervention of NOAF during hospitalization.

MUC1, a tumor associated glycoprotein, is over-expressed in most cancers and can promote proliferation and metastasis. The objective of this research was to study the role of MUC1 in cancer metastasis and its potential mechanism. Pancreatic (PANC1) and breast (MCF-7) cancer cells with stable 'knockdown' of MUC1 expression were created using RNA interference. beta-Catenin and E-cadherin protein expression were upregulated in PANC1 and MCF-7 cells with decreased MUC1 expression. Downregulation of MUC1 expression also induced beta-catenin relocation from the nucleus to the cytoplasm, increased E-cadherin/beta-catenin complex formation and E-cadherin membrane localization in PANC1 cells. PANC1 cells with 'knockdown' MUC1 expression had decreased in vitro cell invasion. This study suggested that MUC1 may affect cancer cell migration by increasing E-cadherin/beta-catenin complex formation and restoring E-cadherin membrane localization.

Ankyrin repeat and SOCS box (ASB) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence of variable repeats belonging to the SOCS superfamily. While SH2-domain-bearing SOCS proteins are mainly involved in the negative feedback regulation of the protein tyrosine kinase-STAT pathway in response to a variety of cytokines, the roles of ASB family members remain largely unknown. To investigate ASB functions, we screened for ASB3-interacting factors by using antibody array technology and identified tumor necrosis factor receptor II (TNF-R2) as an ASB3 binding target. ASB3 expression and activities are required for (i) TNF-R2 ubiquitination both in vivo and in vitro, (ii) TNF-R2 proteolysis via the proteasome pathway, and (iii) the inhibition of TNF-R2-mediated Jun N-terminal protein kinase (JNK) activation. While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-α by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation.

Representation Learning is a significant and challenging task in multimodal learning. Effective modality representations should contain two parts of characteristics: the consistency and the difference. Due to the unified multimodal annotation, existing methods are restricted in capturing differentiated information. However, additional uni-modal annotations are high time- and labor-cost. In this paper, we design a label generation module based on the self-supervised learning strategy to acquire independent unimodal supervisions. Then, joint training the multi-modal and uni-modal tasks to learn the consistency and difference, respectively. Moreover, during the training stage, we design a weight-adjustment strategy to balance the learning progress among different subtasks. That is to guide the subtasks to focus on samples with a larger difference between modality supervisions. Last, we conduct extensive experiments on three public multimodal baseline datasets. The experimental results validate the reliability and stability of auto-generated unimodal supervisions. On MOSI and MOSEI datasets, our method surpasses the current state-of-the-art methods. On the SIMS dataset, our method achieves comparable performance than human-annotated unimodal labels. The full codes are available at https://github.com/thuiar/Self-MM.

Circular RNA (circRNA) have been reported to play important roles in cardiovascular diseases including myocardial infarction and heart failure. However, the role of circRNA in atrial fibrillation (AF) has rarely been investigated. We recently found a circRNA hsa_circ_0099734 was significantly differentially expressed in the AF patients atrial tissues compared to paired control. We aim to investigate the functional role and molecular mechanisms of mmu_circ_0005019 which is the homologous circRNA in mice of hsa_circ_0099734 in AF.In order to investigate the effect of mmu_circ_0005019 on the proliferation, migration, differentiation into myofibroblasts and expression of collagen of cardiac fibroblasts, and the effect of mmu_circ_0005019 on the apoptosis and expression of Ito, INA and SK3 of cardiomyocytes, gain- and loss-of-function of cell models were established in mice cardiac fibroblasts and HL-1 atrial myocytes. Dual-luciferase reporter assays and RIP were performed to verify the binding effects between mmu_circ_0005019 and its target microRNA (miRNA).In cardiac fibroblasts, mmu_circ_0005019 showed inhibitory effects on cell proliferation and migration. In cardiomyocytes, overexpression of mmu_circ_0005019 promoted Kcnd1, Scn5a and Kcnn3 expression. Knockdown of mmu_circ_0005019 inhibited the expression of Kcnd1, Kcnd3, Scn5a and Kcnn3. Mechanistically, mmu_circ_0005019 exerted biological functions by acting as a miR-499-5p sponge to regulate the expression of its target gene Kcnn3.Our findings highlight mmu_circ_0005019 played a protective role in AF development and might serve as an attractive candidate target for AF treatment.

The integrated development of population aging and digital information age has brought an insurmountable “digital divide” to the elderly. We propose a method to profile the digital divide of the elderly by text mining, Baidu index and principal component analysis. The top ten scenarios related to the digital divide of the elderly are extracted, which are mobile, payment, phone, QR code, technology, WeChat, Alipay, cash, insurance and medical. The attention distribution of different scenarios in major cities in China was investigated and classified. The results suggest that the health code, social media, and online insurance need higher policy attention to promote narrow digital divide measure. And an inconsistency between netizens' attention and news reports makes Internet search behaviors have the potential to be a real-time supplement to narrow the digital divide among the elderly. The problem states of different cities reflect spatial heterogeneity and temporal asynchrony. The proposed method timely tracks the scenarios of the elderly's digital divide, providing effective insights and references to policy making and services and products improvement, and also providing suggestions for optimizing the development of “Internet +” aging.

Previous studies have discovered that board-coupled shaft (BCS) can eliminate the plug-holing phenomenon that usually occurs in the traditional shaft and could be applied in shallow-buried and deep-buried tunnels. However, the impact of tunnel burial depth on the smoke exhaust performance with BCS is unknown at present. To better understand this question, 42 simulations were conducted, and the effects of buried depths and board locations on the smoke extraction performance of BCS were investigated. The results indicated that: (a) when the buried depth of the tunnel is large enough (≥10 m) that a plug-holing phenomenon occurs, the overall performance of BCS is better than that of the traditional shaft; (b) the smoke extraction performance of the BCS is controlled by both the buried depth of tunnels and the board locations when the shaft height is lower than 10 m, but mainly dominated by the board position when the shaft height is larger than 30 m; (c) the BCS can achieve a maximum 65.5% improvement in smoke extraction performance over the traditional shaft when the shaft height is 10 m. Besides that, a semi-empirical equation was developed to predict the correlation between non-dimensional volume flow rate and buried depth. These studies can guide extending the application scenarios of shafts and providing technical support.

Fractalkine (FK, also called neurotactin or CX3CL1) is a CX3C chemokine that can chemoattract T lymphocytes, monocytes and NK cells. In our study, we investigated the induction of antitumor response by FK gene transfer. FK gene-modified 3LL lung carcinoma cells (3LL-FK) could both secrete soluble form and express membrane-bound form of FK. The tumor growth of 3LL-FK was decreased. Vaccination with 3LL-FK was effective in the induction of protective immunity and CTL. In vivo depletion analysis demonstrated that CD8(+) T cells are the main participating cells of the antitumor response. Obvious infiltrations of CD8(+) T cells, CD4(+) T cells and dendritic cells (DC) were observed in the tumor sites, suggesting that 3LL-FK might induce antitumor immunity through chemoattraction and activation of T cells and DC. Then we investigated the chemoattraction and activation of DC by 3LL-FK. Chemotaxis assay showed that the supernatants of 3LL-FK could chemoattract immature DC, which were found to express FK receptor CX3CR1, and the immature DC could obviously adhere to 3LL-FK. Adherence of DC to 3LL-FK resulted in phenotypic maturation and upregulated IL-12 secretion of DC, and more strong stimulation of allogeneic T-cell proliferation by DC. The increased production of IL-2 and IFNgamma in 3LL-FK tumor tissue was also observed. Our data suggested that FK gene transfer to tumor cells could induce T-cell-dependent antitumor immunity through chemoattraction and activation of DC.

Pulsing dendritic cells (DCs) with tumor cell-derived mRNA is regarded as an attractive alternative in the development of DC-based tumor vaccines. Our aim is to improve the therapeutic efficacy of DC-based tumor RNA vaccines by augmenting the preferential chemotaxis of DCs to T cells. Mouse bone marrow-derived DCs were genetically modified with lymphotactin (Lptn) by adenovirus vector, which conferred on DCs preferential chemotaxis to CD4+ and CD8+ T cells (Cao et al., 1998). Lptn gene-modified DCs (Lptn-DCs) were pulsed with tumor mRNA and used for vaccination in the tumor models of 3LL lung carcinoma and B16 melanoma. In both tumor models, immunization with 4 X 10(4) tumor RNA-pulsed Lptn-DCs induced more potent CTL activity, compared with their counterparts, specifically against tumor cells and Mut1 or tyrosinase-related protein 2 (TRP-2) peptide-pulsed RMA-S cells, and rendered the immunized mice resistant to tumor challenge much more effectively. CD8+ T cells were necessary and sufficient to generate the protection of Lptn-DC-based RNA tumor vaccines, and CD4+ T cells were required for the induction of tumor rejection. In the preestablished 3LL and B16 tumor models, vaccination with DC-based or LacZ-DC-based tumor RNA vaccines (2 X 10(5) cells) could reduce pulmonary metastasis and extend survival of tumor-bearing mice, but was less effective than the Lptn-DC counterpart (with 60-80% mice surviving). When the immunizing dose was decreased to 4 X 10(4) cells, Lptn-DC-based tumor vaccines rather than their counterparts were still significantly effective. Our studies provide a potential strategy to improve the efficacy of DC-based vaccines, and a new approach to immunological intervention by chemokines.

