This study is an epidemiologic investigation of nosocomial severe fever with thrombocytopenia syndrome virus (SFTSV) transmission among healthcare workers (HCWs) after contact with an index patient. ...The aim of this study was to determine whether exposure to blood or bloody respiratory secretion is associated with human-to-human transmission of SFTSV.
Eleven days after the index patient died, two HCWs who had close exposure to the patient presented with typical symptoms of SFTS. An epidemiological investigation was conducted on all 25 HCWs who had been in close contact with the index patient. Clinical and laboratory data were collected, and transmission rate before and after the index patient had haemorrhagic manifestations was analysed.
Among 25 HCWs who had direct contact with the index patient, five HCWs were confirmed to have SFTS. All five HCWs had contact to blood or bloody respiratory secretions of the index patient without adequate use of personal protective equipment (PPE). No HCW with contact before haemorrhagic manifestations of the index patient contracted SFTS. Overall, the transmission rate was higher for HCWs who had contact after the index patient had haemorrhagic manifestations (33.3%, five of 15 HCWs, vs. 0%, zero of ten HCWs, p 0.041).
In HCWs who are inadequately protected, person-to-person transmission of SFTSV may be associated with contact with blood or bloody respiratory secretions. Therefore, universal precaution and full PPE is highly recommended for protection against SFTSV when there are signs of bleeding.
The ability to design functional sequences and predict effects of variation is central to protein engineering and biotherapeutics. State-of-art computational methods rely on models that leverage ...evolutionary information but are inadequate for important applications where multiple sequence alignments are not robust. Such applications include the prediction of variant effects of indels, disordered proteins, and the design of proteins such as antibodies due to the highly variable complementarity determining regions. We introduce a deep generative model adapted from natural language processing for prediction and design of diverse functional sequences without the need for alignments. The model performs state-of-art prediction of missense and indel effects and we successfully design and test a diverse 10
-nanobody library that shows better expression than a 1000-fold larger synthetic library. Our results demonstrate the power of the alignment-free autoregressive model in generalizing to regions of sequence space traditionally considered beyond the reach of prediction and design.
Methane gas hydrates, crystalline inclusion compounds formed from methane and water, are found in marine continental margin and permafrost sediments worldwide. This article reviews the current ...understanding of phenomena involved in gas hydrate formation and the physical properties of hydrate‐bearing sediments. Formation phenomena include pore‐scale habit, solubility, spatial variability, and host sediment aggregate properties. Physical properties include thermal properties, permeability, electrical conductivity and permittivity, small‐strain elastic P and S wave velocities, shear strength, and volume changes resulting from hydrate dissociation. The magnitudes and interdependencies of these properties are critically important for predicting and quantifying macroscale responses of hydrate‐bearing sediments to changes in mechanical, thermal, or chemical boundary conditions. These predictions are vital for mitigating borehole, local, and regional slope stability hazards; optimizing recovery techniques for extracting methane from hydrate‐bearing sediments or sequestering carbon dioxide in gas hydrate; and evaluating the role of gas hydrate in the global carbon cycle.
Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production ...and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two‐photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT‐mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.
NAD(H) pool size increased during colorectal cancer (CRC) progression due to activation of the enzymes in the salvage pathway of NAD+ synthesis, especially NAMPT. The increases in the NAD(H) pool promoted colon cancer progression by decreasing excessive ROS levels. Detection of NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.
Elucidation of endogenous cellular protein-protein interactions and their networks is most desirable for biological studies. Here we report our study of endogenous human coregulator protein complex ...networks obtained from integrative mass spectrometry-based analysis of 3290 affinity purifications. By preserving weak protein interactions during complex isolation and utilizing high levels of reciprocity in the large dataset, we identified many unreported protein associations, such as a transcriptional network formed by ZMYND8, ZNF687, and ZNF592. Furthermore, our work revealed a tiered interplay within networks that share common proteins, providing a conceptual organization of a cellular proteome composed of minimal endogenous modules (MEMOs), complex isoforms (uniCOREs), and regulatory complex-complex interaction networks (CCIs). This resource will effectively fill a void in linking correlative genomic studies with an understanding of transcriptional regulatory protein functions within the proteome for formulation and testing of future hypotheses.
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► Database of endogenous coregulator complexes containing >10,000 unique proteins ► Analytical approach preserves weaker complex-complex interaction networks ► Many transcriptional coregulators promiscuously share multiple interaction networks ► Protein complex units are hubs for diverse genomic alterations of polygenic diseases
Abstract
Topological superconductors (TSCs) are unconventional superconductors with bulk superconducting gap and in-gap Majorana states on the boundary that may be used as topological qubits for ...quantum computation. Despite their importance in both fundamental research and applications, natural TSCs are very rare. Here, combining state of the art synchrotron and laser-based angle-resolved photoemission spectroscopy, we investigated a stoichiometric transition metal dichalcogenide (TMD), 2M-WS
2
with a superconducting transition temperature of 8.8 K (the highest among all TMDs in the natural form up to date) and observed distinctive topological surface states (TSSs). Furthermore, in the superconducting state, we found that the TSSs acquired a nodeless superconducting gap with similar magnitude as that of the bulk states. These discoveries not only evidence 2M-WS
2
as an intrinsic TSC without the need of sensitive composition tuning or sophisticated heterostructures fabrication, but also provide an ideal platform for device applications thanks to its van der Waals layered structure.
Background and purpose
We analyzed the incidence and causes of oral anticoagulant (OAC) cessation and subsequent stroke after OAC withdrawal in a cohort of Korean stroke patients with atrial ...fibrillation.
Methods
The Korean Atrial Fibrillation Evaluation Registry in Ischemic Stroke patients (K‐ATTENTION) is a multicenter cohort study, merging stroke registries from 11 tertiary centers in Korea. The number of OAC interruption episodes and the reasons were reviewed from hospital records. Stroke after OAC withdrawal was defined when a patient experienced ischaemic stroke within 31 days after OAC withdrawal. Clinical variables were compared between patients who experienced stroke recurrence during OAC interruption and those who did not experience recurrence.
Results
Among 3213 stroke patients with atrial fibrillation, a total of 329 episodes of OAC interruption were detected in 229 patients after index stroke (mean age 72.9 ± 8.3 years, 113 female patients). The most frequent reason for OAC withdrawal was poor compliance 103 episodes (31.3%) followed by extracranial bleeding 96 episodes (29.2%). Stroke after OAC withdrawal was noted in 13 patients. Mean age, vascular risk factor profile and mean CHA2DS2‐VASc score were not significantly different between patients with and without recurrent stroke.
Conclusions
A considerable number of stroke patients with atrial fibrillation experienced temporary interruption of OAC after index stroke, which was associated with stroke recurrence of 4.0 cases per 100 interruption episodes.
Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms ...leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3'-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.
The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and ...PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of BT-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8^＋ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.
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