Over 5,488,000 cases of coronavirus disease-19 (COVID-19) have been reported since December 2019. We aim to explore risk factors associated with mortality in COVID-19 patients and assess the use of ...D-dimer as a biomarker for disease severity and clinical outcome.
We retrospectively analyzed the clinical, laboratory, and radiological characteristics of 248 consecutive cases of COVID-19 in Renmin Hospital of Wuhan University, Wuhan, China from January 28 to March 08, 2020. Univariable and multivariable logistic regression methods were used to explore risk factors associated with in-hospital mortality. Correlations of D-dimer upon admission with disease severity and in-hospital mortality were analyzed. Receiver operating characteristic curve was used to determine the optimal cutoff level for D-dimer that discriminated those survivors versus non-survivors during hospitalization.
Multivariable regression that showed D-dimer > 2.0 mg/L at admission was the only variable associated with increased odds of mortality OR 10.17 (95% CI 1.10-94.38),
= 0.041. D-dimer elevation (≥ 0.50 mg/L) was seen in 74.6% (185/248) of the patients. Pulmonary embolism and deep vein thrombosis were ruled out in patients with high probability of thrombosis. D-dimer levels significantly increased with increasing severity of COVID-19 as determined by clinical staging (Kendall's tau-b = 0.374,
= 0.000) and chest CT staging (Kendall's tau-b = 0.378,
= 0.000). In-hospital mortality rate was 6.9%. Median D-dimer level in non-survivors (
= 17) was significantly higher than in survivors (
= 231) 6.21 (3.79-16.01) mg/L versus 1.02 (0.47-2.66) mg/L,
= 0.000. D-dimer level of > 2.14 mg/L predicted in-hospital mortality with a sensitivity of 88.2% and specificity of 71.3% (AUC 0.85; 95% CI = 0.77-0.92).
D-dimer is commonly elevated in patients with COVID-19. D-dimer levels correlate with disease severity and are a reliable prognostic marker for in-hospital mortality in patients admitted for COVID-19.
Abstract
Seasonal drought occurrences are found to increase across different regions over China under global warming, but with large uncertainties among models. With ten selected Coupled Model ...Intercomparison Project Phase 5 (CMIP5) climate models and seven CMIP6 models according to their performances in reproducing historical drought trends (
p
< 0.1), here we show that future seasonal soil moisture (SM) droughts over China projected by CMIP6 models are less frequent than that by CMIP5 models. We find national mean seasonal drought frequency is projected to increase by 28 ± 4% based on CMIP5 models at 1.5 °C global warming level, but only increase by 18 ± 6% based on CMIP6 models and 12 ± 4% based on land surface model ensemble simulations driven by downscaled CMIP5 models. Compared with CMIP6, CMIP5 projection suggests larger increase in precipitation but also larger increase in evapotranspiration, leading to more frequent seasonal SM droughts. Comparing the results at 3 °C global warming level with those at 1.5 °C, drought frequency over China will increase further by 10 ± 4%, but drought duration will decrease by 6 ± 4%, suggesting more frequent seasonal SM droughts with shorter durations will occur in a warming future. The future increase in China drought frequency will reduce from 12%–45% based on selected climate models to 3%–27% based on all available models (30 CMIP5 models and 31 CMIP6 models), which indicates that the model selection is critical for future drought projection. Nevertheless, CMIP6 still projects less frequent seasonal SM droughts than CMIP5 even without any model discriminations.
Mutations in genes encoding RNA splicing factors were discovered nearly 10 years ago and are now understood to be among the most recurrent genetic abnormalities in patients with all forms of myeloid ...neoplasms and several types of lymphoproliferative disorders, as well as subjects with clonal hematopoiesis. These discoveries implicate aberrant RNA splicing, the process by which precursor RNA is converted into mature messenger RNA, in the development of clonal hematopoietic conditions. Both the protein and the RNA components of the splicing machinery are affected by mutations at highly specific residues, and a number of these mutations alter splicing in a manner distinct from loss of function. Importantly, cells bearing these mutations have now been shown to generate mRNA species with novel aberrant sequences, some of which may be critical to disease pathogenesis and/or novel targets for therapy. These findings have opened new avenues of research to understand biological pathways disrupted by altered splicing. In parallel, multiple studies have revealed that cells bearing change-of-function mutation in splicing factors are preferentially sensitized to any further genetic or chemical perturbations of the splicing machinery. These discoveries are now being pursued in several early-phase clinical trials using molecules with diverse mechanisms of action. Here, we review the molecular effects of splicing factor mutations on splicing, the mechanisms by which these mutations drive clonal transformation of hematopoietic cells, and the development of new therapeutics targeting these genetic subsets of hematopoietic malignancies.
