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Abstract This study aims to understand the repercussions of the COVID-19 pandemic on hospitalized patients with peripheral arterial disease (PAD) in China, who did not contract SARS-CoV-2. We conducted a multicenter cross-sectional analysis comparing the characteristics and outcomes of hospitalized PAD patients across two distinct periods: Pre-pandemic (P1, from January 2018 to December 2019) and during the pandemic (P2, from January 2020 to December 2021). During P1, 762 hospitalized patients were treated, with an average age of 72.3 years, while 478 patients were treated in P2, with an average age of 65.1 years. Notably, hospitalized patients admitted during the pandemic (P2) exhibited a significantly higher incidence of chronic limb-threatening ischemia (CLTI, 70% vs 54%), diabetic foot infection (47% vs 29%), and infra-popliteal lesions (28% vs 22%). Furthermore, these patients demonstrated a marked deterioration in their Rutherford category and an increased mean score in the Wound, Ischemia, and foot Infection classification system (WIfI). Treatment during the pandemic emerged as a predictor of reduced procedural success and increased major adverse limb events. Factors such as the presence of diabetic foot infection, renal impairment, and deteriorating WIfI scores were identified as independent risk indicators for major adverse limb events. Our results demonstrate that intensive care was provided to severe cases of PAD even during the challenging circumstances of the COVID-19 pandemic. Despite the unprecedented pressures on healthcare systems, patients with severe PAD, particularly those with CLTI, continued to receive necessary in-patient care. The findings underscore the importance of timely medical interventions and extended follow-up for patients exhibiting high-risk factors.

Introduction: Classification criteria for systemic lupus erythematosus (SLE) include American College of Rheumatology (ACR) 1997, Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) 2012 and European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria. Their performance in an Asian childhood-onset SLE (cSLE) population remains unclear as the clinical manifestations differ. We aim to evaluate the diagnostic performance in a cSLE cohort in Singapore. Method: Cases were physician-diagnosed cSLE, while controls were children with mixed and undifferentiated connective tissue disease that posed an initial diagnostic challenge. Data were retrospectively reviewed to establish the 3 criteria fulfilled at diagnosis and over time. Results: The study population included 120 cSLE cases and 36 controls. At diagnosis, 102 (85%) patients fulfilled all criteria. SLICC-2012 had the highest sensitivity (97.5%, 95% confidence interval [CI] 92.3–99.5), while ACR-1997 had the highest specificity (91.7%, 95% CI 77.5–98.3). All criteria had diagnostic accuracies at more than 85%. Over time, 113 (94%) fulfilled all criteria. SLICC-2012 remained the criteria with the highest sensitivity (99.2%, 95% CI 95.4–99.9), while ACR-1997 had the highest specificity (75.0%, 95% CI 57.8–87.9). Only SLICC-2012 and ACR-1997 had more than 85% diagnostic accuracy over time. Using a cutoff score of ≥13 for EULAR/ACR-2019 criteria resulted in improved diagnostic performance. Conclusion: SLICC-2012 criteria had the highest sensitivity early in the disease course in this first study evaluating the SLE classification criteria performance in a Southeast Asian cSLE cohort, while the ACR-1997 criteria had the highest specificity. Using a cutoff score of ≥13 for EULAR/ACR-2019 improved the diagnostic performance.

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl− transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl− transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl− concentration ([Cl−]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl−]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.

C16H14N2O3, monoclinic, P21/n (no. 14), a = 4.9621(10) Å, b = 11.828(2) Å, c = 23.727(5) Å, β = 94.527(4)°, V = 1388.2(5) Å3, Z = 4, Rgt(F) = 0.0551, wRref(F2) = 0.1847, T = 296(2) K.