Previously, we demonstrated that antibodies printed on a solid support were able to detect protein-protein interaction in mammalian cells. Here we further developed the antibody array system for detecting proteins with various post-translational modifications in mammalian cells. In this novel approach, immunoprecipitated proteins were labeled with fluorescent dye followed by incubation over antibody arrays. Targeted proteins, captured by the antibodies immobilized on PVDF membrane or glass slide, were detected by means of near infrared fluorescent scanner or fluorescent microscopy. To demonstrate the application of the antibody arrays in protein post-translational modifications, we profiled protein tyrosine phosphorylation, ubiquitination, and acetylation in mammalian cells under different conditions. Our results indicate that antibody array technology can provide a powerful means of profiling a large number of proteins with different post-translational modifications in cells. Previously, we demonstrated that antibodies printed on a solid support were able to detect protein-protein interaction in mammalian cells. Here we further developed the antibody array system for detecting proteins with various post-translational modifications in mammalian cells. In this novel approach, immunoprecipitated proteins were labeled with fluorescent dye followed by incubation over antibody arrays. Targeted proteins, captured by the antibodies immobilized on PVDF membrane or glass slide, were detected by means of near infrared fluorescent scanner or fluorescent microscopy. To demonstrate the application of the antibody arrays in protein post-translational modifications, we profiled protein tyrosine phosphorylation, ubiquitination, and acetylation in mammalian cells under different conditions. Our results indicate that antibody array technology can provide a powerful means of profiling a large number of proteins with different post-translational modifications in cells. Protein function and half-life are often under the tight regulation of post-translational modifications such as phosphorylation, ubiquitination, and acetylation. Tyrosine phosphorylation is a key mechanism for the reversible regulation of protein activity during signal transduction. The polyubiquitination-proteosome pathway plays a substantial role in the degradation of regulatory proteins in a variety of cellular processes. As for acetylation, accumulating evidence indicates that transcriptional regulation is strongly influenced by the acetylation of histones as well as transcription factors. For many proteins, multiple post-translational modifications may occur simultaneously or sequentially. In the case of p53 tumor suppressor, ubiquitination, phosphorylation, and acetylation can all affect its activity (1Brooks C.L. Gu W. Ubiquitination, phosphorylation and acetylation: The molecular basis for p53 regulation..Curr. Opin. Cell Biol. 2003; 15: 164-171Google Scholar). Altered protein tyrosine phosphorylation, protein ubiquitination, and protein acetylation in mammalian cells are closely related to developmental diseases and cancer. Recently, mass spectrometry has been employed for identification of proteins or peptides or more specifically, the residues bearing phosphorylation/acetylation modifications (2Wang Y.H. Tsay Y.G. Tan B.C. Lo W.Y. Le S.C. Identification and characterization of a novel p300-mediated p53 acetylation site, lysine 305..J. Biol. Chem. 2003; 278: 25568-25576Google Scholar, 3Shi Y. Sawada J. Sui G. Affar el B. Whetstine J.R. Lan F. Ogawa H. Luke M.P. Nakatani Y. Shi Y. Coordinated histone modifications mediated by a CtBP co-repressor complex..Nature. 2003; 422: 735-738Google Scholar). However, a convenient and reliable biochemical method for identifying proteins with the aforementioned post-translational modifications as they occur within a cell lysate is still lacking. We recently immobilized 50–100 different antibodies on a PVDF membrane for identification of protein-protein interactions in mammalian cells (4Wang Y. Wu T.R. Cai S. Welte T. Chin Y.E. Stat1 as a component of tumor necrosis factor α receptor 1-TRADD signaling complex to inhibit NF-κB activation..Mol. Cell. Biol. 2000; 20: 4505-4512Google Scholar, 5Wu T.R. Hong Y.K. Wang X.D. Ling M.Y. Dragoi A.M. Chung A.S. Campbell A.G. Han Z.Y. Feng G.S. Chin Y.E. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei..J. Biol. Chem. 2002; 277: 47572-47580Google Scholar), because antibodies when immobilized on a solid support maintain their binding specificity to target proteins in cells. Meanwhile, purified recombinant proteins or synthesized peptides attached covalently to a glass slide were reported by other laboratories to be useful in detecting the interaction specifically with other proteins or with small molecules (6MacBeath G. Schreiber S.L. Printing proteins as microarrays for high-throughput function determination..Science. 2000; 289: 1760-1763Crossref Google Scholar, 7Newman J.R. Keating A.E. Comprehensive identification of human bZIP interactions with coiled-coil arrays..Science. 2003; 300: 2097-2101Google Scholar, 8Ge H. UPA, a universal protein array system for quantitative detection of protein-protein, protein-DNA, protein-RNA and protein-ligand interactions..Nucleic Acids Res. 2000; 28: e3Google Scholar). However, such designed recombinant protein or peptide arrays are mainly used for detecting in vitro protein-protein interactions. Whereas, antibody array technology can be employed to detect both in vitro and in vivo protein-protein interaction. The current study was undertaken to determine whether antibody array technology could be used to profile protein expression and characterize changes in post-translational modifications that accompany treatment of cells with growth factors, cytokines, or drugs. Results demonstrate an expanded application of the use of antibody arrays for profiling proteins with alterations in tyrosine phosphorylation, ubiquitination, and acetylation in mammalian cells in response to various treatments. A431, HeLa, and 293T cell lines were grown in Dulbecco’s modified Eagle’s medium (Sigma, St. Louis, MO) with 10% fetal bovine serum (Invitrogen, Carlsbad, CA) with penicillin (100 U/ml) and streptomycin (100 μg/ml) at 37 °C in 5% CO2 and 95% air. Both 3T3 fibroblasts from signal transducer and activator of transcription (STAT) 1The abbreviations used are: STAT, signal transducer and activator of transcription; ASB, ankyrin repeats and SOCS box; IR, near infrared; SODD, suppressor of death domain; TSA, trichostatin A; Ub, ubiquitin; RIPA, radioimmune precipitation assay; TBST, TBS-Tween 20; HRP, horseradish peroxidase; IgG, immunoglobulin G; EGFR, epidermal growth factor receptor; TRAF, TNF receptor-associated factor; HA, hemagglutinin. 1+/+ and STAT1−/− mice (9Durbin, J. E., Hackenmiller, R., Simon, M. C., and Levy, D. E.(1996) Targeted disruption of the mouseStat1 gene results in compromised innate immunity to viral disease. Cell84, , 443–450Google Scholar) (a kind gift from David Levy) were also maintained under the same conditions. Whole-cell extracts were prepared with radioimmune precipitation assay (RIPA) buffer according to the commercial protocol of Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). RIPA buffer contained 50 mm Tris-HCl, pH 7.4, 1% Nonidet P-40, 0.25% sodium deoxycholate, 150 mm NaCl, 1 mm EDTA, with 1 mm PMSF, 1 μg/ml each of aprotinin, leupeptin, and pepstatin, 1 mm Na3VO4, and 1 mm NaF. The Bio-Rad (Hercules, CA) protein assay was used to measure protein concentrations, and 0.5–1 mg of whole-cell extracts was used to setup immunoprecipitation utilizing our published protocol (4Wang Y. Wu T.R. Cai S. Welte T. Chin Y.E. Stat1 as a component of tumor necrosis factor α receptor 1-TRADD signaling complex to inhibit NF-κB activation..Mol. Cell. Biol. 2000; 20: 4505-4512Google Scholar, 5Wu T.R. Hong Y.K. Wang X.D. Ling M.Y. Dragoi A.M. Chung A.S. Campbell A.G. Han Z.Y. Feng G.S. Chin Y.E. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei..J. Biol. Chem. 2002; 277: 47572-47580Google Scholar). All antibodies tested here were purchased from Santa Cruz Biotechnology, Inc. except anti-acetyl-lysine polyclonal antibody, which was obtained from Upstate USA, Inc. (Charlottesville, VA). The above-prepared whole-cell extracts (0.5–2 mg) were incubated with antibodies coupled to protein G/A-agarose beads (Santa Cruz Biotechnology, Inc.) for immunoprecipitation. After incubation overnight at 4 °C, anti-pY20, anti-ubiquitin (Ub), or anti-acetyl-lysine immunoprecipitates were extensively washed with RIPA buffer for five to eight times and resuspended in 100 μl of RIPA prior to fluorescent staining according to the manufacturer’s directions (Molecular Probes, Eugene, OR). In brief, 7.5 μl of 2 mg ml−1 Alexa680 (excitation/emission maxima of 679/702 nm) obtained from Molecular Probes or 2 mg ml−1 of Cy2 (489/506 nm) or Cy5 (650/667 nm) obtained from Amersham Biosciences (Piscataway, NJ) was added to incubate with the immunoprecipitates for 2–3 h at 4 °C. After washing with RIPA for three times, fluorescent-labeled immunoprecipitates were resuspended in 1 ml of RIPA buffer and boiled for 5 min prior to incubating with antibody arrays. On a PVDF membrane obtained from Bio-Rad, commercial antibodies were spotted manually in a volume of 0.4 μl or less (20–40 ng) to yield spots less than 500 μm in diameter. When poly-l-lysine coated glass slides (CEL & Associates, Los Angeles, CA) were used as the support, antibodies (2–4 ng) were spotted on the top of the slide using the protein-spotter designed by Schleicher & Schuell (Keene, NH), yielding spots less than 200 μm in diameter. It is not necessary to keep antibody arrays hydrated throughout this and subsequent steps. All antibody arrays were stored in sealed plastic bags at 4 °C. Antibody arrays were immersed in a PBS buffer containing 3% BSA for 2 h prior to use. Antibody array assays were performed with two distinct methods: capturing fluorescent proteins and sandwich assay. For capturing fluorescent proteins, the above fluorescent-labeled protein samples (0.05–0.1 mg) were incubated with the above-prepared antibody arrays for 3 h at room temperature followed by three TBS-Tween 20 (TBST) washes. The fluorescent signals trapped on PVDF membrane arrays were analyzed with the near infrared fluorescent scanner LI-COR Odyssey Fluorescent Scanner manufactured by LI-COR Biosciences (Lincoln, NB). The glass slide arrays were visualized with Nikon fluorescent microscope equipped with appropriate excitation/emission filter sets for each dye. Intensities of the signals were analyzed by spot densitometry on the Odyssey software version 1.1.15 (2Wang Y.H. Tsay Y.G. Tan B.C. Lo W.Y. Le S.C. Identification and characterization of a novel p300-mediated p53 acetylation site, lysine 305..J. Biol. Chem. 2003; 278: 25568-25576Google Scholar). For the sandwich assay, unlabeled protein samples (0.5–2 mg) were incubated with the antibody array for 3 h at room temperature. After extensive washes with TBST, the antibody arrays were incubated with horseradish peroxidase (HRP)-conjugated antibody specific for a given post-translational modification (1:1,000 dilution in TBST) for an additional 2 h followed by ECL (Amersham Biosciences) detection. Initial experiments were designed to provide proof-of-principle regarding the capability of antibodies immobilized onto PVDF membranes or glass slides to capture and retain their cognate protein antigens from whole-cell extracts. After incubation with the extracts of STAT1+/+ or STAT1−/− cells labeled with Alexa680, the PVDF antibody arrays were washed and scanned with a LI-COR scanner (Fig. 1a). Caspase1 and IRF-1 proteins were detected in STAT1+/+ but not in STAT1−/− mouse fibroblast cells (Fig. 1a), in accordance with the previous findings that STAT1 plays an essential role in the expression of these two genes (9Durbin, J. E., Hackenmiller, R., Simon, M. C., and Levy, D. E.(1996) Targeted disruption of the mouseStat1 gene results in compromised innate immunity to viral disease. Cell84, , 443–450Google Scholar, 10Meraz M.A. White J.M. Sheehan K.C. Bach E.A. Rodig S.J. Dighe A.S. Kaplan D.H. Riley J.K. Greenlund A.C. Campbell D. Carver-Moore K. DuBois R.N. Clark R. Aguet M. Schreiber R.D. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway..Cell. 1996; 84: 431-442Google Scholar, 11Chin Y.E. Kitagawa M. Kuida K. Flavell R.A. Fu X.Y. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis..Mol. Cell. Biol. 1997; 17: 5328-5337Google Scholar). As an additional control, STAT1 was detected in STAT1+/+ cells but not in STAT1−/− cells (Fig. 1a). To investigate whether the micro-antibody array and fluorescent microscopy systems could be useful for detecting proteins, we spotted antibodies on the poly-l-lysine-coated glass slides (12Haab B.B. Dunham M.J. Brown P.O. Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions..Genome Biol. 2001; 2 (RESEARCH0004)Google Scholar). Cy2- and Cy5-labeled recombinant His6-STAT1 proteins (Fig. 1b) were mixed at different ratios and incubated with a glass slide immobilized with anti-His6 antibody, anti-STAT1 antibody, or control immunoglobulin G (IgG). The linear color change from green to red visualized with a fluorescent microscope provides a semi-quantitative measure of the proteins that were captured by the anti-His6 or anti-STAT1 antibody (Fig. 1c). When Cy2-labeled extracts of HeLa cells were used, fluorescent signals were detected by most of the antibodies that were randomly chosen for printing on the glass slide, although nonspecific interactions between the antibodies immobilized on the slide and the proteins in the sample are not excluded (Fig. 1d). Therefore, antibodies attached to either a PVDF membrane or a glass slide retain their abilities to capture cognate ligands from a mixture of cellular proteins and as will be shown below can then be used for profiling protein post-translational modifications in mammalian cells under different conditions. The antibody array was applied to profile tyrosine phosphorylation in epidermal carcinoma A431 cells. As shown in Fig. 2a and widely reported by others, the activation of EGFR with EGF results in tyrosine phosphorylation of multiple proteins as revealed by Western blot analysis using anti-pY20 (Fig. 2a). To identify phosphorylated proteins, pY20 was used to immunoprecipitate tyrosine-phosphorylated proteins from extracts of untreated and EGF-treated A431 cells and, after labeling with Alexa680, proteins were incubated with a PVDF antibody array containing 25 antibodies against signaling proteins spotted in duplicate. EGF-dependent tyrosine phosphorylation was evident on AKT and JAK2 (Fig. 2, b and c). Elevated EGFR phosphorylation in response to EGF treatment was also detected. In A431 cells, EGF has been widely reported to activate STAT proteins and inhibit cell growth (11Chin Y.E. Kitagawa M. Kuida K. Flavell R.A. Fu X.Y. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis..Mol. Cell. Biol. 1997; 17: 5328-5337Google Scholar). EGF-dependent STAT1, STAT3, and STAT5 phosphorylation (increased 10-fold, 9.5-fold, and 20-fold, respectively, in Fig. 2c) were clearly visualized in the arrays. Previously, we reported using HRP-conjugated antibody/ECL as a detection method for the antibody array analysis (i.e. sandwich method) (4Wang Y. Wu T.R. Cai S. Welte T. Chin Y.E. Stat1 as a component of tumor necrosis factor α receptor 1-TRADD signaling complex to inhibit NF-κB activation..Mol. Cell. Biol. 2000; 20: 4505-4512Google Scholar, 5Wu T.R. Hong Y.K. Wang X.D. Ling M.Y. Dragoi A.M. Chung A.S. Campbell A.G. Han Z.Y. Feng G.S. Chin Y.E. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei..J. Biol. Chem. 2002; 277: 47572-47580Google Scholar). These detection systems were directly compared using A431 cell extracts exposed to an antibody array followed by HRP-pY20 immunoprobing. Though less sensitive as compared with the above pY20 immunoprecipitation/fluorescent-labeling assay, pY20-HRP/ECL analysis clearly displayed differential protein phosphorylation patterns between the cells treated with and without EGF (Fig. 2d). Both methods were able to detect tyrosine phosphorylation of EGFR, STAT1, STAT3, and STAT5 in response to EGF treatment in A431 cells (Fig. 2, b and d). To demonstrate the specificity of the system for detection of tyrosine-phosphorylated proteins, A431 cells were treated with EGF in the presence or absence of the EGFR inhibitor Tyrphostin-AG528. When some antibodies in the array were examined individually, EGF treatment showed an increase in the cellular content of tyrosine-phosphorylated EGFR, JAK2, and SOCS3 (Fig. 2e). Tyrphostin-AG528 cotreatment effectively inhibited JAK2 or SOCS3 phosphorylation by EGF, although its effect on EGFR auto-phosphorylation was less effective (Fig. 2e). To confirm the findings resulting from the antibody arrays in Fig. 2, b and e, EGFR, JAK2, and SOCS3 were each immunoprecipitated from extracts of untreated, EGF-treated, and EGF plus Tyrphostin-AG528-treated A431 cells, and their tyrosine phosphorylation levels were confirmed by pY20 immunoblotting (Fig. 2f). Detected with both methods (Fig. 2, b and d), EGF-dependent tyrosine phosphorylations of STAT1, STAT3, and STAT5 were confirmed by using antibodies that recognize specific phosphorylated STAT proteins (Fig. 1g). Thus, the antibody arrays are capable of identifying multiple pTyr proteins within a signaling network such as that downstream of EGFR ligation. We next applied an antibody array to poly-ubiquitination analysis. TNF-α is a proinflammatory mediator, which exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII) and inducing protein ubiquitination (Fig. 3a). Whole extracts prepared from HeLa cells treated, or not, with TNF-α were subjected to anti-Ub immunoprecipitation. Anti-Ub precipitates labeled with Alexa680 were incubated with the antibody arrays. Overall more signals were detected in the sample that received TNF-α treatment (Fig. 3, b and c), suggesting these proteins were ubiquitinated in response to TNF-α treatment in HeLa cells. Proteins ubiquitinated by TNF-α treatment and trapped by the antibody array include TNF-RI, TNF-RII, TNF receptor-associated factor (TRAF) 2, TRAF6, and suppressor of death domain (SODD), consistent with the model that ubiquitination modification is an important event during TNF receptor signal transduction (13Xia L. Wang L. Chung A.S. Ivanov S.S. Ling M.Y. Dragoi A.M. Platt A. Gilmer T.M. Fu X.Y. Chin Y.E. Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation..J. Biol. Chem. 2002; 277: 30716-30723Google Scholar, 14Takayanagi H. Ogasawara K. Hida S. Chiba T. Murata S. Sato K. Takaoka A. Yokochi T. Oda H. Tanaka K. Nakamura K. Taniguchi T. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ..Nature. 2000; 408: 6000-6005Google Scholar, 15Li X. Yang Y. Ashwell J.D. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2..Nature. 2002; 416: 345-347Google Scholar). Poly-ubiquitinated proteins are short-lived. The proteosome inhibitor MG-132 is well-known to result in the accumulation of ubiquitin-conjugated proteins. In HeLa cells, MG-132 caused accumulation of poly-ubiquitinated proteins both in the absence and presence of TNF-α (Fig. 3d). Consistently, anti-Ub precipitates obtained from HeLa cells treated with MG-132 alone or MG-132 plus TNF-α contain more SODD and TRAF6 proteins as compared with untreated controls as revealed by the fluorescent signals detected by their respective immobilized antibodies (Fig. 3e). SODD was identified as a suppressor of TNF-RI death domain, regulating NF-κB activation (16Jiang Y. Woronicz J.D. Liu W. Goeddel D.V. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains..Science. 1999; 283: 543-546Google Scholar). Therefore, SODD dissociation from TNF-RI or SODD deficiency in mouse accelerates NF-κB activation (16Jiang Y. Woronicz J.D. Liu W. Goeddel D.V. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains..Science. 1999; 283: 543-546Google Scholar, 17Takada H. Chen N.J. Mirtsos C. Suzuki S. Suzuki N. Wakeham A. Mak T.W. Yeh W.C. Role of SODD in regulation of tumor necrosis factor responses..Mol. Cell. Biol. 2003; 23: 4026-4033Google Scholar). In HeLa cells, immunoprecipitated SODD proteins were subjected to Western blotting analysis with anti-Ub antibody or SODD antibody. SODD ubiquitination was evident at 1 h of TNF-α administration (Fig. 3f). Moreover, TNF-α-mediated SODD degradation was markedly blocked by treatment with MG-132 (Fig. 3f). Therefore, TNF-α treatment induced SODD ubiquitination and degradation may be responsible for NF-κB activation by TNF-RI (16Jiang Y. Woronicz J.D. Liu W. Goeddel D.V. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains..Science. 1999; 283: 543-546Google Scholar). To apply an antibody array for functional study of a novel gene, we screened protein ubiquitination in cells that overexpress ankyrin repeats and SOCS box (ASB) 3. ASB is a novel family of adaptor proteins that bind to elongins B/C through its SOCS box and acts as an E3 ubiquitin ligase that targets proteins bound to its ankyrin repeats domain for ubiquitination and proteosomal degradation (18Kamura T. Sato S. Haque D. Liu L. Kaelin Jr., W.G. Conaway R.C. Conaway J.W. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families..Genes Dev. 1998; 12: 3872-3881Google Scholar). In 293T cells, protein ubiquitination was increased by ASB3 transfection (Fig. 4a). Moreover, ubiquitinated proteins were pulled down by anti-cMyc (ASB3) immunoprecipitation (Fig. 4a), suggesting that ASB3 was involved in ubiquitination. To characterize protein ubiquitination mediated by ASB3, the sandwich assay was adopted by incubating the same whole-cell extracts with the PVDF antibody array immobilized with 360 antibodies followed by anti-hemagglutinin (HA)-HRP/ECL blotting analysis. Although protein ubiquitination patterns obtained from the two samples were similar, ASB3 transfection increased the intensity of the anti-HA (ubiquitin) signal for several factors including Bcl-2, Caspase14, FAF-1, Maspin, Rho C, and TNF-RII (Fig. 4b). The fact that anti-HA signal was detected at the spot immobilized with anti-cMyc antibody (Fig. 4b) strongly indicates that ASB3 was either self-ubiquinated or was associated with other proteins that were ubiquitinated. Our unpublished results indicate that by binding to TNF-RII, ASB3 terminates TNF-RII signaling by inducing TNF-RII ubiquitination and proteosome-dependent degradation. 2A. S. Chung and Y. E. Chin. Ankyrin repeats and SOCS box-3 (ASB-3) mediates ubiquitination and degradation of TNFR2, in preparation. TSA is a specific inhibitor of histone deacetylase and can induce protein acetylation in mammalian cells. In HeLa cells, after 1 h of treatment with TSA at indicated doses, a number of proteins including a protein with an apparent molecular mass of 54 kDa were acetylated as revealed by Western blotting analysis using a polyclonal anti-acetyl lysine antibody (Fig. 5a). To evaluate transcription factor acetylation, anti-acetyl-lysine precipitates from TSA-treated HeLa cells were labeled with Alexa680 and subsequently analyzed with 12 antibodies against different STAT family members as well as other relevant transcription factors. While STAT1, STAT2, STAT3, and STAT6 were detected as acetylated proteins in both treated and untreated cells, STAT3 acetylation was enhanced upon TSA treatment (Fig. 5b). p53 acetylation, detected in untreated HeLa cells, was slightly enhanced in the cells that received TSA treatment (Fig. 5b). When the above samples were analyzed with individual antibodies immobilized onto glass slides, p53 acetylation in response to TSA became obvious (Fig. 5c). TSA-dependent acetylation of STAT3, NF-κB p65, and tubulin were clearly detected (Fig. 5c). To confirm the results obtained in the arrays, we chosen STAT3 and tubulin for further examination by performing immunoprecipitation and Western blotting analysis. In anti-STAT3 immunoprecipitates of HeLa cells, we detected STAT3 acetylation, which was elevated by TSA treatment (Fig. 5d). TSA has been reported to induce strong α-tubulin acetylation on lysine-40 residue within the N terminus (19Zhang Y. Li N. Caron C. Matthias G. Hess D. Khochbin S. Matthias P. HDAC-6 interacts with and deacetylates tubulin and microtubulesin vivo..EMBO J. 2003; 22: 1168-1179Google Scholar). Utilizing a monoclonal anti-β-tubulin antibody of Santa Cruz Biotechnology Inc., we show that the strongly acetylated 54-kDa protein by TSA was tubulin (Fig. 5e). This indicates that β-tubulin may also be acetylated by TSA. Antibodies conjugated to protein G- or protein A-agarose beads have long been used for precipitating proteins on an individual basis. The approach of an antibody array offers some advantages including that membranes and glass slides can be spotted with a large number of antibodies in small volumes within a small area. The immediate advantage is that assays of this design provide identification of candidate proteins. Results presented here indicate that the intensity of the fluorescence captured by the array correlates well with the modification the protein molecule carries. Haab et al. reported only 20% of the arrayed antibodies provided specific and accurate measurements of their target antigens at a concentration of 1.6 μg/ml or less (12Haab B.B. Dunham M.J. Brown P.O. Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions..Genome Biol. 2001; 2 (RESEARCH0004)Google Scholar). However, our results indicate that commercial antibodies, immobilized on either a PVDF membrane or a glass slide, were able to capture their target proteins from a total cell extract. Arrays, comprising antibodies specific for various post-translational modifications, are now possible for analysis of site-specific or motif-specific modifications. Protein samples labeled with fluorescent dye and captured by the array for analysis is a more sensitive approach as compared with sandwich assay systems. The application of fluorescent microscope or laser scanners allows one to detect samples with sufficient sensitivity to permit the analysis to be conducted with small amounts of reagents. However, this design has the potential to create signal-to-noise. Although false-positive signals are inevitable for most immunoassays, the specificity of antibodies in recognizing their specific substrates becomes extremely critical for using antibody immobilization technology. For a quantitative or semi-quantitative analysis, immobilizing antibodies with equal amounts in the same orientation on two arrays will be essential for differential display of two samples (20Moreno-Bondi M.C. Alarie J.P. Vo-Dinh T. Multi-analyte analysis system using an antibody-based biochip..Anal. Bioanal Chem. 2003; 375: 120-124Google Scholar). Using a high-precision contact-printing robot will allow one to print nanoliter volumes of antibodies to the array more precisely (6MacBeath G. Schreiber S.L. Printing proteins as microarrays for high-throughput function determination..Science. 2000; 289: 1760-1763Crossref Google Scholar, 21Kuruvilla F.G. Shamji A.F. Sternson S.M. Hergenrother P.J. Schreiber S.L. Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays..Nature. 2002; 416: 653-657Google Scholar). Given that protein G or protein A preferentially interacts with Fc fragments of the antibodies, the solid support coated with protein A or G will be expected to improve antibody immobilization orientation. However, at present, the greatest challenge resides on how to normalize antigen-antibody binding affinity among various antibodies. Because different antibodies have different affinities for their specific antigens, it is difficult to make a comparison among different proteins captured by their specific antibodies even in the same array. Individual antibodies may require precise titration to determine for their antigen peptide or protein binding intensities to overcome this problem. Despite the above weakness, antibody arrays are reliable in comparing changes of one particular protein modification under different cellular conditions. In this work, we have immobilized up to 360 antibodies, and the array can be easily expanded into a larger-scale fabrication (22de Wildt R.M. Mundy C.R. Gorick B.D. Tomlinson I.M. Antibody arrays for high-throughput screening of antibody-antigen interactions..Nat. Biotechnol. 2000; 18: 989-994Google Scholar). Antibody arrays will benefit undoubtedly from improved methods of array preparation, processing and analysis, and preparation of recombinant antibody libraries for generating antibodies with the same affinity. Our work presented here indicates that the antibody array is a potentially powerful approach for profiling protein post-translational modification events, both known and unknown, in mammalian cells. We thank Z. Q. Pan and Z. Ronai for providing HA-Ub constructs and D. Levy for providing wild-type and STAT1-deficient mouse embryonic fibroblasts.

