Effectiveness and safety of rivaroxaban for anticoagulation therapy in COVID-19: A meta-analysis of randomized controlled trials.

OBJECTIVES: To evaluate the effectiveness and safety of rivaroxaban anticoagulation in COVID-19 patients. METHODS: PubMed, Embase, Cochrane Library electronic databases, and ClinicalTrials.gov were searched to identify all relevant randomized controlled trial studies from December 2019 to July 2023. RESULTS: A total of 6 randomized controlled trials, which included a total of 3323 patients, were considered for evaluation. Overall, short-term all-cause mortality and hospitalization rates were not significantly different between the rivaroxaban and control groups. Thrombotic events were significantly reduced in the rivaroxaban prophylaxis group compared to the placebo control group. However, the reduction in thrombotic events was not significantly different between rivaroxaban therapy and heparin or low-molecular-weight heparin (LMWH). Rivaroxaban prophylaxis and the therapeutic dose may be associated with a higher rate of overall bleeding rate, but major bleeding rates did not differ substantially. CONCLUSION: Rivaroxaban may reduce thrombotic events in COVID-19 patients, but it does not appear to have an advantage over heparin or LMWH, and it may increase the risk of bleeding.INPLASY Reg. No.: INPLASY 202370097.

Advances in management of metabolic dysfunction-associated steatotic liver disease: from mechanisms to therapeutics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease that affects over 30% of the world's population. For decades, the heterogeneity of non-alcoholic fatty liver disease (NAFLD) has impeded our understanding of the disease mechanism and the development of effective medications. However, a recent change in the nomenclature from NAFLD to MASLD emphasizes the critical role of systemic metabolic dysfunction in the pathophysiology of this disease and therefore promotes the progress in the pharmaceutical treatment of MASLD. In this review, we focus on the mechanism underlying the abnormality of hepatic lipid metabolism in patients with MASLD, and summarize the latest progress in the therapeutic medications of MASLD that target metabolic disorders.

Airborne atmospheric carbon dioxide measurement using 1.5 µm laser double-pulse IPDA lidar over a desert area.

An integrated path differential absorption (IPDA) lidar can accurately measure regional C O 2 weighted column average concentrations (X C O 2), which are crucial for understanding the carbon cycle in climate change studies. To verify the performance and data inversion methods of space-borne IPDA lidar, in July 2021, we conducted an airborne lidar validation experiment in Dunhuang, Gansu Province, China. An aircraft was equipped with a lidar system developed to measure X C O 2 and an in situ greenhouse gas analyzer (GGA). To minimize measurement errors, energy monitoring was optimized. The system bias error of the DAOD was determined by changing the laser output mode from the off/on to the on/on mode. The X C O 2 inversion results obtained through comparing the schemes of averaging signals before "log (logarithm)" and averaging after "log" indicate that the former performs better. The IPDA lidar measured X C O 2 over the validation site at 405.57 ppm, and both the IPDA lidar and GGA measured sudden changes in the C O 2 concentration. The assimilation data showed a similar trend according to the altitude to the data measured by the in situ instrument. A comparison of the mean X C O 2 derived from the GGA results and assimilation data with the IPDA lidar measurements showed biases of 0.80 and 1.12 ppm, respectively.

Association of vitamin D deficiency and subclinical diabetic peripheral neuropathy in type 2 diabetes patients.

