BioM2: biologically informed multi-stage machine learning for phenotype prediction using omics data.

Navigating the complex landscape of high-dimensional omics data with machine learning models presents a significant challenge. The integration of biological domain knowledge into these models has shown promise in creating more meaningful stratifications of predictor variables, leading to algorithms that are both more accurate and generalizable. However, the wider availability of machine learning tools capable of incorporating such biological knowledge remains limited. Addressing this gap, we introduce BioM2, a novel R package designed for biologically informed multistage machine learning. BioM2 uniquely leverages biological information to effectively stratify and aggregate high-dimensional biological data in the context of machine learning. Demonstrating its utility with genome-wide DNA methylation and transcriptome-wide gene expression data, BioM2 has shown to enhance predictive performance, surpassing traditional machine learning models that operate without the integration of biological knowledge. A key feature of BioM2 is its ability to rank predictor variables within biological categories, specifically Gene Ontology pathways. This functionality not only aids in the interpretability of the results but also enables a subsequent modular network analysis of these variables, shedding light on the intricate systems-level biology underpinning the predictive outcome. We have proposed a biologically informed multistage machine learning framework termed BioM2 for phenotype prediction based on omics data. BioM2 has been incorporated into the BioM2 CRAN package (https://cran.r-project.org/web/packages/BioM2/index.html).

Transcription factor PbNAC71 regulates xylem and vessel development to control plant height.

Dwarfism is an important agronomic trait in fruit breeding programs. However, the germplasm resources required to generate dwarf pear (Pyrus spp.) varieties are limited. Moreover, the mechanisms underlying dwarfism remain unclear. In this study, "Yunnan" quince (Cydonia oblonga Mill.) had a dwarfing effect on "Zaosu" pear. Additionally, the dwarfism-related NAC transcription factor gene PbNAC71 was isolated from pear trees comprising "Zaosu" (scion) grafted onto "Yunnan" quince (rootstock). Transgenic Nicotiana benthamiana and pear OHF-333 (Pyrus communis) plants overexpressing PbNAC71 exhibited dwarfism, with a substantially smaller xylem and vessel area relative to the wild-type controls. Yeast one-hybrid, dual-luciferase, chromatin immunoprecipitation-qPCR, and electrophoretic mobility shift assays indicated that PbNAC71 downregulates PbWalls are thin 1 expression by binding to NAC-binding elements in its promoter. Yeast two-hybrid assays showed that PbNAC71 interacts with the E3 ubiquitin ligase PbRING finger protein 217 (PbRNF217). Furthermore, PbRNF217 promotes the ubiquitin-mediated degradation of PbNAC71 by the 26S proteasome, thereby regulating plant height as well as xylem and vessel development. Our findings reveal a mechanism underlying pear dwarfism and expand our understanding of the molecular basis of dwarfism in woody plants.

Exploring the protective role of Bacillus velezensis BV1704-Y in zebrafish health and disease resistance against Aeromonas hydrophila infection.

Bacillus genus, particularly Bacillus velezensis, is increasingly considered as viable alternatives to antibiotics in aquaculture due to their safety and probiotic potential. However, the specific mechanisms through which probiotic B. velezensis confers protection against Aeromonas hydrophila infection in fish remain poorly understood. This study delved into the multifaceted impacts of B. velezensis BV1704-Y on diverse facets of zebrafish health, including gut barrier function, immune response, oxidative stress, gut environment, microbiome composition, and disease resistance. Our findings demonstrate that supplementation with B. velezensis BV1704-Y significantly alleviated symptoms and reduced mortality in zebrafish infected with A. hydrophila. Furthermore, a notable reduction in the expression of pivotal immune-related genes, such as IL-1ß, IL6, and TNF-α, was evident in the gut and head kidney of zebrafish upon infection. Moreover, B. velezensis BV1704-Y supplementation resulted in elevated activity levels of essential antioxidant enzymes, including SOD, CAT, and GSH, in gut tissue. Notably, B. velezensis BV1704-Y positively modulated the structure and function of the intestinal microbiome, potentially enhancing immune response and resilience in zebrafish. Specifically, supplementation with B. velezensis BV1704-Y promoted the relative abundance of beneficial bacteria, such as Cetobacterium, which showed a noteworthy negative correlation with the expression of pro-inflammatory genes and a positive correlation with gut barrier-related genes. Altogether, our study suggests that B. velezensis BV1704-Y holds promise as an effective probiotic for protecting zebrafish against A. hydrophila infection, offering potential benefits for the aquaculture industry.