Abstract CD1d-dependent NKT cells have been extensively studied; however, the function of CD8 + NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8 + NKT-like cells, which express both T cell markers (TCRβ and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells. Distinct from CD1d-dependent NKT cells, CD8 + NKT-like cells possess a diverse repertoire of TCRs and secrete high levels of IFN-gamma but not IL-4. CD8 + NKT-like cell development is normal in CD1d −/− mice, which suggests that CD8 + NKT-like cells undergo a unique development pathway that differs from iNKT cells. Further functional analyses show that CD8 + NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner. Adoptive transfer of antigen-specific CD8 + NKT-like cells into RIP-OVA mice prevented subsequent development of diabetes in the animals induced by activated OT-I CD8 T cells. Our study suggests that CD8 + NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs. Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.

Thin films with large compressive residual stress and low interface adhesion can buckle and delaminate from relatively rigid substrates, which is a common failure mode of film/substrate interfaces. Current studies mainly focused on the geometry of various buckling patterns and related physical origins based on a static point of view. However, fundamental understanding of dynamic propagation of buckles, particularly for the complicated web buckles, remains challenging. We adopt strained two-dimensional MoS2 thin films to study the phenomenon of web buckling because their interface adhesion, namely van der Waals interaction, is naturally low. With a delicately site-controlled initiation, web buckles can be triggered and their dynamic propagation is in situ observed facilely. Finite element modeling shows that the formation of web buckles involves the propagation and multilevel branching of telephone-cord blisters. These buckled semiconducting films can be patterned by spatial confinement and potentially used in diffuse-reflective coatings, microfluidic channels, and hydrogen evolution reaction electrodes. Our work not only reveals the hidden mechanisms and kinematics of propagation of web buckles on rigid substrates but also sheds light on the development of semiconducting devices based on buckling engineering.

The linewidth of regenerative oscillators is enhanced by amplitude–phase coupling of the oscillator field [ Phys. Rev. 160 , 290 ( 1967 ) ]. In laser oscillators, this effect is well known for its impact on semiconductor laser performance. Here, this coupling is studied in Brillouin lasers. Because their gain is parametric, the coupling and linewidth enhancement are shown to originate from phase mismatch. The theory is confirmed by measurement of linewidth in a microcavity Brillouin laser, and enhancements as large as <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"> <mml:mn>50</mml:mn> <mml:mo>×<!-- × --></mml:mo> </mml:math> are measured. The results show that pump wavelength and device temperature should be carefully selected and controlled to minimize linewidth. More generally, this work provides a new perspective on the linewidth enhancement effect.

Narrow-linewidth lasers are important to many applications spanning precision metrology to sensing systems. Characterization of these lasers requires precise measurements of their frequency noise spectra. Here we demonstrate a correlated self-heterodyne (COSH) method capable of measuring frequency noise as low as 0.01 Hz2/Hz at 1 MHz offset frequency. The measurement setup is characterized by both commercial and lab-built lasers, and features low optical power requirements, fast acquisition time and high intensity noise rejection.

A simple and efficient dynamic pH junction high-speed counter-current chromatography method was developed and further applied to the online extraction, separation and purification of alkaloids from Stephania cepharantha by coupling with microwave-assisted extraction. Mineral acid and organic base were added into the mobile phase and the sample solution, respectively, leading to the formation of a dynamic pH junction in the column and causing focus of alkaloids. Selective focus of analytes can be achieved on the basis of velocity changes of the pH junction through appropriate selection of solvent systems and optimization of additive concentrations. The extract can be directly introduced into the HSCCC for the online extraction, separation and purification of alkaloids from S. cepharantha. Continuous separation can be easily achieved with the same solvent system. Under the optimum conditions, 6.0 g original sample was extracted with 60 mL of the upper phase of hexane–ethyl acetate–methanol–water (1:1:1:1, v/v/v/v) containing 10% triethylamine under 50 °C and 400 W irradiation power for 10 min, the extracts were directly separated and purified by high-speed counter-current chromatography. A total of 5.7 mg sinomenine, 8.3 mg 6,7-di-O-acetylsinococuline, 17.9 mg berbamine, 12.7 mg isotetrandrine and 14.6 mg cepharanthine were obtained with purities of 96.7%, 93.7%, 98.7%, 97.3% and 99.3%, respectively. The online method provides good selectivity to ionizable compounds and improves the separation and purification efficiency of the high-speed counter-current chromatography technique. It has good potential for separation and purification of effective compounds from natural products.

With their compact size and semiconductor-chip-based operation, frequency microcombs can be an invaluable light source for gas spectrcoscopy. However, the generation of mid-infrared (mid-IR) frequency combs with gigahertz line spacing as required to resolve many gas spectra represents a significant challenge for these devices. Here, a technique referred to as interleaved difference-frequency generation (iDFG) is introduced that densifies the spectral line spacing upon conversion of near-IR comb light into the mid-IR light. A soliton microcomb is used as both a comb light source and microwave oscillator in a demonstration, and the spectrum of methane is measured to illustrate how the resulting mid-IR comb avoids spectral undersampling. Beyond demonstration of the iDFG technique, this work represents an important feasibility step towards more compact and potentially chip-based mid-IR gas spectroscopy modules.

M-SENA is an open-sourced platform for Multimodal Sentiment Analysis.It aims to facilitate advanced research by providing flexible toolkits, reliable benchmarks, and intuitive demonstrations.The platform features a fully modular video sentiment analysis framework consisting of data management, feature extraction, model training, and result analysis modules.In this paper, we first illustrate the overall architecture of the M-SENA platform and then introduce features of the core modules.Reliable baseline results of different modality features and MSA benchmarks are also reported.Moreover, we use model evaluation and analysis tools provided by M-SENA to present intermediate representation visualization, on-the-fly instance test, and generalization ability test results.

As an inevitable phenomenon in real-world applications, data imperfection has emerged as one of the most critical challenges for multimodal sentiment analysis. However, existing approaches tend to overly focus on a specific type of imperfection, leading to performance degradation in real-world scenarios where multiple types of noise exist simultaneously. In this work, we formulate the imperfection with the modality feature missing at the training period and propose the noise intimation based adversarial training framework to improve the robustness against various potential imperfections at the inference period. Specifically, the proposed method first uses temporal feature erasing as the augmentation for noisy instances construction and exploits the modality interactions through the self-attention mechanism to learn multimodal representation for original-noisy instance pairs. Then, based on paired intermediate representation, a novel adversarial training strategy with semantic reconstruction supervision is proposed to learn unified joint representation between noisy and perfect data. For experiments, the proposed method is first verified with the modality feature missing, the same type of imperfection as the training period, and shows impressive performance. Moreover, we show that our approach is capable of achieving outstanding results for other types of imperfection, including modality missing, automation speech recognition error and attacks on text, highlighting the generalizability of our model. Finally, we conduct case studies on general additive distribution, which introduce background noise and blur into raw video clips, further revealing the capability of our proposed method for real-world applications.

Multimodal sentiment analysis (MSA), which supposes to improve text-based sentiment analysis with associated acoustic and visual modalities, is an emerging research area due to its potential applications in Human-Computer Interaction (HCI). However, existing researches observe that the acoustic and visual modalities contribute much less than the textual modality, termed as text-predominant. Under such circumstances, in this work, we emphasize making non-verbal cues matter for the MSA task. Firstly, from the resource perspective, we present the CH-SIMS v2.0 dataset, an extension and enhancement of the CH-SIMS. Compared with the original dataset, the CH-SIMS v2.0 doubles its size with another 2121 refined video segments containing both unimodal and multimodal annotations and collects 10161 unlabelled raw video segments with rich acoustic and visual emotion-bearing context to highlight non-verbal cues for sentiment prediction. Secondly, from the model perspective, benefiting from the unimodal annotations and the unsupervised data in the CH-SIMS v2.0, the Acoustic Visual Mixup Consistent (AV-MC) framework is proposed. The designed modality mixup module can be regarded as an augmentation, which mixes the acoustic and visual modalities from different videos. Through drawing unobserved multimodal context along with the text, the model can learn to be aware of different non-verbal contexts for sentiment prediction. Our evaluations demonstrate that both CH-SIMS v2.0 and AV-MC framework enable further research for discovering emotion-bearing acoustic and visual cues and pave the path to interpretable end-to-end HCI applications for real-world scenarios. The full dataset and code are available for use at https://github.com/thuiar/ch-sims-v2.

A multitude of toxic online behaviors, ranging from network attacks to anonymous traffic and spam, have severely disrupted the smooth operation of networks. Due to the inherent sender-receiver nature of network behaviors, graph-based frameworks are commonly used for detecting anomalous behaviors. However, in real-world scenarios, the boundary between normal and anomalous behaviors tends to be ambiguous. The local heterophily of graphs interferes with the detection, and existing methods based on nodes or edges introduce unwanted noise into representation results, thereby impacting the effectiveness of detection. To address these issues, we propose PhoGAD, a graph-based anomaly detection framework. PhoGAD leverages persistent homology optimization to clarify behavioral boundaries. Building upon this, the weights of adjacent edges are designed to mitigate the effects of local heterophily. Subsequently, to tackle the noise problem, we conduct a formal analysis and propose a disentangled representation-based explicit embedding method, ultimately achieving anomaly behavior detection. Experiments on intrusion, traffic, and spam datasets verify that PhoGAD has surpassed the performance of state-of-the-art (SOTA) frameworks in detection efficacy. Notably, PhoGAD demonstrates robust detection even with diminished anomaly proportions, highlighting its applicability to real-world scenarios. The analysis of persistent homology demonstrates its effectiveness in capturing the topological structure formed by normal edge features. Additionally, ablation experiments validate the effectiveness of the innovative mechanisms integrated within PhoGAD.

A method of microwave-assisted extraction coupled with countercurrent chromatography using evaporative light scattering detection was successfully developed for the separation and purification of steroidal saponins from Paris polyphylla. The main extraction conditions including microwave power, liquid/solid ratio, irradiation time, and extraction temperature were optimized using an orthogonal array design method. A suitable two-phase solvent system consisting of n-heptane/n-butanol/acetonitrile/water (10:19:6:20, v/v/v/v) was employed in the separation and purification of the extracts of P. polyphylla. A total of 7.1 mg polyphyllin VII, 4.3 mg gracillin, 9.2 mg dioscin, and 10.2 mg polyphyllin I were obtained from 1.5 g P. polyphylla in less than 300 min, the purities of which determined by HPLC were 96.7, 97.3, 98.7, and 98.6%, respectively. The identification and characterization of these compounds were performed by LC-ESI-MS and 1H NMR spectroscopy. The results demonstrated that the proposed method is feasible, economical and efficient for the extraction, separation and purification of effective compounds from natural products.