Background: Diabetic peripheral neuropathy (DPN) contributes to disability and imposes heavy burdens, while subclinical DPN is lack of attention so far. We aimed to investigate the relationship between vitamin D and distinct subtypes of subclinical DPN in type 2 diabetes (T2DM) patients. Methods: This cross-sectional study included 3629 T2DM inpatients who undertook nerve conduction study to detect subclinical DPN in Zhongshan Hospital between March 2012 and December 2019. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25(OH)D) level < 50 nmol/L. Results: 1620 (44.6%) patients had subclinical DPN and they were further divided into subgroups: distal symmetric polyneuropathy (DSPN) (n=685), mononeuropathy (n=679) and radiculopathy (n=256). Compared with non-DPN, DPN group had significantly lower level of 25(OH)D (P < 0.05). In DPN subtypes, only DSPN patients had significantly lower levels of 25(OH)D (36.18 ± 19.47 vs. 41.03 ± 18.47 nmol/L, P < 0.001) and higher proportion of vitamin D deficiency (78.54% vs. 72.18%, P < 0.001) than non-DPN. Vitamin D deficiency was associated with the increased prevalence of subclinical DPN [odds ratio (OR) 1.276, 95% confidence interval (CI) 1.086-1.501, P = 0.003] and DSPN [OR 1. 646, 95% CI 1.31-2.078, P < 0.001], independent of sex, age, weight, blood pressure, glycosylated hemoglobin, T2DM duration, calcium, phosphorus, parathyroid hormone, lipids and renal function. The association between vitamin D deficiency and mononeuropathy or radiculopathy was not statistically significant. A negative linear association was observed between 25(OH)D and subclinical DSPN. Vitamin D deficiency maintained its significant association with subclinical DSPN in all age groups. Conclusions: Vitamin D deficiency was independently associated with subclinical DSPN, rather than other DPN subtypes.

Characterization of sodium alginate-carrageenan films prepared by adding peanut shell flavonoids as an antioxidant: Application in chilled pork preservation.

This study prepared and characterized sodium alginate and carrageenan (SAC) composite films incorporated with peanut shell flavonoids (PSFs). PSFs compound identification research was implemented. The physicochemical features of PSFs-SAC composite films and their ability to preserve chilled pork in a 4 °C refrigerator were determined. PSFs consist of luteolin, eriodictyol, 5,7-dihydroxychromone, and 8 other components. They significantly improved the mechanical properties, barrier properties, thermal stability, and antioxidant properties of SAC composite films (P < 0.05). PSFs were also responsible for increasing the density of the film structure between the sodium alginate and carrageenan molecules. During storage, compared with the control group, the prepared PSFs-SAC composite films did not allow the total viable count (TVC), pH and total volatile base nitrogen (TVB-N) of the chilled pork to increase rapidly. Further, they were able to inhibit lipid oxidation more effectively (P < 0.05). For these reasons, the use of the PSFs-SAC composite films prolonged shelf life of chilled pork from 6 days to the 12 days. Therefore, PSFs-SAC composite films are expected to be used as bioactive substances in food preservation.

The physiological response of the clam Ruditapes philippinarum and scallop Chlamys farreri to varied concentrations of microplastics exposure.

Microplastics (MPs) pollution's impact on the marine ecosystem is widely recognized. This study compared the effects of polyethylene (PE) and polyethylene terephthalate (PET) on two bivalve species, Ruditapes philippinarum (clam) and Chlamys farreri (scallop), at two particle concentrations (10 and 1000 µg/L). MPs were found in the digestive glands and gills of both species. Although clearance rates showed no significant changes, exposure to different MPs caused oxidative stress, energy disruption, and lipid metabolism disorders in both clam and scallop. Histopathological damage was observed in gills and digestive glands. IBR values indicated increasing toxicity with concentration, with PET being more toxic than PE. WOE model suggested increasing hazard with concentration, highlighting higher PET toxicity on clam digestive glands. In contrast, PE hazard increased in gills, showing different species responses. R. philippinarum exhibited higher sensitivity to MPs than C. farreri, providing insights for assessing ecological risk under realistic conditions and stress conditions.

Predictive Values of Homeobox Gene A-Antisense Transcript 3 (HOXA-AS3), Cystatin 6 (CST6), and Chromobox Homolog 4 (CBX4) Expressions in Cancer Tissues for Recurrence of Early Colon Cancer After Surgery.

