Search

Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute to depressed cardiac function. However, the pathogenic mechanisms underlying the increased vulnerability to heart failure in SARS-CoV-2 infected patients are still largely unknown. Here, we found that the senescent outcome of SARS-CoV-2 spike protein (SARS-2-S)-induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia withoutdenovosynthesis of SARS-2-S. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNF α . We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by pseudovirus expressing SARS-2-S (SARS-2-Spp). Signs of senescent multinucleated cells are identified in ascending aorta from SARS-CoV-2 omicron variant-infected patient. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy.Significance StatementIn this paper, we directly linked SARS-2-S-triggered syncytium formation with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2-expressing cells. This is important because of the persistent existence of SARS-2-S or extracellular vesicles containing SARS-2-S during the acute and post-acute stages of SARS-CoV-2 infection in human subjects. In searching for the underlying molecular mechanisms determining syncytial fate, the formation of functional MAVS aggregates dependent on RIG-I was observed at an early stage during fusion and regulated the anti-death to senescence fate of SARS-2-S syncytia through the TNFα-TNFR2 axis. We also found impaired cardiac metabolism in SARS-2-S syncytia induced by condensed WNK1. Importantly, SARS-2-Spp-exacerbated heart failure could be largely rescued by WNK1 inhibitor, anti-syncytial drug or senolytic agent. Together, we suggest that rescuing metabolism dysfunction in senescent SARS-2-S syncytia should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection.

Intrinsically Disordered Proteins (IDPs) and Regions (IDRs) exist widely. Although without well-defined structures, they participate in many important biological processes. In addition, they are also widely related to human diseases and have become potential targets in drug discovery. However, there is a big gap between the experimental annotations related to IDPs/IDRs and their actual number. In recent decades, the computational methods related to IDPs/IDRs have been developed vigorously, including predicting IDPs/IDRs, the binding modes of IDPs/IDRs, the binding sites of IDPs/IDRs, and the molecular functions of IDPs/IDRs according to different tasks. In view of the correlation between these predictors, we have reviewed these prediction methods uniformly for the first time, summarized their computational methods and predictive performance, and discussed some problems and perspectives.

Recommender system plays a crucial role in modern E-commerce platform. Due to the lack of historical interactions between users and items, cold-start recommendation is a challenging problem. In order to alleviate the cold-start issue, most existing methods introduce content and contextual information as the auxiliary information. Nevertheless, these methods assume the recommended items behave steadily over time, while in a typical E-commerce scenario, items generally have very different performances throughout their life period. In such a situation, it would be beneficial to consider the long-term return from the item perspective, which is usually ignored in conventional methods. Reinforcement learning (RL) naturally fits such a long-term optimization problem, in which the recommender could identify high potential items, proactively allocate more user impressions to boost their growth, therefore improve the multi-period cumulative gains. Inspired by this idea, we model the process as a Partially Observable and Controllable Markov Decision Process (POC-MDP), and propose an actor-critic RL framework (RL-LTV) to incorporate the item lifetime values (LTV) into the recommendation. In RL-LTV, the critic studies historical trajectories of items and predict the future LTV of fresh item, while the actor suggests a score-based policy which maximizes the future LTV expectation. Scores suggested by the actor are then combined with classical ranking scores in a dual-rank framework, therefore the recommendation is balanced with the LTV consideration. Our method outperforms the strong live baseline with a relative improvement of 8.67% and 18.03% on IPV and GMV of cold-start items, on one of the largest E-commerce platform., Accepted by CIKM 2021

Mobility is the most distinctive and important feature of Mobile Wireless Ad Hoc Networks(MANET), which brings many limitations along with its wide applications. A good mobility model is a good basis for further improving the performance of routing layer and MAC layer. Therefore, a movement strategy is proposed for the node movement problem. Only those nodes that are poorly distributed and meet the conditions are selected to form the set of mobile nodes. Neighborhood distribution information and residual energy information are fully considered for improving the initial population and fitness function of the genetic algorithm. Then, the improved genetic algorithm is used to search for the optimal next mobile position for each node in the set. The simulation results show that the nodes in the network can achieve higher network coverage and connectivity with fewer moves, regardless of whether the nodes are well or poorly distributed.