Abstract Background Gas hydrate-bearing subseafloor sediments harbor a large number of microorganisms. Within these sediments, organic matter and upward-migrating methane are important carbon and energy sources fueling a light-independent biosphere. However, the type of metabolism that dominates the deep subseafloor of the gas hydrate zone is poorly constrained. Here we studied the microbial communities in gas hydrate-rich sediments up to 49 m below the seafloor recovered by drilling in the South China Sea. We focused on distinct geochemical conditions and performed metagenomic and metatranscriptomic analyses to characterize microbial communities and their role in carbon mineralization. Results Comparative microbial community analysis revealed that samples above and in sulfate-methane interface (SMI) zones were clearly distinguished from those below the SMI. Chloroflexota were most abundant above the SMI, whereas Caldatribacteriota dominated below the SMI. Verrucomicrobiota, Bathyarchaeia, and Hadarchaeota were similarly present in both types of sediment. The genomic inventory and transcriptional activity suggest an important role in the fermentation of macromolecules. In contrast, sulfate reducers and methanogens that catalyze the consumption or production of commonly observed chemical compounds in sediments are rare. Methanotrophs and alkanotrophs that anaerobically grow on alkanes were also identified to be at low abundances. The ANME-1 group actively thrived in or slightly below the current SMI. Members from Heimdallarchaeia were found to encode the potential for anaerobic oxidation of short-chain hydrocarbons. Conclusions These findings indicate that the fermentation of macromolecules is the predominant energy source for microorganisms in deep subseafloor sediments that are experiencing upward methane fluxes. Video Abstract

Abstract Euodiae Fructus, referred to as “Wuzhuyu” in Chinese, has been used as local and traditional herbal medicines in many regions, especially in China, Japan and Korea, for the treatment of gastrointestinal disorders, headache, emesis, aphtha, dermatophytosis, dysentery, etc. Substantial investigations into their chemical and pharmacological properties have been performed. Recently, interest in this plant has been focused on the different structural types of alkaloids like evodiamine, rutaecarpine, dehydroevodiamine and 1-methyl-2-undecyl-4(1H)-quinolone, which exhibit a wide range of pharmacological activities in preclinical models, such as anticancer, antibacterial, anti-inflammatory, anti-cardiovascular disease, etc. This review summarizes the up-to-date and comprehensive information concerning the botany, traditional uses, phytochemistry, pharmacology of Euodiae Fructus together with the toxicology and quality control, and discusses the possible direction and scope for future research on this plant.

Abstract Background Evidence regarding the relationship between in-hospital mortality and SpO2 was low oxygen saturations are often thought to be harmful, new research in patients with brain damage has found that high oxygen saturation actually enhances mortality. However, there is currently no clear study to point out the appropriate range for oxygen saturation in patients with craniocerebral diseases. Methods By screening all patients in the MIMIC IV database, 3823 patients with craniocerebral diseases (according to ICD-9 codes and ICD-10) were selected, and non-linear regression was used to analyze the relationship between in-hospital mortality and oxygen saturation. Covariates for all patients included age, weight, diagnosis, duration of ICU stay, duration of oxygen therapy, etc. Results In-hospital mortality in patients with TBI and SAH was kept to a minimum when oxygen saturation was in the 94–96 range. And in all patients, the relationship between oxygen saturation and in-hospital mortality was U-shaped. Subgroup analysis of the relationship between oxygen saturation and mortality in patients with metabolic encephalopathy and other encephalopathy also draws similar conclusions In-hospital mortality and oxygen saturation were all U-shaped in patients with subarachnoid hemorrhage, metabolic and toxic encephalopathy, cerebral infarction, and other encephalopathy, but the nonlinear regression was statistically significant only in patients with cerebral infarction (p for nonlinearity = 0.002). Conclusion Focusing too much on the lower limit of oxygen saturation and ignoring too high oxygen saturation can also lead to increase in-hospital mortality. For patients with TBI and SAH, maintaining oxygen saturation at 94–96% will minimize the in-hospital mortality of patients.

Abstract Immunotherapy has dramatically revolutionized the therapeutic landscape for patients with cancer. Although immune checkpoint inhibitors are now accepted as effective anticancer therapies, they introduce a novel class of toxicity, termed immune‐related adverse events, which can lead to the temporary or permanent discontinuation of immunotherapy and life‐threatening tumor progression. Therefore, the effective prevention and treatment of immune‐related adverse events is a clinical imperative to maximize the utility of immunotherapies. Immune‐related adverse events are related to the intestinal microbiota, baseline gut microbiota composition is an important determinant of immune checkpoint inhibitor‐related colitis, and antibiotics exacerbate these undesirable side‐effects. Supplementation with specific probiotics reduces immune checkpoint inhibitor‐related colitis in mice, and fecal microbiota transplantation has now been shown to effectively treat refractory immune checkpoint inhibitor‐related colitis in the clinic. Hence, modifying the microbiota holds great promise for preventing and treating immune‐related adverse events. Microbiomes and their metabolites play important roles in the potential underlying mechanisms through interactions with both innate and adaptive immune cells. Here we review the gut microbiota and immune regulation; the changes occurring in the microbiota during immune checkpoint inhibitor therapy; the relationship between the microbiota and immune‐related adverse events, antibiotics, probiotics/prebiotics, and fecal microbiota transplantation in immune checkpoint inhibitor‐related colitis; and the protective mechanisms mediated by the microbiome and metabolites in immune‐related adverse events.

Background and Aims: Embryo quality is directly related to pregnancy rate as previously demonstrated by CHLOE-EQ. CHLOE-EQ Score is an automatic embryo viability score provided by CHLOE (Fairtility). It might provide key performance indicators (KPI) to measure how different protocols impact embryo quality. KPIs are objective measures for systematically monitoring and evaluating the IVF laboratory, a critical element of every IVF clinic Quality Management System. KPIs currently rely on definitions which are simple to assess (fertilisation, cleavage, blastulation), we do not routinely use other biomarkers to monitor operations. The aim of the study was to assess how trigger protocols influence CHLOE-EQ embryo viability score. Method: Retrospective comparative analysis with 1684 time-lapse videos collected between February-June 2022 in a single private clinic. Embryos were automatically assessed by CHLOE-EQ, an AI embryologist support tool. Assessment of trigger protocol, CHLOE-EQ Score and demographic bias was measured using t-test. Results: Embryos derived from cycles triggered with Triptorelin had better quality than those triggered with HCG (CHLOE EQ Score: 3.4±4.03, n=524 vs 3.02±3.85, n=1127, p=0.03). The difference could not be explained by age, PCOS, low ovarian reserve, fibroids, polyps. However, the type of trigger did not affect embryo utilisation [250/524 (47.70% vs 485/1127(43.03%), p>0.05]. CHLOE-EQ Score is predictive of utilisation (AUC=0.88, n=1677, baseline=45%, p

To obtain the characteristics of the gas hydrate reservoirs at GMGS3-W19, extensive geophysical logging data and cores were analyzed to assess the reservoir properties. Sediment porosities were estimated from density, neutron, and nuclear magnetic resonance (NMR) logs. Both the resistivity and NMR logs were used to calculate gas hydrate saturations, the Simandoux model was employed to eliminate the effects of high clay content determined based on the ECS and core data. The density porosity was closely in agreement with the core-derived porosity, and the neutron porosity was higher while the NMR porosity was lower than the density porosity of sediments without hydrates. The resistivity log has higher vertical resolution than the NMR log and thus is more favorable for assessing gas hydrate saturation with strong heterogeneity. For the gas hydrate reservoirs at GMGS3-W19, the porosity, gas hydrate saturation and free gas saturation was 52.7%, 42.7% and 10%, on average, respectively. The various logs provide different methods for the comprehensive evaluation of hydrate reservoir, which supports the selection of candidate site for gas hydrate production testing.©2022 China Geology Editorial Office.

Abstract SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl− is a crucial regulator of host defense, whereas the role of Cl− signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl− concentration ([Cl−]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl−]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl−]i. Our findings suggested that Cl− acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl− signaling pathway might be a novel therapeutic strategy for COVID-19.