Purpose: We aim to explore the predictive values of homeobox gene A-antisense transcript 3 (HOXA-AS3), cystatin 6 (CST6), and chromobox homolog 4 (CBX4) expressions in cancer tissues for the recurrence of early colon cancer after surgery. Patients and Methods: A total of 136 patients who received surgery from January 2020 to January 2021 were enrolled and followed up for 24 months to observe the recurrence after surgery, based on which they were assigned into recurrence and non-recurrence groups. All patients underwent a histopathological examination on admission. Results: The recurrence group had a lower degree of differentiation as well as a higher HOXA-AS3 level and CST6 and CBX4 expression scores than those of the non-recurrence group (P<0.05). HOXA-AS3 level, CST6 expression score, and CBX4 expression score were risk factors for the recurrence of early colon cancer after surgery [odds ratio (OR)>1, P<0.05]. The receiver operating characteristic curve analysis showed that the areas under the curves of HOXA-AS3 level, CST6 expression score, CBX4 expression score, and their combination for predicting recurrence were 0.909 [95% confidence interval (95% CI): 0.785-1.000], 0.819 (95% CI: 0.690-0.948), 0.794 (95% CI: 0.663-0.926), and 0.942 (95% CI: 0.882-1.000), respectively. Conclusion: The expressions of HOXA-AS3, CST6, and CBX4 in cancer tissues have close correlations with the recurrence of early colon cancer after surgery and are thus of high predictive values.

DiffDomain enables identification of structurally reorganized topologically associating domains.

Topologically associating domains (TADs) are critical structural units in three-dimensional genome organization of mammalian genome. Dynamic reorganizations of TADs between health and disease states are associated with essential genome functions. However, computational methods for identifying reorganized TADs are still in the early stages of development. Here, we present DiffDomain, an algorithm leveraging high-dimensional random matrix theory to identify structurally reorganized TADs using high-throughput chromosome conformation capture (Hi-C) contact maps. Method comparison using multiple real Hi-C datasets reveals that DiffDomain outperforms alternative methods for false positive rates, true positive rates, and identifying a new subtype of reorganized TADs. Applying DiffDomain to Hi-C data from different cell types and disease states demonstrates its biological relevance. Identified reorganized TADs are associated with structural variations and epigenomic changes such as changes in CTCF binding sites. By applying to a single-cell Hi-C data from mouse neuronal development, DiffDomain can identify reorganized TADs between cell types with reasonable reproducibility using pseudo-bulk Hi-C data from as few as 100 cells per condition. Moreover, DiffDomain reveals differential cell-to-population variability and heterogeneous cell-to-cell variability in TADs. Therefore, DiffDomain is a statistically sound method for better comparative analysis of TADs using both Hi-C and single-cell Hi-C data.

Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis.

Inter-organ crosstalk has gained increasing attention in recent times; however, the underlying mechanisms remain unclear. In this study, we elucidate an endocrine pathway that is regulated by skeletal muscle interferon regulatory factor (IRF) 4, which manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice exhibited ameliorated hepatic steatosis, inflammation, and fibrosis, without changes in body weight, when put on a nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis results suggested that follistatin-like protein 1 (FSTL1) may constitute a link between muscles and the liver. Dual luciferase assays showed that IRF4 can transcriptionally regulate FSTL1. Further, inducing FSTL1 expression in the muscles of F4MKO mice is sufficient to restore liver pathology. In addition, co-culture experiments confirmed that FSTL1 plays a distinct role in various liver cell types via different receptors. Finally, we observed that the serum FSTL1 level is positively correlated with NASH progression in humans. These data indicate a signaling pathway involving IRF4-FSTL1-DIP2A/CD14, that links skeletal muscle cells to the liver in the pathogenesis of NASH.

Synthesis, Activity, and Application of Fluorescent Analogs of [D1G, Δ14Q]LvIC Targeting α6ß4 Nicotinic Acetylcholine Receptor.