Background While surgical reduction with adjuvant chemotherapy is the traditional treatment for high-grade serous ovarian cancer (HGSOC), neoadjuvant chemotherapy (NACT) has increasingly been applied. This work aims to investigate the expression profiles before and after NACT, explore changes in the tumor microenvironment, expand current treatments, and design a combination of treatment options for patients. Methods We downloaded 326 pre-NACT RNA sequencing data and 37 matched pre- and post-NACT samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) were determined with EdgeR, and Gene Ontology analysis was performed to identify the clusters responsible for the biological processes and pathways of HGSOC. Immune infiltration was analyzed using Single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. Kaplan-Meier (KM) survival analysis was performed to assess prognosis, and the potential correlations between modules and phenotypes were explored using weighted gene co-expression network analysis (WGCNA). Results After NACT, a total of 352 genes showed significant changes in RNA expression, among which 180 genes were up-regulated and 172 down-regulated. The most influential pathway was the positive regulation of mitogen-activated protein kinase (MAPK) cascade. Correlation analysis and KM survival analysis showed that overexpression of MAPK cascade genes correlated with shorter survival time in HGSOC patients. ssGSEA results showed that the expressions of anti-tumor cells (central memory CD4+ T cell and central memory CD8+ T cell) and pro-tumor cells (neutrophil and dendritic cells) were significantly increased after NACT. CIBERSORT showed that the abundances of memory B cells, NK cells, and monocytes were increased and the abundance of plasma cells was decreased after NACT. WGCNA and KM survival analysis showed that a lower abundance of Regulatory T cells (Tregs) was correlated with a better prognosis. Conclusions Gene expression of the MAPK pathway is up-regulated and the abundance of CD4+ T regulation cell decreases after NACT. Thus, the MAPK pathway may promote the differentiation of CD4+ T cells into Th17 cells while inhibiting Tregs development. The inhibited Tregs' development can lead to a better prognosis. Therefore, it is speculated that Tregs inhibitors combined with platinum-based NACT are potential treatment options for HGSOC.

Background Pulmonary embolism (PE) is a leading cause of cardiovascular mortality worldwide. Rapid and accurate diagnosis and risk stratification are crucial for timely treatment options, especially in high-risk PE. Objectives The study aims to profile the comprehensive changes of plasma proteomes in PE patients and identify the potential biomarkers for both diagnosis and risk stratification. Patients/methods Based on the data-independent acquisition mass spectrometry and antibody array proteomic technology, we screened the plasma samples (13 and 32 proteomes, respectively) in two independent studies consisting of high-risk PE patients, non-high-risk PE patients, and healthy controls. Some significantly differentially expressed proteins were quantified by enzyme-linked immunosorbent assay in a new study group with 50 PE patients and 26 healthy controls. Results We identified 207 and 70 differentially expressed proteins in PE and high-risk PE. These proteins were involved in multiple thrombosis-associated biological processes including blood coagulation, inflammation, injury, repair, and chemokine-mediated cellular response. It was verified that five proteins including SAA1, S100A8, TNC, GSN and HRG had significant change in PE and/or in high-risk PE. The Receiver Operating Characteristic curve analysis based on binary Logistic regression showed that the area under the curve (AUC) of SAA1, S100A8, and TNC in PE diagnosis were 0.882, 0.788, and 0.795, and AUC of S100A8 and TNC in high-risk PE diagnosis were 0.773 and 0.720. Conclusion As predictors of inflammation or injury repair, SAA1, S100A8, and TNC are potential plasma biomarkers for the diagnosis and risk stratification of PE.

Background The commutability of electrolyte trueness verification materials (ETVs) and commercial general chemistry materials (GCs) was evaluated to investigate their suitability for use in an external quality assessment (EQA) program for serum sodium and potassium measurements. Methods Eighty fresh individual human samples (40 for sodium measurements and 40 for potassium measurements), six ETVs and three GCs were analyzed by five routine methods (validated methods) and by inductively coupled plasma mass spectrometry reference methods (comparative methods) for the determination of sodium and potassium. The commutability was analyzed according to Clinical and Laboratory Standards Institute (CLSI) EP14-A3 protocol and difference in bias approach, respectively. The linearity, bias and imprecision of the routine methods were also assessed according to CLSI guidelines. Results According to EP14-A3 protocol, ETVs were commutable for all assays, and GCs were commutable for 3/5 assays for sodium. ETVs were commutable in most assays except Cobas C501, while GCs showed no commutability except in case of AU5821 for potassium. According to a difference in bias approach, the commutability of ETVs was inconclusive for most routine assays for both sodium and potassium, and GCs were inconclusive for sodium and non-commutable for potassium in most routine assays. The routine methods exhibited excellent linearities and precisions. The majority and minority of relative biases between the routine and reference methods were beyond the bias limits for sodium and potassium, respectively. Conclusions Superiority in the commutability of ETVs over GCs was observed among the sodium and potassium assays whichever evaluation approach was applied.

Background Current laboratory examinations for hypercoagulable diseases focus on the biomarker content of the activated coagulation cascade and fibrinolytic system. Direct detection of physiologically important protease activities in blood remains a challenge. This study aims to develop a general approach that enables the determination of activities of crucial coagulation factors and plasmin in blood. Methods This assay is based on the proteolytic activation of an engineered zymogen of l-phenylalanine oxidase (proPAO), for which the specific blood protease cleavage sites were engineered between the inhibitory and activity domains of proPAO. Specific cleavage of the recombinant proenzyme leads to the activation of proPAO, followed by oxidation and oxygenation of l-phenylalanine, resulting in an increase of chromogenic production when coupled with the Trinder reaction. Results We applied this method to determine the activities of both coagulation factor IIa and plasmin in their physiologically relevant basal state and fully activated state in sodium citrate–anticoagulated plasma respectively. Factor IIa and plasmin activities could be dynamically monitored in patients with thrombotic disease who were taking oral anticoagulants and used for assessing the hypercoagulable state in pregnant women. Conclusions The high specificity, sensitivity, and stability of this novel assay not only makes it useful for determining clinically important protease activities in human blood and diagnosing thrombotic diseases but also provides a new way to monitor the effectiveness and safety of anticoagulant drugs.