Catechol compounds as dual-targeting agents for fish protection against Ichthyophthirius multifiliis infections.

Aquaculture is one of the fastest growing sectors in global food production, recognized as a significant contributor to poverty alleviation, food security, and income generation. However, the frequent occurrence of diseases caused by pathogen infections result in reduced yields and economic losses, posing a substantial constraint to the sustainable development of aquaculture. Here, our study identified that four catechol compounds, quercetin, luteolin, caffeic acid, and chlorogenic acid, exhibited potent antiparasitic effects against Ichthyophthirius multifiliis in both, in vitro and in vivo. The parasite is recognized as one of the most pathogenic to fish worldwide. Using a combination of in silico methods, the dipeptidyl peptidase (DPP) was identified as a critical target for catechol compounds. The two hydroxyl radicals of the catechol group were essential for its binding to and interacting with the DPP protein. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that catechol compounds disrupt pathways associated with the metabolism and growth of I. multifiliis, thereby exerting antiparasitic effects. Furthermore, these compounds attenuated the expression of proinflammatory cytokines in vivo in fish and promoted macrophage polarization toward M2 phenotype by inhibiting the STAT1 signaling pathway. The dual activity of catechol compounds, acting as both direct antiparasitic and anti-inflammatory agents in fish, offers a promising therapeutic approach for combating I. multifiliis infections in aquaculture.

Intestinal epithelial Krüppel-like factor 4 alleviates endotoxemia and atherosclerosis through improving NF-κB/miR-34a-mediated intestinal permeability.

Maintenance of intestinal barrier function contributes to gastrointestinal homeostasis and therefore cardiovascular diseases. A number of studies show that intestinal permeability is affected by excessive inflammatory responses. Krüppel-like factor (KLF) 4 is one of the critical transcriptional factors, which controls multiple immune responses. In this study we investigated the role of KLF4 in regulating intestinal inflammation and permeability during the atherosclerotic process. Atherosclerotic model was established in ApoE-/- mice by feeding a high fat high cholesterol (HFHC) diet. We showed that colon expression levels of KLF4 and tight junction proteins were significantly decreased whereas inflammatory responses increased in atherosclerotic mice. Overexpression of colon epithelial Klf4 decreased atherosclerotic plaque formation and vascular inflammation in atherosclerotic mice, accompanied by remarkable suppression of intestinal NF-κB activation. We found that overexpression of epithelial Klf4 in atherosclerotic mice significantly increased intestinal tight junction expression and ameliorated endotoxemia, whereas replenishment of LPS abolished these benefits. Overexpression of Klf4 reversed LPS-induced permeability and downregulation of ZO-1 and Occludin in Caco-2 cells in vitro. HFHC diet stimulated the expression of epithelial microRNA-34a, whereas silence of epithelial Klf4 abolished the benefits of microRNA-34a sponge, a specific miR-34a inhibitor, on intestinal permeability and atherosclerotic development. A clinical cohort of 24 atherosclerotic patients supported colon KLF4/NF-κB/tight junction protein axis mediated intestine/cardiovascular interaction in patients with atherosclerosis. Taken together, intestinal epithelial KLF4 protects against intestinal inflammation and barrier dysfunction, ameliorating atherosclerotic plaque formation.

Tight focusing of the vector optical field with polarization varying along complex curves of the Poincaré sphere.

