Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to ...increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.
Signals from 800 G-protein-coupled receptors (GPCRs) to many SH3 domain-containing proteins (SH3-CPs) regulate important physiological functions. These GPCRs may share a common pathway by signaling ...to SH3-CPs via agonist-dependent arrestin recruitment rather than through direct interactions. In the present study,
F-NMR and cellular studies revealed that downstream of GPCR activation engagement of the receptor-phospho-tail with arrestin allosterically regulates the specific conformational states and functional outcomes of remote β-arrestin 1 proline regions (PRs). The observed NMR chemical shifts of arrestin PRs were consistent with the intrinsic efficacy and specificity of SH3 domain recruitment, which was controlled by defined propagation pathways. Moreover, in vitro reconstitution experiments and biophysical results showed that the receptor-arrestin complex promoted SRC kinase activity through an allosteric mechanism. Thus, allosteric regulation of the conformational states of β-arrestin 1 PRs by GPCRs and the allosteric activation of downstream effectors by arrestin are two important mechanisms underlying GPCR-to-SH3-CP signaling.
Carbon dots (CDs), as a new type of carbon-based nanomaterial, have attracted broad research interest for years, because of their diverse physicochemical properties and favorable attributes like good ...biocompatibility, unique optical properties, low cost, ecofriendliness, abundant functional groups (e.g., amino, hydroxyl, carboxyl), high stability, and electron mobility. In this Outlook, we comprehensively summarize the classification of CDs based on the analysis of their formation mechanism, micro-/nanostructure and property features, and describe their synthetic methods and optical properties including strong absorption, photoluminescence, and phosphorescence. Furthermore, the recent significant advances in diverse applications, including optical (sensor, anticounterfeiting), energy (light-emitting diodes, catalysis, photovoltaics, supercapacitors), and promising biomedicine, are systematically highlighted. Finally, we envisage the key issues to be challenged, future research directions, and perspectives to show a full picture of CDs-based materials.
Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell ...therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
cells/kg range, 0.07 to 2.1 × 10
) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval CI, 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid phase separation (LLPS) occurs in ...a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).
Nitrogen is the main limiting nutrient after carbon, hydrogen and oxygen for photosynthetic process, phyto-hormonal, proteomic changes and growth-development of plants to complete its lifecycle. ...Excessive and inefficient use of N fertilizer results in enhanced crop production costs and atmospheric pollution. Atmospheric nitrogen (71%) in the molecular form is not available for the plants. For world's sustainable food production and atmospheric benefits, there is an urgent need to up-grade nitrogen use efficiency in agricultural farming system. The nitrogen use efficiency is the product of nitrogen uptake efficiency and nitrogen utilization efficiency, it varies from 30.2 to 53.2%. Nitrogen losses are too high, due to excess amount, low plant population, poor application methods etc., which can go up to 70% of total available nitrogen. These losses can be minimized up to 15-30% by adopting improved agronomic approaches such as optimal dosage of nitrogen, application of N by using canopy sensors, maintaining plant population, drip fertigation and legume based intercropping. A few transgenic studies have shown improvement in nitrogen uptake and even increase in biomass. Nitrate reductase, nitrite reductase, glutamine synthetase, glutamine oxoglutarate aminotransferase and asparagine synthetase enzyme have a great role in nitrogen metabolism. However, further studies on carbon-nitrogen metabolism and molecular changes at omic levels are required by using "whole genome sequencing technology" to improve nitrogen use efficiency. This review focus on nitrogen use efficiency that is the major concern of modern days to save economic resources without sacrificing farm yield as well as safety of global environment, i.e. greenhouse gas emissions, ammonium volatilization and nitrate leaching.
The strong mutual coupling of and even the opposite change in the key parameters, such as the band gap (Eg) and second‐order harmonic generation (SHG), leads to the extreme scarcity in ...high‐performance IR nonlinear optical (NLO) chalcogenides. Herein, we report 8 new sulfides, Na2Ba(AgxNa1−x)2Sn2S7 (1, x=0; 1 series, x=0.1–0.6; Na2Ba(Li0.58Na0.42)2Sn2S7, 1‐0.6Li); Na2SrCu2Sn2S7 (2); and Na2BaCu2Sn2S7 (3). We use the structural tolerance factor (
tIexp
${{t}_{I}^{exp}}$
) to connect the chemical composition, crystal structure, and NLO properties. Guided by these correlations, a better balance between Eg and SHG is realized in 1, which exhibits a large Eg of 3.42 eV and excellent NLO properties (SHG: 1.5×AGS; laser‐induced damage threshold: 12×AGS), representing the best performance among the known Hg‐ or As‐free sulfides to date.
Guided by the relationships between the structural tolerance factor and the dopant concentration and second‐order susceptibility, a better balance between Eg and SHG is realized in Na2Ba Na2Sn2S7 1, which exhibits a large Eg of 3.42 eV and excellent NLO properties (SHG: 1.5×AGS; laser‐induced damage threshold: 12×AGS), representing the best performance among the known Hg‐ or As‐free sulfides to date.
Carbonation of Ca/Mg minerals in industrial alkaline residues is a technology to sequester CO2 and reduce its emissions to the atmosphere. In this work, BSE-EDS were used to determine the mineral ...phase in steel slag; compositions of RO phase were identified and simulated. The carbon sequestration of steel slag was studied, and RO phase was activated by carbonation. Result shows that the amount of CO2 sequestered in steel slag and RO phase increases as carbonation time increases. Under autoclaving condition, the hydration ratio of MgO in RO phase was 20.10%. Through carbonation, up to 58.83% of MgO in RO phase can be converted into MgCO3, and the activation of RO phase by carbonation was manifested. The mechanical properties and volume stability of carbonated steel slag were improved, proving that the positive effect of carbonation on steel slag when applied in cement and cementitious materials.
Background/Aims: Poultry meat quality is affected by many factors, among which intramuscular fat (IMF) is predominant. IMF content affects the tenderness, juiciness, and favor of chicken. An ...increasing number of studies are focusing on the functions of microRNAs (miRNAs) during the adipogenic process. However, little is known about miRNAs associated with poultry IMF deposition, especially intramuscular adipocyte differentiation. Methods: The IMF content of two physiological stages was measured, and miRNA-Seq and RNA-Seq data were integrated and analyzed. A chicken intramuscular adipocyte cell differentiation model was constructed. A luciferase reporter assay, miRNA overexpression, and Oil Red O staining were used to confirm the targets of gga-miR-140-5p. Results: Our results showed that late-laying-period hens, which had a higher IMF content, exhibited lower global expression levels of miRNAs than juvenile hens. A total of 104 differentially expressed (DE) miRNAs were identified between the two groups. Integrated analysis of differentially expressed genes and DE miRNAs identified a total of 378 miRNA-mRNA pairs. Functional enrichment analysis revealed that these intersecting genes are involved in ubiquitin-mediated proteolysis, the peroxisome proliferator-activated receptor signaling pathway, glycerophospholipid metabolism, and fatty acid elongation and degradation pathways. Furthermore, we demonstrated that gga-miR-140-5p promoted intramuscular adipocyte differentiation via targeting retinoid X receptor gamma. Conclusion: Our findings may contribute to a more thorough understanding of chicken IMF deposition and the improvement of poultry meat quality.
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