Background Chloride is the main anion in human body. A simple and accurate method for serum chloride measurement was developed using ion chromatography (IC) in China. Methods In the measurement, serum samples were diluted 500 times with water, filtered and injected into ion chromatography column. A mixed eluent (2 mmol/L CO32- + 12 mmol/L OH-) was used and peak area signal was collected. Five calibrators made from Standard Reference Material (SRM) 919b were used in the bracketing method. The IC method was applied as the comparative method and six ion selective electrode (ISE) measurement systems were evaluated using 60 individual patient serums. Results The IC method was proven to be accurate. The precision was 0.18% - 0.30%, the recovery was 99.66% - 100.60%, the bias was 0.19% to -0.06%, and the related expanded uncertainty was 0.775% (k = 2). The precisions of the ISE systems were smaller than the 0.9% tolerable CV except for the Beckman DXC (0.91% - 1.16%). In comparison, the results of linear regression analysis showed that the correlation coefficients were 0.9876 to 0.9979. For all systems, the range of mean biases was -5.96 - 1.48 mmol/L (-5.57% - 1.36%); the expected biases at the medical decision levels were -4.97% - 0.84% at 90 mmol/L and -6.02% - 1.76% at 120 mmol/L. All biases of the Beckman AU met the requirement of within ± 1.5%. Conclusions The IC measurement method is proven to be of high precision and trueness, and the quality of routine ISE measurement of serum chloride still needs significant improvement. The establishment of the IC method can improve the measurement quality and promote its standardization process in China.

Chen, D.; Chen, Y., and Han B., 2015. Toll policy for load balancing research based on data mining in port logistics. Studies on the scheduling and decision-making at Port Logistics have mostly been limited to the turn round of ships and/or the throughput capacity of harbors previously, and it has rarely been explored from the perspective of load balancing among logistics service activity lines. Tolling is generally considered to be a method for balancing the supply and demand of social resources. This paper explored the emergence and development of the logistics toll policy. It examined the influence of tolls on consumers' logistics choices, and even the departure time choices. The modern toll policy was mainly designed to reduce traffic congestion. We listed potential motivations for applying the toll policy to balance traffic supply and demand, and then uncovered how it worked. We discussed the approaches for evaluating the logistics toll pricing policy. By introducing a case study, Los Angele...

Background: Serum calcium level is an important clinical index that reflects pathophysiological states. However, detection accuracy in laboratory tests is not ideal; as such, a high accuracy method is needed. Methods: We developed a reference method for measuring serum calcium levels by isotope dilution inductively coupled plasma mass spectrometry (ID ICP-MS), using 42Ca as the enriched isotope. Serum was digested with 69% ultrapure nitric acid and diluted to a suitable concentration. The 44Ca/42Ca ratio was detected in H2 mode; spike concentration was calibrated by reverse IDMS using standard reference material (SRM) 3109a, and sample concentration was measured by a bracketing procedure. We compared the performance of ID ICP-MS with those of three other reference methods in China using the same serum and aqueous samples. Results: The relative expanded uncertainty of the sample concentration was 0.414% (k=2). The range of repeatability (within-run imprecision), intermediate imprecision (between-run imprecision), and intra-laboratory imprecision were 0.12%–0.19%, 0.07%–0.09%, and 0.16%–0.17%, respectively, for two of the serum samples. SRM909bI, SRM909bII, SRM909c, and GBW09152 were found to be within the certified value interval, with mean relative bias values of 0.29%, −0.02%, 0.10%, and −0.19%, respectively. The range of recovery was 99.87%–100.37%. Results obtained by ID ICP-MS showed a better accuracy than and were highly correlated with those of other reference methods. Conclusions: ID ICP-MS is a simple and accurate candidate reference method for serum calcium measurement and can be used to establish and improve serum calcium reference system in China.

Background Potassium is an important serum ion that is frequently assayed in clinical laboratories. Quality assurance requires reference methods; thus, the establishment of a candidate reference method for serum potassium measurements is important. Methods An inductively coupled plasma mass spectrometry (ICP-MS) method was developed. Serum samples were gravimetrically spiked with an aluminum internal standard, digested with 69% ultrapure nitric acid, and diluted to the required concentration. The 39K/27Al ratios were measured by ICP-MS in hydrogen mode. The method was calibrated using 5% nitric acid matrix calibrators, and the calibration function was established using the bracketing method. Results The correlation coefficients between the measured 39K/27Al ratios and the analyte concentration ratios were >0.9999. The coefficients of variation were 0.40%, 0.68%, and 0.22% for the three serum samples, and the analytical recovery was 99.8%. The accuracy of the measurement was also verified by measuring certified reference materials, SRM909b and SRM956b. Comparison with the ion selective electrode routine method and international inter-laboratory comparisons gave satisfied results. Conclusions The new ICP-MS method is specific, precise, simple, and low-cost, and it may be used as a candidate reference method for standardizing serum potassium measurements.