Different from the scalar optical field with spatially uniform polarization, the vector optical field exhibits inhomogeneous distribution of polarization on the cross section. Manipulating the variation of polarization in a single optical beam is important to acquire a flexible and controllable focused optical field. Previous studies mainly focused on the vector optical field with its polarization varying along a circular trajectory of the Poincaré sphere. Here, we demonstrate the tight focusing behaviors of the vector optical field with the polarization varying along complex curves of the Poincaré sphere, which is generated by the joint modulation of azimuthal phase and amplitude distributions of orthogonally polarized components. The longitudinal polarization component with a multipolar pattern in rotational symmetry can be achieved with similar distribution of the total focused field. The transverse and longitudinal spin angular momentum distributions in the focal space are discussed. Approximately pure transverse spin angular momentum can be constructed and manipulated in the focal space, which provides the possibility to manipulate the 3D spin flux for the applications of nano and spin photonics.

Natural product honokiol exhibits antiviral effects against Micropterus salmoides rhabdovirus (MSRV) both in vitro and in vivo.

Micropterus salmoides rhabdovirus (MSRV) is a formidable pathogen, presenting a grave menace to juvenile largemouth bass. This viral infection frequently leads to epidemic outbreaks, resulting in substantial economic losses within the aquaculture industry. Unfortunately, at present, there are no commercially available vaccines or pharmaceutical treatments to combat this threat. In order to address the urgent need for therapeutic strategy to resist MSRV infection, the antiviral activity of natural product honokiol against MSRV was explored in this study. Firstly, cellular morphology was directly observed in an inverted microscope when treated with honokiol after MSRV infection. The results clarified that honokiol significantly lessened cytopathic effect (CPE) induced by MSRV and protected the integrity of GCO cells. Furthermore, the viral nucleic acid expression (G gene) was detected by reverse transcription real-time quantitative PCR (RT-qPCR) and the results indicated that honokiol significantly decreased the viral loads of MSRV in a concentration-dependent manner, and honokiol showed a high antiviral activity with IC50 of 2.92 µM. Besides, honokiol significantly decreased the viral titre and suppressed apoptosis caused by MSRV. Mechanistically, honokiol primarily inhibited the initial replication of MSRV and discharge of progeny virus to exert anti-MSRV activity. More importantly, in vivo experiments suggested that honokiol (40 mg/kg) expressed a fine antiviral activity against MSRV when administrated with intraperitoneal injection, which led to a notable 40% improvement in the survival rate among infected largemouth bass. In addition, it also resulted in significant reduction in the viral nucleic acid expression within liver, spleen and kidney at 2, 4 and 6 days following infection. What is more, 100 mg/kg honokiol with oral administration also showed certain antiviral efficacy in MSRV-infected largemouth bass via improving the survival rate by 10.0%, and decreasing significantly the viral nucleic acid expression in liver, spleen and kidney of largemouth bass on day 2. In summary, natural product honokiol is a good candidate to resist MSRV infection and has promising application prospects in aquaculture.

Enterobacteriaceae as a Key Indicator of Huanglongbing Infection in Diaphorina citri.

Extensive microbial interactions occur within insect hosts. However, the interactions between the Huanglongbing (HLB) pathogen and endosymbiotic bacteria within the Asian citrus psyllid (ACP, Diaphorina citri Kuwayama) in wild populations remain elusive. Thus, this study aimed to detect the infection rates of HLB in the ACP across five localities in China, with a widespread prevalence in Ruijin (RJ, 58%), Huidong (HD, 28%), and Lingui (LG, 15%) populations. Next, microbial communities of RJ and LG populations collected from citrus were analyzed via 16S rRNA amplicon sequencing. The results revealed a markedly higher microbial diversity in the RJ population compared to the LG population. Moreover, the PCoA analysis identified significant differences in microbial communities between the two populations. Considering that the inter-population differences of Bray-Curtis dissimilarity in the RJ population exceeded those between populations, separate analyses were performed. Our findings indicated an increased abundance of Enterobacteriaceae in individuals infected with HLB in both populations. Random forest analysis also identified Enterobacteriaceae as a crucial indicator of HLB infection. Furthermore, the phylogenetic analysis suggested a potential regulatory role of ASV4017 in Enterobacteriaceae for ACP, suggesting its possible attractant activity. This research contributes to expanding the understanding of microbial communities associated with HLB infection, holding significant implications for HLB prevention and treatment.

Development of an imidazole-based N,N-bidentate ligand for the manganese catalyzed direct coupling of nitriles with alcohols.