•THP positively affected the organics solubilization of high-solid sludge.•THP of high solid sludge greatly determined the performance of anaerobic digestion.•HTHP significantly sped up the gas ...production rate and increased the total gas volume.•The SRT could be reduced after the thermal hydrolysis at 140–160°C.
Anaerobic digestion of sludge not only decreases the mass/volume of sludge, but also increases the production of energy-rich biogas. The effects of a thermal hydrolysis process (THP) on the solubilization of main organics of sludge, as well as the performance of the followed biochemical methane potential (BMP) tests under mesophilic condition (35°C), were systematically evaluated. Organic compounds such as proteins and carbohydrates which have relatively high yield coefficients are solubilized efficiently during the THP. Good linear relations were obtained between the amounts of soluble chemical oxygen demand and soluble proteins/carbohydrates. The viscosity of sludge dramatically reduced after the THP, particularly at higher temperatures. In contrast to the treatments by low-temperature THP (60–90°C), the treatments by high-temperature THP (120–160°C) accelerated the digestion rate and increased the biogas yield in the following BMP tests. Meanwhile, the solid retention time could be reduced from 18–20days to 12–14days when high solid samples were pre-treated under THP at 140–160°C based on the corresponding results of acceleration of methane production after the treatment. As a result, this study elucidated the appropriate operational conditions for high solid sludge (TS>10%) under THP, and their mechanisms of the acceleration of biogas production.
•Amino acids were decomposed evidently by THP at 120 °C (8.9%) and 160 °C (26.7%).•Amino acids degradation in AD was promoted largely via decomposition during THP.•Varied THP temperature changed ...dominating bacteria utilizing amino acids in AD.•120 °C played little role in promoting amino acids metabolic pathways during AD.•160 °C effectively enhanced amino acids metabolism via Stickland pathway during AD.
Three semi-continuous anaerobic digesters with raw sludge (R1) or thermally hydrolyzed sludge (120 °C (R2) or 160 °C (R3)) were operated to investigate the effects of thermal hydrolysis on the metabolism of amino acids during high solid anaerobic digestion with sewage sludge. Thermal hydrolysis pretreatment (THP) decomposed protein in terms of hydrolytic amino acid in raw sludge by 8.90% and 26.69% under 120 °C and 160 °C, respectively. The decomposition of amino acids during THP was the main contributor to the final enhanced amino acids degradation in sewage sludge with THP after anaerobic digestion. The dominating bacterial genera related to amino acids degradation in R2 and R3 shifted to Fastidiosipila and Proteiniphilum/Tissierella, respectively, from Gelria in R1, influencing the utilization of amino acids, especially glutamic acid, glycine and proline. Different from 120 °C, THP at 160 °C played an important role in promoting amino acid metabolism during AD through the Stickland pathway by the bacteria belonged to order Clostridiales.
Understanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown. Here, we attempt to model ...human early embryo development with expanded pluripotent stem cells (EPSCs) in 3-dimensions. We define a protocol that allows us to generate self-organizing cystic structures from human EPSCs that display some hallmarks of human early embryogenesis. These structures mimic polarization and cavitation characteristic of pre-implantation development leading to blastocyst morphology formation and the transition to post-implantation-like organization upon extended culture. Single-cell RNA sequencing of these structures reveals subsets of cells bearing some resemblance to epiblast, hypoblast and trophectoderm lineages. Nevertheless, significant divergences from natural blastocysts persist in some key markers, and signalling pathways point towards ways in which morphology and transcriptional-level cell identities may diverge in stem cell models of the embryo. Thus, this stem cell platform provides insights into the design of stem cell models of embryogenesis.