α6ß4* nicotinic acetylcholine receptor (nAChR) (* represents the possible presence of additional subunits) is mainly distributed in the central and peripheral nervous system and is associated with neurological diseases, such as neuropathic pain; however, the ability to explore its function and distribution is limited due to the lack of pharmacological tools. As one of the analogs of α-conotoxin (α-CTx) LvIC from Conus lividus, [D1G, Δ14Q]LvIC (Lv) selectively and potently blocks α6/α3ß4 nAChR (α6/α3 represents a chimera). Here, we synthesized three fluorescent analogs of Lv by connecting fluorescent molecules 6-carboxytetramethylrhodamine succinimidyl ester (6-TAMRA-SE, R), Cy3 NHS ester (Cy3, C) and BODIPY-FL NHS ester (BDP, B) to the N-terminus of the peptide and obtained Lv-R, Lv-C, and Lv-B, respectively. The potency and selectivity of three fluorescent peptides were evaluated using two-electrode voltage-clamp recording on nAChR subtypes expressed in Xenopus laevis oocytes, and the potency and selectivity of Lv-B were almost maintained with the half-maximal inhibition (IC50) of 64 nM. Then, we explored the stability of Lv-B in artificial cerebrospinal fluid and stained rat brain slices with Lv-B. The results indicated that the stability of Lv-B was slightly improved compared to that of native Lv. Additionally, we detected the distribution of the α6ß4* nAChR subtype in the cerebral cortex using green fluorescently labeled peptide and fluorescence microscopy. Our findings not only provide a visualized pharmacological tool for exploring the distribution of the α6ß4* nAChR subtype in various situ tissues and organs but also extend the application of α-CTx [D1G, Δ14Q]LvIC to demonstrate the involvement of α6ß4 nAChR function in pathophysiology and pharmacology.

Structure-Activity Relationships of Alanine Scan Mutants αO-Conotoxins GeXIVA[1,2] and GeXIVA[1,4].

αO-Conotoxin GeXIVA is a selective α9α10 nicotinic acetylcholine receptor (nAChR) inhibitor displaying two disulfide bonds that can form three isomers. The bead (GeXIVA[1,2]) and ribbon (GeXIVA[1,4]) isomers possess the highest activity on rat and human α9α10 nAChRs. However, the molecular mechanism by which they inhibit the α9α10 nAChR is unknown. Here, an alanine scan of GeXIVA was used to elucidate key interactions between the peptides and the α9α10 nAChR. The majority of GeXIVA[1,2] analogues preserved affinity at α9α10 nAChR, but [R17A]GeXIVA[1,2] enhanced selectivity on the α9α10 nAChR. The I23A replacement of GeXIVA[1,4] increased activity at both rat and human α9α10 nAChRs by 10-fold. Surprisingly, these results do not support the molecular model of an interaction in the orthosteric binding site proposed previously, but rather may involve allosteric coupling with the voltage-sensitive domain of the α9α10 nAChR. These results could help to guide further development of GeXIVA analogues as analgesics.

Mitogenome Characterization of Four Conus Species and Comparative Analysis.

Cone snails, as a type of marine organism, have rich species diversity. Traditionally, classifications of cone snails were based mostly on radula, shell, and anatomical characters. Because of these phenotypic features' high population variability and propensity for local adaptation and convergence, identifying species can be difficult and occasionally inaccurate. In addition, mitochondrial genomes contain high phylogenetic information, so complete mitogenomes have been increasingly employed for inferring molecular phylogeny. To enrich the mitogenomic database of cone snails (Caenogastropoda: Conidae), mitogenomes of four Conus species, i.e., C. imperialis (15,505 bp), C. literatus (15,569 bp), C. virgo (15,594 bp), and C. marmoreus (15,579 bp), were characterized and compared. All 4 of these mitogenomes included 13 protein-coding genes, 2 ribosomal RNA genes, 22 tRNA genes, and non-coding regions. All the Protein Codon Genes (PCGs) of both newly sequenced mitogenomes used TAA or TAG as a terminal codon. Most PCGs used conventional start codon ATG, but an alternative initiation codon GTG was detected in a gene (NADH dehydrogenase subunit 4 (nad4)) of C. imperialis. In addition, the phylogenetic relationships were reconstructed among 20 Conus species on the basis of PCGs, COX1, and the complete mitogenome using both Bayesian Inference (BI) and Maximum Likelihood (ML). The phylogenetic results supported that C. litteratus, C. quercinus, and C. virgo were clustered together as a sister group (PP = 1, BS = 99), but they did not support the phylogenetic relation of C. imperialis and C. tribblei (PP = 0.79, BS = 50). In addition, our study established that PCGs and complete mitogenome are the two useful markers for phylogenetic inference of Conus species. These results enriched the data of the cone snail's mitochondrion in the South China Sea and provided a reliable basis for the interpretation of the phylogenetic relationship of the cone snail based on the mitochondrial genome.