3d-Metal catalyzed borrowing hydrogen (BH) reactions represent powerful and environmentally friendly approaches for the direct coupling of alcohols with nitriles to assemble various important branched nitriles. The development of simple and efficient ligands is a crucial issue in this field. In this study, we designed a series of readily available N,N-bidentate ligands that demonstrated good efficiency in the Mn-catalyzed BH reaction of alcohols and nitrile derivatives, yielding the targeted nitriles in moderate to good yields. Remarkably, the mildness and practicality of this protocol were further demonstrated by the successful synthesis of anipamil via a two-cascade borrowing hydrogen procedure.

Structure-based discovery of potent myosin inhibitors to guide antiparasite drug development.

Monogenea, a prevalent parasite in aquaculture, poses significant threats to the industry, leading to substantial losses. Current preventive measures have proven insufficient, necessitating the development of novel and effective anti-parasitic drugs. In this investigation, we obtained the full-length myosin cDNA sequence by analyzing three-generation transcriptome data, revealing a 5817-base sequence encoding 1938 amino acids. Subsequently, we modeled and analyzed the characteristics of the secondary and tertiary of myosin, pinpointing the crucial functional region within the motor domain (amino acids 1-768). The prokaryotic expression of this domain yielded a protein of 87.44 kDa, confirmed as myosin by Western Blotting. Molecular docking identified ASN439 as the key amino acid residue involved in arctigenin and myosin binding, a result corroborated by site-directed mutagenesis, affirming the active cavity of this interaction. Chalcone and shikonin were chosen from a virtual sieve of molecular library of natural drugs based on the active cavity. Chalcone and shikonin exhibited EC50 values of 1.085 mg/L and 0.371 mg/L, respectively, with corresponding IC50 values for myosin of 0.44 mM and 0.14 mM. Given its superior activity and structure, shikonin was selected for further optimization of drug molecule design, culminating in the discovery of 1,4-naphthoquinone as a potent antiparasitic agent. This compound demonstrated an EC50 of 0.047 mg/L, LC50 of 0.23 mg/L, and a TI index of 4.893. These findings collectively highlight the potential of shikonin and 1,4-naphthoquinone as alternative compounds to control Gyrodactylus infections. Further optimization of medicinal chemistry holds promise for the development of more potent 1,4-naphthoquinone analogues, offering prospects for future anthelmintic control through combinatorial or replacement strategies.

The Advancement and Application of the Single-Cell Transcriptome in Biological and Medical Research.

Single-cell RNA sequencing technology (scRNA-seq) has been steadily developing since its inception in 2009. Unlike bulk RNA-seq, scRNA-seq identifies the heterogeneity of tissue cells and reveals gene expression changes in individual cells at the microscopic level. Here, we review the development of scRNA-seq, which has gone through iterations of reverse transcription, in vitro transcription, smart-seq, drop-seq, 10 × Genomics, and spatial single-cell transcriptome technologies. The technology of 10 × Genomics has been widely applied in medicine and biology, producing rich research results. Furthermore, this review presents a summary of the analytical process for single-cell transcriptome data and its integration with other omics analyses, including genomes, epigenomes, proteomes, and metabolomics. The single-cell transcriptome has a wide range of applications in biology and medicine. This review analyzes the applications of scRNA-seq in cancer, stem cell research, developmental biology, microbiology, and other fields. In essence, scRNA-seq provides a means of elucidating gene expression patterns in single cells, thereby offering a valuable tool for scientific research. Nevertheless, the current single-cell transcriptome technology is still imperfect, and this review identifies its shortcomings and anticipates future developments. The objective of this review is to facilitate a deeper comprehension of scRNA-seq technology and its applications in biological and medical research, as well as to identify avenues for its future development in alignment with practical needs.

Uncovering the Pre-Deterioration State during Disease Progression Based on Sample-Specific Causality Network Entropy (SCNE).

Complex diseases do not always follow gradual progressions. Instead, they may experience sudden shifts known as critical states or tipping points, where a marked qualitative change occurs. Detecting such a pivotal transition or pre-deterioration state holds paramount importance due to its association with severe disease deterioration. Nevertheless, the task of pinpointing the pre-deterioration state for complex diseases remains an obstacle, especially in scenarios involving high-dimensional data with limited samples, where conventional statistical methods frequently prove inadequate. In this study, we introduce an innovative quantitative approach termed sample-specific causality network entropy (SCNE), which infers a sample-specific causality network for each individual and effectively quantifies the dynamic alterations in causal relations among molecules, thereby capturing critical points or pre-deterioration states of complex diseases. We substantiated the accuracy and efficacy of our approach via numerical simulations and by examining various real-world datasets, including single-cell data of epithelial cell deterioration (EPCD) in colorectal cancer, influenza infection data, and three different tumor cases from The Cancer Genome Atlas (TCGA) repositories. Compared to other existing six single-sample methods, our proposed approach exhibits superior performance in identifying critical signals or pre-deterioration states. Additionally, the efficacy of computational findings is underscored by analyzing the functionality of signaling biomarkers.

INDELpred: Improving the prediction and interpretation of indel pathogenicity within the clinical genome.

Small insertions and deletions (indels) are critical yet challenging genetic variations with significant clinical implications. However, the identification of pathogenic indels from neutral variants in clinical contexts remains an understudied problem. Here, we developed INDELpred, a machine-learning-based predictive model for discerning pathogenic from benign indels. INDELpred was established based on key features, including allele frequency, indel length, function-based features, and gene-based features. A set of comprehensive evaluation analyses demonstrated that INDELpred exhibited superior performance over competing methods in terms of computational efficiency and prediction accuracy. Importantly, INDELpred highlighted the crucial role of function-based features in identifying pathogenic indels, with a clear interpretability of the features in understanding the disease-causing variants. We envisage INDELpred as a desirable tool for the detection of pathogenic indels within large-scale genomic datasets, thereby enhancing the precision of genetic diagnoses in clinical settings.

Effects of UV/H2O2 degradation on Moringa oleifera Lam. leaves polysaccharides: Composition, in vitro fermentation and prebiotic properties on gut microorganisms.

Moringa oleifera Lam. leaves are a new raw food material rich in polysaccharides. These polysaccharides exhibit various biological properties, including antioxidant, hypoglycemic and immunoregulatory effects. However, the use of Moringa oleifera Lam. leaves polysaccharides (MOLP) may be limited by their large molecular weight (MW) and presence of numerous impurities, such as pigments. Research has indicated that degraded polysaccharides usually exhibit high biological activity because of changes in physical structure and chemical properties. In this study, we focused on the extraction of a degraded-modified fraction from MOLP using the Ultraviolet/ Hydrogen peroxide (UV/H2O2) method. Specifically, the physicochemical properties and glycosidic bond composition of a particular fraction (UV/H2O2 degraded Moringa oleifera Lam. leaves polysaccharides in 3 h called DMOLP-3) were investigated. In addition, in vitro simulated digestion experiments showed that DMOLP-3 was only partially degraded during gastrointestinal digestion, indicating that DMOLP-3 can be utilised by gut microorganisms. Furthermore, the prebiotic properties of MOLP and DMOLP-3 was studied using an in vitro faecal fermentation model. The results indicated that compared with MOLP, DMOLP-3 led to a decrease in both the colour and MW of the polysaccharides. In addition, this model exhibited enhanced solubility and antioxidant capabilities while also influencing the surface morphology. Moreover, DMOLP-3 can facilitate the proliferation of advantageous microorganisms and enhance the synthesis of short-chain fatty acids (SCFAs). These results provide valuable insights into the utilization of bioactive components in Moringa oleifera Lam. leaves for the intestinal health.

Alleviation of allergic asthma by rosmarinic acid via gut-lung axis.

BACKGROUND: Asthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity. PURPOSE: To investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis. METHODS: We used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma. RESULTS: RosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress. CONCLUSIONS: The anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment.

Human amniotic mesenchymal stem cell-islet organoids enhance the efficiency of islet engraftment in a mouse diabetes model.

AIMS: Despite islet transplantation has proved a great potential to become the standard therapy for type 1 diabetes mellitus (T1DM), this approach remains limited by ischemia, hypoxia, and poor revascularization in early post-transplant period as well as inflammation and life-long host immune rejection. Here, we investigate the potential and mechanism of human amniotic mesenchymal stem cells (hAMSCs)-islet organoid to improve the efficiency of islet engraftment in immunocompetent T1DM mice. MAIN METHODS: We generated the hAMSC-islet organoid structure through culturing the mixture of hAMSCs and islets on 3-dimensional-agarose microwells. Flow cytometry, whole-body fluorescent imaging, immunofluorescence, Calcein-AM/PI staining, ELISA, and qPCR were used to assess the potential and mechanism of shielding hAMSCs to improve the efficiency of islet transplantation. KEY FINDINGS: Transplant of hAMSC-islet organoids results in remarkably better glycemic control, an enhanced glucose tolerance, and a higher ß cell mass in vivo compared with control islets. Our results show that hAMSCs shielding provides an immune privileged microenvironment for islets and promotes graft revascularization in vivo. In addition, hAMSC-islet organoids show higher viability and reduced dysfunction after exposure to hypoxia and inflammatory cytokines in vitro. Finally, our results show that shielding with hAMSCs leads to the activation of PKA-CREB-IRS2-PI3K and PKA-PDX1 signaling pathways, up-regulation of SIL1 mRNA levels, and down-regulation of MT1 mRNA levels in ß cells, which ultimately promotes the synthesis, folding and secretion of insulin, respectively. SIGNIFICANCE: hAMSC-islet organoids can evidently increase the efficiency of islet engraftment and might develop into a promising alternative for the clinical treatment of T1DM.

Interfacial Spinel Local Interlocking Strategy Toward Structural Integrity in P3 Oxide Cathodes.

P3-layered transition oxide cathodes have garnered considerable attention owing to their high initial capacity, rapid Na+ kinetics, and less energy consumption during the synthesis process. Despite these merits, their practical application is hindered by the substantial capacity degradation resulting from unfavorable structural transformations, Mn dissolution and migration. In this study, we systematically investigated the failure mechanisms of P3 cathodes, encompassing Mn dissolution, migration, and the irreversible P3-O3' phase transition, culminating in severe structural collapse. To address these challenges, we proposed an interfacial spinel local interlocking strategy utilizing P3/spinel intergrowth oxide as a proof-of-concept material. As a result, P3/spinel intergrowth oxide cathodes demonstrated enhanced cycling performance. The effectiveness of suppressing Mn migration and maintaining local structure of interfacial spinel local interlocking strategy was validated through depth-etching X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and in situ synchrotron-based X-ray diffraction. This interfacial spinel local interlocking engineering strategy presents a promising avenue for the development of advanced cathode materials for sodium-ion batteries.

Effect of Chinese Medicine in Patients with COVID-19: A Multi-center Retrospective Cohort Study.

OBJECTIVE: To evaluate the effectiveness and safety of Chinese medicine (CM) in the treatment of coronavirus disease 2019 (COVID-19) in China. METHODS: A multi-center retrospective cohort study was carried out, with cumulative CM treatment period of ⩾3 days during hospitalization as exposure. Data came from consecutive inpatients from December 19, 2019 to May 16, 2020 in 4 medical centers in Wuhan, China. After data extraction, verification and cleaning, confounding factors were adjusted by inverse probability of treatment weighting (IPTW), and the Cox proportional hazards regression model was used for statistical analysis. RESULTS: A total of 2,272 COVID-19 patients were included. There were 1,684 patients in the CM group and 588 patients in the control group. Compared with the control group, the hazard ratio (HR) for the deterioration rate in the CM group was 0.52 [95% confidence interval (CI): 0.41 to 0.64, P<0.001]. The results were consistent across patients of varying severity at admission, and the robustness of the results were confirmed by 3 sensitivity analyses. In addition, the HR for all-cause mortality in the CM group was 0.29 (95% CI: 0.19 to 0.44, P<0.001). Regarding of safety, the proportion of patients with abnormal liver function or renal function in the CM group was smaller. CONCLUSION: This real-world study indicates that the combination of a full-course CM therapy on the basic conventional treatment, may safely reduce the deterioration rate and all-cause mortality of COVID-19 patients. This result can provide the new evidence to support the current treatment of COVID-19. Additional prospective clinical trial is needed to evaluate the efficacy and safety of specific CM interventions. (Registration No. ChiCTR2200062917).

Mechanism study of OVA-induced allergic asthma in mice based on lipid metabolomics / 中国药理学通报

Aim To investigate the mechanism and search for potential biomarkers of ovalbumin ( OVA ) -induced asthma in mice base on lipidomics. Methods A BALB/c mouse model of asthma was prepared by OVA. TNF-α, IL-4, IL-10, IFN-γ levels in BALF and IgE level in serum were measured by ELISA. The inflammatory changes in mouse lung tissue were observed using HE staining. Lipid mediators ( LMs) in lung tissue and serum were quantified with UPLC-MS/ MS strategy. Results IgE level in serum and TNF-α, IFN-γ levels in BALF were higher (P <0.05) of asthmatic mice.Typical inflammatory manifestations were seen in lung tissue of asthmatic mice. A total of 57 lipid mediators were quantified with UPLC-MRM. LMs metabolic profiles differed significantly in serum and lung tissue between asthmatic and normal mice, 17 significantly different LMs were found in lung tissue and 6 LMs were found in serum, and the differential metabolites were produced through the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 oxidase (P450) metabolic pathways. Conclusions OVA-induced allergic asthma can cause disorder of lip-id mediators, LMs and cytokines are involved in the occurrence and development of asthma. The differential LMs have potential research value as biomarkers for the development of allergic asthma.

Clinical analysis of 31 cases of fetal umbilical artery thrombosis / 中华妇产科杂志

Objective: To analyze the ultrasonic manifestations, clinical features, high risk factors and key points of pregnancy management in prenatal diagnosis of umbilical artery thrombosis (UAT). Methods: The data of 31 pregnant women of UAT diagnosed by prenatal ultrasonography and confirmed after birth from July 2017 to July 2022 at the Women's Hospital, Zhejiang University School of Medicine were retrospectively analyzed, including the maternal characteristics, pregnancy outcomes and fetal complications. In addition, the baseline data and pregnancy outcomes were compared in 21 patients who continued pregnancy after diagnosis of UAT. Of the 21 UAT cases that continued pregnancy, 10 cases were treated with low molecular weight heparin (LMWH; LMWH treatment group), while the other 11 patients had expectant treatment(expectant treatment group). Results: The age of the 31 pregnant women was (30.2±4.7) years, of which 5 cases (16%,5/31) were advanced age pregnant women. The gestational age at diagnosis was (32.9±4.0) weeks, and the gestational age at termination of pregnancy was (35.6±2.9) weeks. In 31 fetuses with UAT, 15 cases (48%) had fetal distress, 11 cases (35%) had fetal growth restriction, and 3 cases (10%) had intrauterine stillbirth. There were 28 cases of live births, including 26 cases by cesarean section and 2 cases by vaginal delivery. There were also 3 stillbirths, all delivered vaginally. Four neonates had mild asphyxia and two newborns had severe asphyxia. Among the 31 cases, 10 cases were terminated immediately after diagnosis, the gestational age at diagnosis was (35.9±2.9) weeks. Another 21 pregnancies continued, and their gestational age at diagnosis was (31.4±3.7) weeks. The median prolonged gestational age in LMWH treatment group was 7.9 weeks (4.6-9.4 weeks), and all were live births. The median prolonged gestational age in the expectant treatment group was 0.6 weeks (0.0-1.0 weeks), and 2 cases were stillbirths. There was a statistically significant difference in prolonged gestational age (P=0.002). Conclusions: Ultrasound is the preferred method for prenatal detection of UAT. Clinicians need to be vigilant for UAT when a newly identified single umbilical artery is detected by ultrasound in the second or third trimesters. The decision to continue or terminate the pregnancy depends on the gestational age and the condition of fetus. Attention should be paid to fetal movements as the pregnancy continues. The treatment of LMWH as soon as possible after diagnosis of UAT may improve the pregnancy outcome.