A deep understanding of the relationship between the knowledge acquired and the graduation requirements is essential for students to precisely meet the graduation requirements and to become human ...resources with specific knowledge, skills and professionalism. In this paper, we define the ontology layer of the knowledge graph by deeply analyzing the relationship between graduation requirement, course and knowledge. Based on the implementation of the concept of Outcome Based Education, we use Knowledge extraction, fusion, reasoning techniques to construct a hierarchical knowledge graph with the main line of "knowledge-course-graduation requirements. In the process of knowledge extraction, in order to alleviate the huge labor overhead brought by traditional extraction methods, this paper adopts a transfer learning method to extract triadic knowledge using the multi-task framework EERJE, Finally, knowledge reasoning was also performed with the help of LLM to further expand the knowledge scope. The comprehensiveness, correctness and relatedness of the data were evaluated through the experiment, and the F1 value of the ternary group extraction was 87.76%, the accuracy rate of entity classification was 85.42%, the data coverage was more comprehensive, and the results showed that the data quality was better, and the knowledge graph constructed in this way can fully optimize the organization and management of teaching resources, help students intuitively and comprehensively grasp the correlation and difference between graduation requirements and various knowledge points, and let the Students can carry out personalized independent learning through the navigation mode of knowledge graph, strengthen their weak links, and complete the relevant graduation requirements, which effectively improves the degree of students’ graduation requirements achievement. This new paradigm of knowledge graph enabled teaching is of reference significance for engineering education majors to improve the degree of graduation requirements achievement.
Inflammation is a risk factor for cancer development. Individuals with preleukemic TET2 mutations manifest clonal hematopoiesis and are at a higher risk of developing leukemia. How inflammatory ...signals influence the survival of preleukemic hematopoietic stem and progenitor cells (HSPCs) is unclear. We show a rapid increase in the frequency and absolute number of Tet2-KO mature myeloid cells and HSPCs in response to inflammatory stress, which results in enhanced production of inflammatory cytokines, including interleukin-6 (IL-6), and resistance to apoptosis. IL-6 induces hyperactivation of the Shp2-Stat3 signaling axis, resulting in increased expression of a novel anti-apoptotic long non-coding RNA (lncRNAs), Morrbid, in Tet2-KO myeloid cells and HSPCs. Expression of activated Shp2 in HSPCs phenocopies Tet2 loss with regard to hyperactivation of Stat3 and Morrbid. In vivo, pharmacologic inhibition of Shp2 or Stat3 or genetic loss of Morrbid in Tet2 mutant mice rescues inflammatory-stress-induced abnormalities in HSPCs and mature myeloid cells, including clonal hematopoiesis.
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•Tet2-KO HSPCs maintain repopulation advantage after acute inflammatory insult•Hyperactivation of IL-6/Shp2/Stat3/Morrbid and reduced apoptosis occurs in Tet2-KO HPSCs•Anti-inflammation drugs E3330 or SHP099 inhibit survival advantage of Tet2-KO HSPCs•Morrbid+/− counters emergency granulopoiesis and clonal hematopoiesis in Tet2+/−
Cai et al. report that Tet2-deficient hematopoietic stem and progenitor cells manifest a hyperactive IL-6/Shp2/Stat3/Morrbid pathway, which promotes cell survival under basal conditions and in response to inflammatory stress. Blocking this pathway using anti-inflammatory drugs (E3330 and SHP099) or by genetic loss of Morrbid mitigates this response.
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also ...associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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•Type 2 cytokines directly activate both mouse and human sensory neurons•IL-4 enhances neuronal responsiveness to multiple pruritogens•Sensory neuron-specific deletion of IL-4Rα or JAK1 reduces chronic itch•Clinical studies demonstrate that JAK inhibitors relieve chronic itch
Type 2 cytokines directly stimulate itch-sensory neurons, and blocking this pathway is effective in a proof-of-concept study in patients with recalcitrant chronic itch.
Abstract
SARS-CoV-2 vaccination has been launched worldwide to build effective population-level immunity to curb the spread of this virus. The effectiveness and duration of protective immunity is a ...critical factor for public health. Here, we report the kinetics of the SARS-CoV-2 specific immune response in 204 individuals up to 1-year after recovery from COVID-19. RBD-IgG and full-length spike-IgG concentrations and serum neutralizing capacity decreases during the first 6-months, but is maintained stably up to 1-year after hospital discharge. Even individuals who had generated high IgG levels during early convalescent stages had IgG levels that had decreased to a similar level one year later. Notably, the RBD-IgG level positively correlates with serum neutralizing capacity, suggesting the representative role of RBD-IgG in predicting serum protection. Moreover, viral-specific cellular immune protection, including spike and nucleoprotein specific, persisted between 6 months and 12 months. Altogether, our study supports the persistence of viral-specific protective immunity over 1 year.
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