Combined effects of salinity and polystyrene microplastics exposure on the Pacific oysters Crassostrea gigas: Oxidative stress and energy metabolism.

Microplastics (MPs) pollution and salinity variation are two environmental stressors, but their combined effects on marine mollusks are rarely known. Oysters (Crassostrea gigas) were exposed to 1 × 104 particles L-1 spherical polystyrene MPs (PS-MPs) of different sizes (small polystyrene MPs (SPS-MPs): 6 µm, large polystyrene MPs (LPS-MPs): 50-60 µm) under three salinity levels (21, 26, and 31 psu) for 14 days. Results demonstrated that low salinity reduced PS-MPs uptake in oysters. Antagonistic interactions between PS-MPs and low salinity mainly occurred, and partial synergistic effects were mainly induced by SPS-MPs. SPS-MPs induced higher lipid peroxidation (LPO) levels than LPS-MPs. In digestive glands, low salinity decreased LPO levels and glycometabolism-related gene expression, which was related to salinity levels. Low salinity instead of MPs mainly affected metabolomics profiles of gills through energy metabolism and osmotic adjustment pathway. In conclusion, oysters can adapt to combined stressors through energy and antioxidative regulation.

Potential Mechanisms of Metformin-Induced Apoptosis in HeLa Cells.

Metformin is a traditional antidiabetic drug that also shows potential antitumor effects in cervical cancer. However, some of its apoptosis-related mechanisms are still unclear. In this study, flow cytometry, western blotting, and RNA sequencing (RNA-seq) were used to evaluate the molecular mechanisms of metformin in HeLa cells. The results showed that metformin inhibited cell viability and promoted apoptosis, the protein expression level of Caspase-3 (CASP3) was increased and that of BCL-2 was decreased in HeLa cells treated with metformin. The RNA-seq results indicated a total of 239 differentially expressed genes between the metformin and control check (CK) groups, with 136 genes upregulated and 103 genes downregulated, and 14 of them were found to be associated with apoptosis signaling pathways. The DDIT3 and HRK genes were robustly upregulated in HeLa cells by the endoplasmic reticulum (ER) stress and the mitochondrial pathway of apoptosis. Metformin also affects the expression of PPP2R5C, PPP2R5A, and RRAGA, which participate in biological processes such as PI3K-AKT, mTOR, and AMPK signaling pathways. Metformin mediates the expression of related genes to induce apoptosis.

Substitution of D-Arginine at Position 11 of α-RgIA Potently Inhibits α7 Nicotinic Acetylcholine Receptor.

Conotoxins are a class of disulfide-rich peptides found in the venom of cone snails, which have attracted considerable attention in recent years due to their potent activity on ion channels and potential for therapeutics. Among them, α-conotoxin RgIA, a 13-residue peptide, has shown great promise as a potent inhibitor of α9α10 nAChRs for pain management. In this study, we investigated the effect of substituting the naturally occurring L-type arginine at position 11 of the RgIA sequence with its D-type amino acid. Our results indicate that this substitution abrogated the ability of RgIA to block α9α10 nAChRs, but instead endowed the peptide with the ability to block α7 nAChR activity. Structural analyses revealed that this substitution induced significant alteration of the secondary structure of RgIA[11r], which consequently affected its activity. Our findings underscore the potential of D-type amino acid substitution as a promising strategy for designing novel conotoxin-based ligands targeting different types of nAChRs.