Two-dimensional semiconductors, such as transition-metal dichalcogenides (TMDs) and black phosphorous (BP), have found various potential applications in electronic and opto-electronic devices. However, several problems including low carrier mobility and low photoluminescence efficiencies still limit the performance of these devices. Interfacing 2D semiconductors with functional oxides provides a way to address the problems by overcoming the intrinsic limitations of 2D semiconductors and offering them multiple functionalities with various mechanisms. In this review, we first focus on the physical effects of various types of functional oxides on 2D semiconductors, mostly on MoS2 and BP as they are the intensively studied 2D semiconductors. Insulating, semiconducting, conventional piezoelectric, strongly correlated, and magnetic oxides are discussed. Then we introduce the applications of these 2D semiconductors/functional oxides systems in field-effect devices, nonvolatile memory, and photosensing. Finally, we discuss the perspectives and challenges within this research field. Our review provides a comprehensive understanding of 2D semiconductors/functional oxide heterostructures, and could inspire novel ideas in interface engineering to improve the performance of 2D semiconductor devices.

Dissipative soliton Kerr frequency combs in microresonators have recently been demonstrated with the self-injection locking process. They have the advantage of turnkey deterministic comb generation and simplifying dark soliton generation in the normal dispersion regime. Here, the formation process of dark pulses triggered by self-injection locking is studied by regarding them as a pair of domain walls that connect domains having different intracavity powers. The self-injection locking mechanism allows the domain walls to self-regulate their position so that a wide range of dark comb states can be accessed, and the duty cycle is controlled by the feedback phase. Direct imaging of the dark pulse shape using the electro-optic sampling technique is used to verify the theory. The results provide new physical insights as well as a new operational modality for this important class of nonlinear waves.

Interleukin (IL)-34 and IL-38 are associated with cardiovascular disease (CVD). However, their involvement in atrial fibrillation (AF) and AF-associated adverse events remains uncertain. Therefore, we aimed to investigate their association with various AF prognostic factors in a cohort study and assessed their predictive value for the prognosis of patients with AF.Patients with new-onset non-valvular AF were consecutively enrolled between 2013 and 2015 at the Department of Cardiovascular Medicine of the Southwest Hospital of the Army Medical University (Third Military Medical University) in Chongqing, China. The endpoints included stroke and all-cause mortality. The baseline levels of plasma IL-34, IL-38, NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT), and GDF-15 were measured and their correlation with AF-related adverse events were analyzed in a Cox proportional-hazards regression model. The C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the performance of the AF prognostic models. Decision curve analysis (DCA) was used to evaluate the clinical net benefit of the original and modified models.A total of 299 patients with new-onset AF were enrolled. During the median follow-up time of 28 (IQR: 27, 29) months, the higher levels of IL-34 were associated with a lower risk of stroke, and the higher levels of IL-38 were associated with an increased risk of all-cause death (all adjusted P < 0.05). In addition, elevated hs-cTnT and NT-proBNP concentrations were associated with a higher risk of stroke and all-cause mortality (all adjusted P < 0.05). Furthermore, the CHA2DS2-VASc score combined with IL-38 and NT-proBNP significantly improved the C-statistic, IDI, and NRI (all P < 0.01). There was no statistically significant difference (all P > 0.05) in the discrimination power between the preference models and the ABC (age, biomarkers, and clinical history) score for the two prognostic outcomes.Our results suggested that IL-34 and IL-38 were independently associated with stroke and all-cause mortality in patients with AF. Moreover, adding IL-38 and NT-proBNP to the CHA2DS2-VASc score significantly improved its predictive ability of AF-related all-cause death. Finally, the preference model performed equally well as the ABC score in predicting AF prognosis.

Summary Tartary buckwheat flour, highland barley flour and glutinous rice flour were utilised as the raw materials to prepare coarse‐cereal glutinous rice cakes. Their quality was compared to that of traditional glutinous rice cakes (made with japonica and glutinous rice flours), based on nutritional composition, physical structure and flavour. The addition of tartary buckwheat and highland barley flours significantly increased the contents of protein, total flavonoids and β‐glucan ( P &lt; 0.05). The tartary buckwheat flour gave the glutinous rice cakes a yellow‐green colour, and the coarse‐cereal glutinous rice cakes had better hardness and chewiness. Aldehydes, alcohols as well as ketones were the chief volatile flavour components of the coarse‐cereal glutinous rice cake. These coarse‐cereal glutinous rice cakes were more popular compared to the traditional glutinous rice cakes with evaluators on a sensory panel. This may give some guidance for the development of coarse‐cereal products, such as tartary buckwheat and highland barley.

The safety issue of ethanol gasoline and the methods to control or weaken its explosion have attracted attention. To clarify the effect of C6F12O (perfluoro(2-methyl-3-pentanone)) on the explosion of ethanol gasoline-air mixtures and intrinsic mechanism, the explosion overpressure and flame propagation behavior under different equivalence ratios (φ = 0.6–0.8) and C6F12O concentrations (χinh = 0–4.0%) were experimentally obtained. The detailed inhibitor reaction process was also obtained by CHEMKIN based on a new assembly kinetic mechanism. The results show that the effects of C6F12O on the explosion characteristics of ethanol gasoline varied with χinh and φ. For rich flames, C6F12O is more effective than and heptafluoropropane (C₃HF₇) and nitrogen (N2) in suppressing explosions; for lean and equivalence ratio flames, the addition of C6F12O may result in more severe explosions. The decrease in chemical reactivity is mainly because the mole fractions of OH and H radicals and the proportion of paths H radicals involved decrease after adding C6F12O, and R1500: CF3COF + H = CF3CO + HF, R965: CF2:O + H = CF:O + HF, R863: CF3 + H = CF2 + HF are main suppressing reactions.

Femtosecond pulse pairs are generated in coupled microresonators featuring nor-mal dispersion. This bright soliton mode locking modality is observed to recur at multiple spectral windows and is shown to extend to additional coupled rings.

Sortase A (SrtA) is a membrane-associated cysteine transpeptidase required for bacterial virulence regulation and anchors surface proteins to cell wall, thereby assisting biofilm formation. SrtA is targeted in antivirulence treatments against Gram-positive bacterial infections. However, the development of potent small-molecule SrtA inhibitors is constrained owing to the limited understanding of the mode of action of inhibitors in the SrtA binding pocket. Herein, we designed and synthesized a novel class of covalent SrtA inhibitors based on the binding mode detailed in the X-ray crystal structure of the ML346/Streptococcus pyogenes SrtA complex. ML346 analog Y40 exhibited 2-fold increased inhibitory activity on Staphylococcus aureus SrtA and showed superior inhibitory effects on biofilm formation in vitro. Y40 protected Galleria mellonella larvae fromS. aureusinfections in vivo while minimally attenuating staphylococcal growth in vitro. Our study indicates that the covalent SrtA inhibitor Y40 is an antivirulence agent that is effective againstS. aureusinfections.

In real-world applications, an object detector often encounters object instances from new classes and needs to accommodate them effectively. Previous work formulated this critical problem as incremental object detection (IOD), which assumes the object instances of new classes to be fully annotated in incremental data. However, as supervisory signals are usually rare and expensive, the supervised IOD may not be practical for implementation. In this work, we consider a more realistic setting named semi-supervised IOD (SSIOD), where the object detector needs to learn new classes incrementally from a few labelled data and massive unlabelled data without catastrophic forgetting of old classes. A commonly-used strategy for supervised IOD is to encourage the current model (as a student) to mimic the behavior of the old model (as a teacher), but it generally fails in SSIOD because a dominant number of object instances from old and new classes are coexisting and unlabelled, with the teacher only recognizing a fraction of them. Observing that learning only the classes of interest tends to preclude detection of other classes, we propose to bridge the coexistence of unlabelled classes by constructing two teacher models respectively for old and new classes, and using the concatenation of their predictions to instruct the student. This approach is referred to as DualTeacher, which can serve as a strong baseline for SSIOD with limited resource overhead and no extra hyperparameters. We build various benchmarks for SSIOD and perform extensive experiments to demonstrate the superiority of our approach (e.g., the performance lead is up to 18.28 AP on MS-COCO). Our code is available at \url{https://github.com/chuxiuhong/DualTeacher}.

Improving the robustness of models against feature noise has emerged as one of the most crucial research topics in the field of multimodal sentiment analysis. Recent studies assume that the training instances are free of noise and develop either translation or reconstruction based method under the guidance of perfect training data for robust testing time performance. However, such an ideal assumption neglects the potential presence of the feature noise in training instances and inevitably results in degradation for the scenario where high-quality training instances are unavailable. In order to achieve robust training with noisy instances, we propose the Meta Noise Adaption (Meta-NA) learning strategy, a meta learning method accumulating the experience of dealing with various types of feature noise. Specifically, we first formulate the tasks distribution where each task is corresponding to one specific pattern of noise, and propose the feature adaption module adding on the unimodal encoder in late fusion based architecture. Through an nested online optimization between the auxiliary feature adaption module and the late fusion backbone modules, the proposed method can leverage shared knowledge across different noisy source tasks and learn how to learn from the noisy instances for robust testing performances. Extensive experiments are conducted on two benchmark multimodal sentiment analysis datasets, namely MOSI and CH-SIMS v2. The results demonstrate that our proposed method can rapidly adapt to various unseen types of feature noise and outperforms all baseline methods, particularly when the training instances are limited.

The synthesis of gwanakoside A, a chlorinated naphthol bis-glycoside, and its analogues was achieved through stepwise chlorination and donor-equivalent controlled regioselective phenol glycosylation with glycosyl N-phenyltrifluoroacetimidates as donors. Gwanakoside A displayed considerable inhibitory effects against various cancer cells and Staphylococcus aureus strains.

A novel full-length cDNA was cloned from human dendritic cells (DC) by subtractive cloning and RACE. The deduced protein is a type II lectin-like membrane protein that contains an ITIM proximal to N terminal and is designated as lectin-like immunoreceptor (LLIR). The gene of LLIR is located in a region of chromosomal 12p13 and shows highest homologous with ASGPR. Two alternatively spliced transmembraneless variants of LLIR were identified by RT-PCR and named as LLIRv1 and LLIRv2. RT-PCR and immunoblotting analysis revealed that LLIR was expressed with much higher level in immature DC than in mature DC. The ITIM in LLIR was demonstrated to bind SHP-1 in HL-60 cell after the tyrosine had been phosphorylated. In addition, the mRNA expression level of LLIRv2 was raised when leukemia cells were induced to differentiate by PMA.

Mitogen-activated protein kinase (MAPK) cascades are the major signaling systems transducing extracellular signals into intracellular responses, which mainly include the extracellular signal-regulated kinase (ERK) pathway, the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway, and the p38 pathway. From dendritic cell cDNA library, we isolated a full-length cDNA encoding a potentially novel 898-residue kinase, which was designated DPK. The protein contained a potential kinase domain at the N-terminal exhibiting homology with MEKK1-, MEKK2-, MEKK3-, MEKK4-, MEKK5-, Tpl-2-, and p21-activated kinases (PAKs), but no GTPase-binding domain which is characteristic of PAKs. Northern blotting analysis showed that DPK was ubiquitously expressed in normal tissues, with abundant expression in kidney, skeletal muscle, heart, and liver. When overexpressed in transfected NIH3T3 cells, it could activate both the ERK1/ERK2 pathway and the SAPK pathway in a dose-dependent manner, but not affect the p38 pathway. These findings suggested that DPK might be a novel candidate MAPKKK.

We aimed to investigate the role of Fasting Plasma Glucose (FPG) and glucose fluctuation in the prognosis of COVID-19 patients stratified by pre-existing diabetes.The associations of FPG and glucose fluctuation indexes with prognosis of COVID-19 in 2,642 patients were investigated by multivariate Cox regression analysis. The primary outcome was in-hospital mortality; the secondary outcome was disease progression. The longitudinal changes of FPG over time were analyzed by the latent growth curve model in COVID-19 patients stratified by diabetes and severity of COVID-19.We found FPG as an independent prognostic factor of overall survival after adjustment for age, sex, diabetes and severity of COVID-19 at admission (HR: 1.15, 95% CI: 1.06-1.25, P = 1.02 × 10-3). Multivariate logistic regression analysis indicated that the standard deviation of blood glucose (SDBG) and largest amplitude of glycemic excursions (LAGE) were also independent risk factors of COVID-19 progression (P = 0.03 and 0.04, respectively). The growth trajectory of FPG over the first 3 days of hospitalization was steeper in patients with critical COVID-19 in comparison to moderate patients.Hyperglycemia and glucose fluctuation were adverse prognostic factors of COVID-19 regardless of pre-existing diabetes. This stresses the importance of glycemic control in addition to other therapeutic management.

The receptor of severe respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2, is more abundant in kidney than in lung tissue, suggesting that kidney might be another important target organ for SARS-CoV-2. However, our understanding of kidney injury caused by Coronavirus Disease 2019 (COVID-19) is limited. This study aimed to explore the association between kidney injury and disease progression in patients with COVID-19.A retrospective cohort study was designed by including 2630 patients with confirmed COVID-19 from Huoshenshan Hospital (Wuhan, China) from 1 February to 13 April 2020. Kidney function indexes and other clinical information were extracted from the electronic medical record system. Associations between kidney function indexes and disease progression were analyzed using Cox proportional-hazards regression and generalized linear mixed model.We found that estimated glomerular filtration rate (eGFR) and creatinine clearance (Ccr) decreased in 22.0% and 24.0% of patients with COVID-19, respectively. Proteinuria was detected in 15.0% patients and hematuria was detected in 8.1% of patients. Hematuria (HR 2.38, 95% CI 1.50-3.78), proteinuria (HR 2.16, 95% CI 1.33-3.51), elevated baseline serum creatinine (HR 2.84, 95% CI 1.92-4.21) and blood urea nitrogen (HR 3.54, 95% CI 2.36-5.31), and decrease baseline eGFR (HR 1.58, 95% CI 1.07-2.34) were found to be independent risk factors for disease progression after adjusted confounders. Generalized linear mixed model analysis showed that the dynamic trajectories of uric acid was significantly related to disease progression.There was a high proportion of early kidney function injury in COVID-19 patients on admission. Early kidney injury could help clinicians to identify patients with poor prognosis at an early stage.

Abstract Background During outbreak of Coronavirus Disease 2019 (COVID-19), healthcare providers are facing critical clinical decisions based on the prognosis of patients. Decision support tools of risk stratification are needed to predict outcomes in patients with different clinical types of COVID-19. Methods This retrospective cohort study recruited 2425 patients with moderate or severe COVID-19. A logistic regression model was used to select and estimate the factors independently associated with outcomes. Simplified risk stratification score systems were constructed to predict outcomes in moderate and severe patients with COVID-19, and their performances were evaluated by discrimination and calibration. Results We constructed two risk stratification score systems, named as STPCAL (including significant factors in the prediction model: number of clinical symptoms, the maximum body temperature during hospitalization, platelet count, C-reactive protein, albumin and lactate dehydrogenase) and TRPNCLP (including maximum body temperature during hospitalization, history of respiratory diseases, platelet count, neutrophil-to-lymphocyte ratio, creatinine, lactate dehydrogenase, and prothrombin time), to predict hospitalization duration for moderate patients and disease progression for severe patients, respectively. According to STPCAL score, moderate patients were classified into three risk categories for a longer hospital duration: low (Score 0–1, median = 8 days, with less than 20.0% probabilities), intermediate (Score 2–6, median = 13 days, with 30.0–78.9% probabilities), high (Score 7–9, median = 19 days, with more than 86.5% probabilities). Severe patients were stratified into three risk categories for disease progression: low risk (Score 0–5, with less than 12.7% probabilities), intermediate risk (Score 6–11, with 18.6–69.1% probabilities), and high risk (Score 12–16, with more than 77.9% probabilities) by TRPNCLP score. The two risk scores performed well with good discrimination and calibration. Conclusions Two easy-to-use risk stratification score systems were built to predict the outcomes in COVID-19 patients with different clinical types. Identifying high risk patients with longer stay or poor prognosis could assist healthcare providers in triaging patients when allocating limited healthcare during COVID-19 outbreak.

<h2>Abstract</h2><h3>Background</h3> Chemokines play an important role in inflammation and atherosclerosis. However, little is known about the relationship between chemokines and the prognosis of atrial fibrillation (AF). This "real-world" cohort study was designed to observe the prognostic value of plasma CC motif chemokine ligand (CCL) 18, CCL23, CCL28, CXC motif chemokine ligand (CXCL) 14, CXCL16 in newly diagnosed AF patients. <h3>Methods</h3> Baseline plasma levels of chemokines were measured in a cohort with 299 AF patients using Bio-plex Pro™ xMAP arrays. A Cox proportional hazard model was used to evaluate the associations of chemokines with AF outcomes. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated to evaluate the improvement of chemokines to CHA₂DS₂-VASc score. <h3>Results</h3> High CCL18 (hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.18–5.98, <i>P</i> = 0.019) and CCL23 levels (HR 2.78, 95%CI 1.07–7.22, <i>P</i> = 0.036) were associated with stroke in AF patient. Patients with low CXCL14 (HR 0.39, 95%CI 0.15–0.97, <i>P</i> = 0.042) and high CXCL16 levels (HR 3.02, 95%CI 1.39–6.58, <i>P</i> = 0.005) have increased risk of all-cause mortality. High CCL16 levels (HR 5.41, 95%CI 2.32–12.63, <i>P</i> < 0.001) were associated with cardiovascular death. However, CCL28 had no significant association with outcomes. Adding chemokines to CHA₂DS₂-VASc score increased the reclassification and clinical net benefit. <h3>Conclusions</h3> Plasma levels of CCL18, CCL23, CXCL14, and CXCL16 were independently associated with AF outcomes. Chemokines added to CHA₂DS₂-VASc score significantly enhanced risk assessment for the outcomes. Incorporation of chemokines into clinical decisions may help the management of AF treatment.

To better understand the immunobiology of dendritic cells (DCs), we took the expressed sequence tag (EST) approach to describe their transcript profile and discovered novel genes. ESTs (n = 25,668) were generated from monocyte-derived DCs, and 15,863 ESTs (61.8%) represented unique genes in GenBank. Integration of ESTs allowed for the generation of a profile of 4,367 known genes and identification of > 100 novel genes. HLA-DR invariant chain p33, cathepsin D, HLA-DR alpha chain, beta2-microglobulin, HLA-DP beta chain, CD11a, and mannose receptor were in the top 30 transcripts, and 451 known genes were potentially associated with the immunobiology of DCs. This transcript profile was consistent with the unique antigen-presenting capacity of DCs and provided invaluable information to better understand the immunobiology of DCs. On the basis of the EST database, a full-length novel gene was identified that exhibited close homology with CD84; it was designated CD84-H1. The full-length cDNA of CD84-H1 contained an open reading frame of 870 bp encoding a type I transmembrane protein of 289 amino acids. Consistent with the structural feature of the CD2 family, the predicted 270-amino acid mature protein of CD84-H1 contained two extracellular immunoglobulin-like domains that shared homology with CD2 family members, e.g., CD84, Ly-9, CD48, and signaling lymphocyte activation molecule. Its intracellular domain was short and contained no putative signaling structure. Northern blot analysis revealed that CD84-H1 expression was predominantly restricted in hematopoietic tissues. Reverse transcription-PCR analysis showed that it was widely expressed in the immune cells, including monocytes, DCs, B cells, and T cells. These data indicate that CD84-H1 may be relevant to immune responses.

MUC1, a transmembrane glycoprotein, is abnormally over-expressed in most human adenocarcinomas. MUC1 association with cytoplasmic cell signal regulators and nuclear accumulation are important for its tumor related activities. Little is known about how MUC1 translocates from the cell membrane to the cytoplasm. In this study, live cell imaging was used to study MUC1 intracellular trafficking. The interaction between EGFR and MUC1 was mapped by FRET analysis and EGF stimulated MUC1 endocytosis was observed directly through live cell imaging. MUC1-CT endocytosis was clathrin and dynamin dependent. Rab5 over-expression resulted in decreased cell membrane localization of MUC1, with accumulation of MUC1 endocytic vesicles in the peri-nuclear region. Conversely, over-expression of a Rab5 dominant negative mutant (S34N) resulted in redistribution of MUC1 from the peri-nuclear region to the cytoplasm. Collectively, these results indicated that MUC1 intra-cellular trafficking occurs through a regulated process that was stimulated by direct EGFR and MUC1 interaction, mediated by clathrin coated pits that were dynamin dependent and regulated by Rab5.

Abstract The graft-versus-leukemia effect reminds us to observe the allogeneic cell elicited anti-tumor immune responses. Here we immunized recipient B6 mice with different types of allogenic leukocytes and found that vaccination with allogenic dendritic cells (alloDC) elicited the most efficient protection against broad-spectrum tumors. The recipient lymphocytes were analyzed and the data showed that CD8 T cells increased significantly after immunization and expressed effector memory T cell marker KLRG1. Functional evaluation demonstrated that these KLRG1 + CD8 T cells could kill tumor cells in vitro and in vivo in Granzyme B- and Fas/FasL-dependent manners with no tumor antigen specificity, and tend to migrate into tumor sites by high expression of heparanase. Adoptive transfer of these cells could provide antitumor protection against tumors. AlloDC could also treat mice with residual tumors and combination of anti-PD1 antibody could enhance this effects. Together, our study showed that alloDC-immunization could induce potent antitumor effect through the expansion of KLRG1 + CD8 T cells, which can work as both preventive and therapeutic tumor vaccines.

The timeliness, precision, and low cost of search data have great potential for projecting tourist volume. Obtaining valuable information for decision-making, particularly for predicting, is hampered by the vast amount of search data. A systematic investigation of keyword selection and processing has been conducted. Using Beijing tourist volume as an example, 11 different feature extraction algorithms were selected and combined with long short-term memory (LSTM), random forest (RF) and fuzzy time series (FTS) for forecasting tourist volume. A total of 1612 keywords were retrieved from Baidu Index demand mapping using the direct word extraction method, range word extraction method and empirical selection method. The remaining 813 keywords were subjected to feature extraction. Based on the forecasting results of medium and short-term (1-day, 7-days and 10-days), the forecasting results of Kernel principal component analysis (KPCA) and locally linear embedding (LLE) are relatively stable when the dimensionality is reduced to 5 dimensions. The forecasting results of t-stochastic neighbor embedding (t-SNE), isometric mapping (IsoMap) and locally linear embedding (LLE), locality preserving projections (LPP), independent component correlation (ICA) are relatively stable when the dimensionality is reduced to 10 dimensions. Accurately forecasting many factors (transportation, attraction, food, lodging, travel, tips, tickets, and weather) provides a solid foundation for tourism demand optimization and scientific management and a resource for tourists' holistic vacation planning.

Soliton microcombs are helping to advance the miniaturization of a range of comb systems. These combs mode lock through the formation of short temporal pulses in anomalous dispersion resonators. Here, a new microcomb is demonstrated that mode locks through the formation of pulse pairs in normal-dispersion coupled-ring resonators. Unlike conventional microcombs, pulses in this system cannot exist alone, and instead must phase lock in pairs to form a bright soliton comb. Also, the pulses can form at recurring spectral windows and the pulses in each pair feature different optical spectra. This pairwise mode-locking modality extends to higher dimensions and we demonstrate 3-ring systems in which 3 pulses mode lock through alternating pairwise pulse coupling. The results are demonstrated using the new CMOS-foundry platform that has not previously produced bright solitons on account of its inherent normal dispersion. The ability to generate multi-color pulse pairs over multiple rings is an important new feature for microcombs. It can extend the concept of all-optical soliton buffers and memories to multiple storage rings that multiplex pulses with respect to soliton color and that are spatially addressable. The results also suggest a new platform for the study of quantum combs and topological photonics.

Perfluoro(2-methyl-3-pentanone) (C6F12O, Novec 1230) has been considered as an emerging alternative to halon fire extinguishing agents, but its inhibiting characteristics for different concentrations of gasoline blended with biomass ethanol is still unclear. A new kinetic mechanism containing 241 substances and 1346 radical reactions was developed to investigate the combustion characteristics of ethanol gasoline and the inhibition characteristics of C6F12O. Experiments and previous data was used to confirme the mechanism's reliability. The results show that increasing the volume fraction of ethanol increases the laminar burning velocity and decreases the flame temperature of the mixture. A similar inhibitory effect of C6F12O is observed for gasoline at different ethanol blending concentrations. For rich flames, the fluorinated substances produced by C6F12O reduce the intensity of the reaction by trapping free radicals (OH, H, etc.), thereby reducing flame temperature and laminar burning velocity. For lean flames, adding sub-inerting concentrations of C6F12O produces large amounts of CO, which is an essential intermediate in promoting R24: CO + OH <=> CO2 + H, resulting in increased reaction strength. Combustion intensity is significantly reduced as more C6F12O is added, as the trapping of free radicals by the inhibitor becomes dominant.

Improving model robustness against potential modality noise, as an essential step for adapting multimodal models to real-world applications, has received increasing attention among researchers. For Multimodal Sentiment Analysis (MSA), there is also a debate on whether multimodal models are more effective against noisy features than unimodal ones. Stressing on intuitive illustration and in-depth analysis of these concerns, we present Robust-MSA, an interactive platform that visualizes the impact of modality noise as well as simple defence methods to help researchers know better about how their models perform with imperfect real-world data.

Mercury removal is very important to solve environmental pollution problems. However, the elemental mercury (Hg0) is difficult to be removed due to its low solubility, volatility, and closed electron structure of 5d106s2. In this work, using first principles study, the adsorption properties of Hg0 on nonmetal (B, C, N, O, and F) doped monolayer MoS2. The results of adsorption energy show that acceptor (B, C, and N) doped MoS2 has a strong adsorption capacity for Hg0, while the same group (O) and donor (F) doped system has almost no such capacity. Meanwhile, the adsorption strength of Hg0 in acceptor doped system decreases with the increase of valence electrons. In other words, 6 valence electron is the critical value, lower than this value is conducive to Hg0 adsorption, while higher or equal to this value is not conducive to Hg0 adsorption. This is due to the fact that the amount of charge transferred by Hg0 to the dopant atom decreases as the number of valence electrons increases. Therefore, B and C doped MoS2 can be used as a gas scavenger for Hg0 removal.

Visible, high-coherence optical sources are important to a wide range of applications spanning spectroscopy to precision timing. Integration of these sources on a semiconductor chip is a necessary step if the systems that use these devices are to be made compact, portable, and low power. Here, by self-injection-locking a 1560 nm distributed feedback semiconductor laser to a high-Q silicon-nitride resonator, a high-coherence 780 nm second-harmonic signal is generated via the photogalvanic-induced second-order nonlinearity. A record-low frequency noise floor of 4Hz 2 /Hz is achieved for the 780 nm emission. The approach can potentially generate signals over a wide range of visible and near-visible bands, and thereby help transition many table-top systems into a fieldable form.

Yin-Qiao-Jie-Du (YQJD) tablet is a well-known non-prescription Chinese patent drug widely used for the prevention and treatment of diseases in China. However, documented studies for assessing and controlling the quality of YQJD tablet are limited. In this article, a rapid and comprehensive method for the quality assessment and control of YQJD tablets was developed, via qualitative and quantitative analysis of the major active ingredients of YQJD tablets by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) in combination with multivariate statistical analysis. The samples of YQJD tablets were triturated and then extracted with methanol, and the extracts were analyzed by UHPLC-QTOF-MS. A good separation was achieved within 30 min by using an Agilent RRHD SB-C18 (150 mm × 2.1mm I.D., 1.8 μm) column with a gradient elution of water (0.5% formic acid) and acetonitrile. Forty-one major chromatographic peaks were obtained, and 31 of them were identified according to the obtained data from the measurements of accurate mass, isotopic composition, and collision-induced dissociation. Among them, 21 were confirmed by the comparison of retention times, MS, and MS/MS information with those of their references. Quantitative analysis was performed based on the peak areas of extracted ion chromatograms of the exact pseudo-molecular ions (with a 0.01 Da window), and the result of method validation demonstrated that the proposed method possessed desirable specificity, linearity, precision, and accuracy. Subsequently, the method was utilized to analyze the major constituents in YQJD tablets of 18 batches produced by different manufacturers. The obtained contents of the 21 confirmed ingredients were applied for orthogonal partial-least squares to latent structures discriminant analysis (OPLS-DA). An assessment of the quality consistency and stability as well as tracing the origins of the investigated YQJD tablets were successfully achieved by OPLS-DA. All of these results demonstrated that the UHPLC-QTOF-MS method developed in this study was a rapid and desirable approach for differentiating the origin, discriminating the authenticity, and assessing and controlling the quality of YQJD tablets.

MUC1, a tumor associated glycoprotein over-expressed in 95% of pancreatic cancers, has been shown to be associated with a worse prognosis. The objective of this study was to determine the impact of loss of MUC1 expression on pancreatic tumor growth. PANC1 human pancreatic carcinoma cells with stable “knockdown” MUC1 expression were created using a MUC1 specific short interfering RNA (siRNA). PANC1 cells with “knockdown” MUC1 expression had decreased in vitro proliferation compared with PANC1 wild type and control cells. PANC1-MUC1siRNA cells grew significantly slower in severe combined immunodeficient (SCID) mice compared with wild type and negative controls. Our data suggested that decreasing MUC1 tumor expression by RNA interference may be a novel molecular approach for the treatment of pancreatic cancer. MUC1, a tumor associated glycoprotein over-expressed in 95% of pancreatic cancers, has been shown to be associated with a worse prognosis. The objective of this study was to determine the impact of loss of MUC1 expression on pancreatic tumor growth. PANC1 human pancreatic carcinoma cells with stable “knockdown” MUC1 expression were created using a MUC1 specific short interfering RNA (siRNA). PANC1 cells with “knockdown” MUC1 expression had decreased in vitro proliferation compared with PANC1 wild type and control cells. PANC1-MUC1siRNA cells grew significantly slower in severe combined immunodeficient (SCID) mice compared with wild type and negative controls. Our data suggested that decreasing MUC1 tumor expression by RNA interference may be a novel molecular approach for the treatment of pancreatic cancer.

A fundamental frequency noise of 9 mHz·Hz/Hz is demonstrated in an on-chip Brillouin laser. The noise measurement uses the frequency discrimination method enhanced by cross-correlator. The results set new performance targets for chip-based laser platforms.

Conversation understanding, as a necessary step for many applications, including social media, education, and argumentation mining, has been gaining increasing attention from the research community. Reasoning over long-term dependent contextual information is the key to utterance-level conversation understanding. Aiming to emphasize the importance of contextual reasoning, an end-to-end graph attention reasoning network which takes both word-level and utterance-level context into concern is proposed. To be specific, a word-level encoder with a novel convolution gate is first built to filter out irrelevant contextual information. Based on the representation extracted by word-level encoder, a graph reasoning network is designed to utilize the context among utterance-level, where the entire conversation is treated as a fully connected graph, utterances as nodes, and attention scores between utterances as edges. The proposed model is a general framework for conversation understanding tasks, which can be flexibly applied on most conversation datasets without changing the network architecture. Furthermore, we revise the tensor fusion network by adding a residual connection to explore cross-modal conversation understanding. For uni-modal scene (text modality), experiments show that the proposed method surpasses current state-of-the-art methods on emotion recognition, intent classification, and dialogue act identification tasks. For cross-modal scenes (text modality and audio modality), experiments on IEMOCAP and MELD datasets show that the proposed method can use cross-modal information to improve model performance.2

High coherence visible and near-visible laser sources are centrally important to the operation of advanced position/navigation/timing systems as well as classical/quantum sensing systems. However, the complexity and size of these bench-top lasers is an impediment to their transitioning beyond the laboratory. Here, a system-on-a-chip that emits high-coherence visible and near-visible lightwaves is demonstrated. The devices rely upon a new approach wherein wavelength conversion and coherence increase by self-injection-locking are combined within in a single nonlinear resonator. This simplified approach is demonstrated in a hybridly-integrated device and provides a short-term linewidth around 10-30 kHz. On-chip, converted optical power over 2 mW is also obtained. Moreover, measurements show that heterogeneous integration can result in conversion efficiency higher than 25% with output power over 11 mW. Because the approach uses mature III-V pump lasers in combination with thin-film lithium niobate, it can be scaled for low-cost manufacturing of high-coherence visible emitters. Also, the coherence generation process can be transferred to other frequency conversion processes including optical parametric oscillation, sum/difference frequency generation, and third-harmonic generation.

The CHA 2 DS 2 -VASc score was initially applied to stratify stroke risk in patients with atrial fibrillation (AF) and was found to be effective in predicting all-cause mortality outcomes. To date, it is still unclear whether circulating long non-coding RNAs (lncRNAs) as emerging biomarkers, can improve the predictive power of the CHA 2 DS 2 -VASc score in stroke and all-cause mortality.Candidate lncRNAs were screened by searching the literature and analyzing previous RNA sequencing results. After preliminary verification in 29 patients with AF, the final selected lncRNAs were evaluated by Cox proportional hazards regression in 192 patients to determine whether their relative expression levels were associated with stroke and all-cause mortality. The c-statistic, net reclassification improvement (NRI), and integrated discrimination improvement of the patients were calculated to evaluate the discrimination and reclassification power for stroke and all-cause mortality when adding lncRNA expression levels to the CHA 2 DS 2 -VASc score model.Five plasma lncRNAs associated with stroke and all-cause mortality in AF patients were selected in our screening process. Patients with elevated H19 levels were found to have a higher risk of stroke (hazard ratio [HR] 3.264, 95% confidence interval [CI]: 1.364-7.813, P = 0.008). Adding the H19 expression level to the CHA 2 DS 2 -VASc score significantly improved the discrimination and reclassification power of the CHA 2 DS 2 -VASc score for stroke in AF patients. In addition, the H19 level showed a marginally significant association with all-cause mortality (HR 2.263, 95% CI: 0.889-5.760, P = 0.087), although it appeared to have no significant improvement for the CHA 2 DS 2 -VASc model for predicting all-cause mortality.Plasma expression of H19 was associated with stroke risk in AF patients and improved the discriminatory power of the CHA 2 DS 2 -VASc score. Therefore, lncRNA H19 served as an emerging non-invasive biomarker for stroke risk prediction in patients with AF.

Background: Post-adolescent acne is a common skin disease faced by adults. However, whether air pollution (AP) serves as a risk factor for post-adolescent acne remains elusive. Aim: To determine the relationship between short-term AP exposure (within 7 days) and outpatient visits for post-adolescent acne. Methods: Daily outpatient visit data for post-adolescent acne and routinely AP data between 2010 and 2013 were collected from Xi’an, China. A generalized additive regression model was used to analyze the relationship between outpatient visits for post-adolescent acne and short-term ambient AP exposure. The gender-specific analyses were conducted as well. Results: Totally, 27,190 outpatient visits for post-adolescent acne were included. The results revealed that a 10 μg/m 3 increase in PM 10 , SO 2 , and NO 2 at lag 0– 7 day was associated with the increase of outpatient visits for post-adolescent acne at 0.84% (95% CI: 0.53%, 1.16%), 1.61% (95% CI: 0.12%, 3.10%), and 3.50% (95% CI: 1.60%, 5.40%), respectively. The significant positive associations of PM 10 , SO 2 , and NO 2 were found at both single-lag models and moving average models. The gender-specific analyses showed that the effect estimates of PM 10 was stronger for females than for males, while there was no observed gender difference in the effects of SO 2 and NO 2 . Conclusion: Short-term exposure to AP was associated with increased outpatient visits for post-adolescent acne, especially for females in the effects of PM 10 . Keywords: short-term, air pollution, post-adolescent acne, adult acne, time-series analysis

Contemporary energy challenges have triggered a growing interest in the fuel cell membrane technology in recent years, embracing Nafion® membranes. Creep-induced failure caused by temperature and load is an important lifetime limiting failure mode in fuel cell applications. In this study, experiments were conducted to measure the creep behaviors in Nafion® (115, 117, 211, 212) membranes in thickness direction on the basis of nanoindentation method. It was carried out for a range of temperatures (40–80 °C) and applied peak loads (24–56 μN) respectively. Findley's and Burger's models were used to analyze the results and it illustrates the instantaneous elastic deformation, retarded elastic deformation and retardation time increase significantly as the test temperature or peak load rises. A substantial increase of creep displacement is found over 70 °C due to glass transition. The mechanism of polymer creep is interpreted with an emphasis on microstructure molecular. Based on a defined dimensionless parameter, load effect on creep is higher than that of temperature effect.

The efficacy of tocilizumab on the prognosis of severe/critical COVID-19 patients is still controversial so far.We aimed to delineate the inflammation characteristics of severe/critical COVID-19 patients and determine the impact of tocilizumab on hospital mortality.Here, we performed a retrospective cohort study which enrolled 727 severe or critical inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Huoshenshan Hospital (Wuhan, China), among which 50 patients received tocilizumab.This study confirmed that most recovered patients manifested relatively normal inflammation levels at admission, whereas most of the deceased cases presented visibly severe inflammation at admission and even progressed into extremely aggravated inflammation before their deaths, proved by some extremely high concentrations of interleukin-6, procalcitonin, C-reactive protein and neutrophil count.Moreover, based on the Cox proportional-hazards models before or after propensity score matching, we demonstrated that tocilizumab treatment could lessen mortality by gradually alleviating excessive inflammation and meanwhile continuously enhancing the levels of lymphocytes within 14 days for severe/critical COVID-19 patients, indicating potential effectiveness for treating COVID-19.

Normal group velocity dispersion (GVD) microcombs offer high comb line power and high pumping efficiency compared to bright pulse microcombs. The recent demonstration of normal GVD microcombs using CMOS-foundry-produced microresonators is an important step towards scalable production. However, the chromatic dispersion of CMOS devices is large and impairs generation of broadband microcombs. Here, we report the development of a microresonator in which GVD is reduced due to a couple-ring resonator configuration. Operating in the turnkey self-injection-locking mode, the resonator is hybridly integrated with a semiconductor laser pump to produce high-power-efficiency combs spanning a bandwidth of 9.9 nm (1.22 THz) centered at 1560 nm, corresponding to 62 comb lines. Fast, linear optical sampling of the comb waveform is used to observe the rich set of near-zero GVD comb behaviors, including soliton molecules, switching waves (platicons) and their hybrids. Tuning of the 20 GHz repetition rate by electrical actuation enables servo locking to a microwave reference, which simultaneously stabilizes the comb repetition rate, offset frequency and temporal waveform. This hybridly integrated system could be used in coherent communications or for ultra-stable microwave signal generation by two-point optical frequency division.

High-Q optical resonators offer access to nonlinear physics at low pumping powers attainable using non-amplified semiconductor lasers. Recent resonator advances offer Q factors over 200 million in platforms that are fully CMOS compatible. I will review these new systems and how they are making possible a new generation of frequency microcombs.

By self-injection-locking a 1560 nm distributed feedback semiconductor laser to a high-$Q$ silicon nitride resonator, a high-coherence 780 nm second harmonic signal is generated via the photogalvanic-induced second-order nonlinearity. A record-low frequency noise floor of 4 Hz$^2$/Hz is achieved for the 780 nm emission. The approach can be generalized for signal generation over a wide range of visible and near-visible bands.

The wavelength of zero group-velocity-dispersion is engineered in a silicon-nitride coupled-ring resonator. The resonator is hybridly-integrated with a semiconductor laser pump to produce high-power-efficiency microcombs spanning a bandwidth of 9.9 nm near 1560 nm.

Femtosecond pulse pairs are formed in coupled-resonators featuring normal dispersion. The pairs collectively obey the optical Dirac equation and through their coherent interaction induce net round-trip anomalous dispersion. The asymmetrical Dirac comb spectrum is observed.

Kelly sidebands are excited between optical frequency bands in vernier-coupled high-Q microresonators. Continuous wave and electro-optic pump pulses are used to excite the sidebands. The spectral location of the sidebands agrees with dispersion measurements.

Since the reform and opening up, China's economy has been developing rapidly, and has made remarkable achievements, but at the same time, it is also facing the problems of environmental pollution, climate anomalies and resource depletion, etc. How to realize energy saving and emission reduction while developing the economy is a major problem for China. How to realize energy saving and emission reduction while developing economy is a major problem facing China now. This project starts from the micro level, takes the financing penalty effect and investment inhibition effect as the entry point, and constructs a quasi-natural experiment with the Green Credit Guidelines issued in 2012 as the event. Selecting the data of Chinese A-share listed companies from 2008 to 2015 in CSMAR database, the DID model is used to explore the impact of green credit policy on the performance of heavy polluters, to provide suggestions for the promotion and improvement of green credit policy, and to provide a theoretical basis for the green innovation and transformation and upgrading of heavy polluters in China. The above study is of great significance to China, which is in the process of developing a low-carbon economy and promoting the realization of the "dual-carbon" goal.

Infection is the most common complication after burn injury and one of the leading causes of death in burn patients. Thus, how to effectively prevent the occurrence and development of infection is an important task in treating burns. Till now, there are still many controversies in the clinical definition, diagnosis, and treatment of infection, especially burn infection. The authors of this article put forward their opinions and views on this subject, hoping to deepen the readers' understanding of burn infection.感染是烧伤最常见的并发症，是引起烧伤患者死亡的主要原因之一。因此，如何有效防治感染的发生发展是烧伤治疗的重要任务。临床上对感染尤其是烧伤感染的定义、诊断及救治仍存在较多的争议。该文作者就此提出了自己的观点与看法，希望能加深读者对烧伤感染的认识。.

Sepsis is a life-threatening condition for patients. Biomarkers can be used for the diagnosis, treatment, and prognostic assessment of sepsis. In recent years, new biomarkers for sepsis have been discovered, and more than 250 biomarkers have been identified so far. The complexity of the sepsis process and the increased sensitivity of various detection techniques will lead to the emergence of new biomarkers. However, there is still a lack of specific diagnostic biomarkers and effective therapeutic approaches for sepsis in clinical practice. Therefore, the search for reliable biomarkers and the evaluation of the role of biomarkers in sepsis will undoubtedly aid in clinical decision-making. This article reviews the advances on research of sepsis biomarkers in order to improve understanding of current biomarkers of sepsis, and provide reference for the application of biomarkers in clinical diagnosis, treatment, and prognosis of sepsis.脓毒症是危及患者生命的疾病。生物标志物可用于对脓毒症的诊断、治疗和预后评估。近年来不断有新的脓毒症生物标志物被发现，迄今已确定的生物标志物超过250种。脓毒症发生过程的复杂性以及各种检测技术灵敏度的提高将会导致新的生物标志物不断涌现。但针对脓毒症，目前临床上仍缺乏特异性的用于诊断的生物标志物以及有效的治疗方法。因此，寻找可靠的生物标志物以及评估生物标志物在脓毒症中的运用无疑有助于指导临床决策。该文综述了脓毒症生物标志物的研究现状，以期加强对目前脓毒症生物标志物的认识，为生物标志物运用于脓毒症的诊断、治疗和预后评估提供参考。.

Expanding the optical absorption of blue-phosphorene phase GeSe and designing it as infrared light driven photocatalysts and photodetectors is of particular significance. In this work, the mechanism of p-block metals (Al, Ga, In, An, Pb, Sb and Bi) doping enhancing the optical performance of monolayer blue-phosphorene phase GeSe was investigated. The effect of all p-block metal doping on the lattice constant of GeSe is very weak. Pb doped system has the smallest formation energy (−4.82 eV). Except for Sn and Pb, other p-block metal doping can introduce deep impurity levels into the band gap of monolayer GeSe, and they can significantly absorb infrared light, especially Ga doped systems. This is due to the emergence of impurity levels that assist the photon transition. The results of this work provide guidance for promoting the application of blue-phosphorene phase GeSe in the field of photocatalysts and photodetectors.

Abstract Blurred images pose a significant challenge in many applications, including medical imaging, remote sensing, and surveillance systems. These images suffer from low resolution, noise, and missing data, which can hinder their interpretation and analysis. Traditional methods for image restoration and enhancement have their limitations, such as low quality and slow processing times. To overcome these challenges, this paper proposes an innovative method using Super-resolution Generative Adversarial Networks (SRGANs) to enhance image quality and fidelity. The proposed method employs adversarial training, perceptual loss, residual learning, and feature reconstruction to generate visually realistic and high-quality super-resolution (SR) images from low-resolution (LR) inputs. The SRGANs approach outperforms traditional methods, demonstrating its potential to advance image restoration and enhancement techniques. The paper also discusses possible improvements and future directions for this technique.

This is source data of the manuscript entitled " Soliton pulse pairs at multiple colors in normal dispersion microresonators".

This is source data of the manuscript entitled " Soliton pulse pairs at multiple colors in normal dispersion microresonators".

Integrated photonics has profoundly impacted a wide range of technologies underpinning modern society. The ability to fabricate a complete optical system on a chip offers unrivalled scalability, weight, cost and power efficiency. Over the last decade, the progression from pure III-V materials platforms to silicon photonics has significantly broadened the scope of integrated photonics by combining integrated lasers with the high-volume, advanced fabrication capabilities of the commercial electronics industry. Yet, despite remarkable manufacturing advantages, reliance on silicon-based waveguides currently limits the spectral window available to photonic integrated circuits (PICs). Here, we present a new generation of integrated photonics by directly uniting III-V materials with silicon nitride (SiN) waveguides on Si wafers. Using this technology, we present the first fully integrated PICs at wavelengths shorter than silicon's bandgap, demonstrating essential photonic building blocks including lasers, photodetectors, modulators and passives, all operating at sub-um wavelengths. Using this platform, we achieve unprecedented coherence and tunability in an integrated laser at short wavelength. Furthermore, by making use of this higher photon energy, we demonstrate superb high temperature performance and, for the first time, kHz-level fundamental linewidths at elevated temperatures. Given the many potential applications at short wavelengths, the success of this integration strategy unlocks a broad range of new integrated photonics applications.

M-SENA is an open-sourced platform for Multimodal Sentiment Analysis. It aims to facilitate advanced research by providing flexible toolkits, reliable benchmarks, and intuitive demonstrations. The platform features a fully modular video sentiment analysis framework consisting of data management, feature extraction, model training, and result analysis modules. In this paper, we first illustrate the overall architecture of the M-SENA platform and then introduce features of the core modules. Reliable baseline results of different modality features and MSA benchmarks are also reported. Moreover, we use model evaluation and analysis tools provided by M-SENA to present intermediate representation visualization, on-the-fly instance test, and generalization ability test results. The source code of the platform is publicly available at https://github.com/thuiar/M-SENA.

Acute kidney injury (AKI) is a common complication after severe burn, which portends a worse prognosis. Sepsis is the leading etiology of late AKI after severe burn. The pathogenesis of sepsis-induced AKI remains incompletely understood. Although there have been numerous preventive and therapeutic measures evaluated for sepsis-induced AKI, the precise and available intervention in sepsis-induced AKI after burn has yet to be defined.

Phages are traditionally deemed to lyse host bacteria, while new evidences have convinced their immunomodulation effects in metazoan hosts during period of anti-infection treatment. For sepsis induced by bacteria, phage therapy has attracted widespread attention of researchers at home and abroad for its lytic and immunoregulation functions. Clinical and basic researches in mechanism, usage, dosage, and safety of phages in China are inadequate and urgent to be carried out in depth and strengthened. Here we review overall anti-inflammation functions of phages in the treatment of sepsis, influence of phages in human immune cells, and clinical advances in present researches of phage therapy for sepsis.传统上认为噬菌体只裂解宿主菌，但是新的证据证明噬菌体在抗感染治疗过程中对后生宿主具有免疫调节作用。针对细菌导致的脓毒症，噬菌体疗法由于兼具裂菌和免疫调节作用，受到国内外研究者的广泛关注。但中国噬菌体疗法的临床和基础研究在噬菌体治疗的机制、用法用量、安全性等方面的探讨都不充分，亟须深入开展和加强。本文对噬菌体在治疗脓毒症方面的总体抗炎作用、对各种人体免疫细胞的影响及目前开展的噬菌体治疗脓毒症的临床研究进展做一综述。.