Effect of the number of unhealthy lifestyles in middle-aged and elderly people on hypertension and the first occurrence of ischemic stroke after the disease.

Background: To determine the relationship between the number of controllable unhealthy lifestyles on the risk of the first occurrence of ischemic stroke after the disease in middle-aged and elderly people in the community, and to provide data support and basis for community physicians to guide hypertensive patients to control modifiable risk factors to prevent the first occurrence of ischemic stroke. Methods: The relationship between the number of unhealthy lifestyles and the risk of hypertension was analyzed by binary logistic regression in 584 subjects using a medical record control study. A retrospective cohort study of 629 hypertensive patients was used to analyze the relationship between the number of unhealthy lifestyles and the risk of the first occurrence of ischemic stroke within 5 years of developing hypertensive disease using Cox proportional risk regression models. Results: Logistic regression model analysis showed that taking an unhealthy lifestyle as a reference, the OR (95% CI) values of, 2, 3, 4 and 5 unhealthy lifestyle were 4.050 (2.595-6.324), 4 (2.251-7.108), 9.297 (3.81-22.686), and 16.806 (4.388-64.365), respectively. Cox Proportional risk regression model analysis showed that the risk of ischemic stroke within 5 years after developing hypertension was referenced to 5 unhealthy lifestyles, and the HR (95% CI) for 3, 2, and 1 unhealthy lifestyle were 0.134 (0.023-0.793), 0.118 (0.025-0.564), and 0.046 (0.008-0.256), respectively. Conclusion: The number of controllable unhealthy lifestyles in middle-aged and elderly people was positively associated with the risk of hypertension and first ischemic stroke after hypertension, and there was a dose-effect relationship between them. The risk of hypertension and first ischemic stroke within 5 years after hypertension onset increased with the number of unhealthy lifestyles.

Circ-PDZD8 promotes cell growth and glutamine metabolism in non-small cell lung cancer by enriching LARP1 via sequestering miR-330-5p.

BACKGROUND: The deregulation of circular RNA (circRNA) is widely reported in carcinogenesis. The purpose of this study was to investigate the role of circRNA-PDZ domain containing 8 (circ-PDZD8) in non-small cell lung cancer (NSCLC) progression. METHODS: The histological structure of tissues was identified by hematoxylin-eosin (HE) staining analysis. The expression levels of circ-PDZD8, miR-330-5p and la ribonucleoprotein 1 (LARP1) mRNA were ascertained by qPCR. Cell counting kit-8, colony formation, flow cytometry, and transwell assays were employed for functional analysis. Glutamine metabolism was monitored by glutamine consumption, alpha ketoglutarate (α-KG) level and adenosine triphosphate (ATP) level. A xenograft model was established to ascertain the role of circ-PDZD8 in vivo. The putative binding relationships were verified by dual-luciferase and RIP studies. RESULTS: Circ-PDZD8 expression was highly increased in NSCLC. Circ-PDZD8 knockdown inhibited cell growth, migratory capacity, invasiveness and glutamine metabolism but enhanced cell apoptosis in NSCLC cells. Circ-PDZD8 blocked miR-330-5p expression, and miR-330-5p inhibition overturned the effects of circ-PDZD8 absence. LARP1 targeted by miR-330-5p, and miR-330-5p upregulation-impaired cell growth, motility and glutamine metabolism were recovered by LARP1 overexpression. Circ-PDZD8 knockdown was also shown to impede solid tumor growth. CONCLUSION: Circ-PDZD8 promotes NSCLC cell growth and glutamine metabolism by increasing LARP1 via competitively targeting miR-330-5p.

Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID.

α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3ß4 and rα6/α3ß4 nicotinic acetylcholine receptors (nAChRs) with IC50 values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants [+9A]TxID, [+10A]TxID, [+14A]TxID, and all the 4/5-subfamily mutants against rα3ß4 and rα6/α3ß4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs.