Transcription factor shapes chromosomal conformation and regulates gene expression in bacterial adaptation.

Genomic mutations allow bacteria to adapt rapidly to adverse stress environments. The three-dimensional conformation of the genome may also play an important role in transcriptional regulation and environmental adaptation. Here, using chromosome conformation capture, we investigate the high-order architecture of the Zymomonas mobilis chromosome in response to genomic mutation and ambient stimuli (acetic acid and furfural, derived from lignocellulosic hydrolysate). We find that genomic mutation only influences the local chromosome contacts, whereas stress of acetic acid and furfural restrict the long-range contacts and significantly change the chromosome organization at domain scales. Further deciphering the domain feature unveils the important transcription factors, Ferric uptake regulator (Fur) proteins, which act as nucleoid-associated proteins to promote long-range (>200 kb) chromosomal communications and regulate the expression of genes involved in stress response. Our work suggests that ubiquitous transcription factors in prokaryotes mediate chromosome organization and regulate stress-resistance genes in bacterial adaptation.

Advanced Cardiac Patches for the Treatment of Myocardial Infarction.

Myocardial infarction is a cardiovascular disease characterized by a high incidence rate and mortality. It leads to various cardiac pathophysiological changes, including ischemia/reperfusion injury, inflammation, fibrosis, and ventricular remodeling, which ultimately result in heart failure and pose a significant threat to global health. Although clinical reperfusion therapies and conventional pharmacological interventions improve emergency survival rates and short-term prognoses, they are still limited in providing long-lasting improvements in cardiac function or reversing pathological progression. Recently, cardiac patches have gained considerable attention as a promising therapy for myocardial infarction. These patches consist of scaffolds or loaded therapeutic agents that provide mechanical reinforcement, synchronous electrical conduction, and localized delivery within the infarct zone to promote cardiac restoration. This review elucidates the pathophysiological progression from myocardial infarction to heart failure, highlighting therapeutic targets and various cardiac patches. The review considers the primary scaffold materials, including synthetic, natural, and conductive materials, and the prevalent fabrication techniques and optimal properties of the patch, as well as advanced delivery strategies. Last, the current limitations and prospects of cardiac patch research are considered, with the goal of shedding light on innovative products poised for clinical application.

Fluoropolymer Nanoparticles Synthesized via Reversible-Deactivation Radical Polymerizations and Their Applications.

Fluorinated polymeric nanoparticles (FPNPs) combine unique properties of fluorocarbon and polymeric nanoparticles, which has stimulated massive interest for decades. However, fluoropolymers are not readily available from nature, resulting in synthetic developments to obtain FPNPs via free radical polymerizations. Recently, while increasing cutting-edge directions demand tailored FPNPs, such materials have been difficult to access via conventional approaches. Reversible-deactivation radical polymerizations (RDRPs) are powerful methods to afford well-defined polymers. Researchers have applied RDRPs to the fabrication of FPNPs, enabling the construction of particles with improved complexity in terms of structure, composition, morphology, and functionality. Related examples can be classified into three categories. First, well-defined fluoropolymers synthesized via RDRPs have been utilized as precursors to form FPNPs through self-folding and solution self-assembly. Second, thermally and photoinitiated RDRPs have been explored to realize in situ preparations of FPNPs with varied morphologies via polymerization-induced self-assembly and cross-linking copolymerization. Third, grafting from inorganic nanoparticles has been investigated based on RDRPs. Importantly, those advancements have promoted studies toward promising applications, including magnetic resonance imaging, biomedical delivery, energy storage, adsorption of perfluorinated alkyl substances, photosensitizers, and so on. This Review should present useful knowledge to researchers in polymer science and nanomaterials and inspire innovative ideas for the synthesis and applications of FPNPs.

Sequencing polymers to enable solid-state lithium batteries.

Rational designs of solid polymer electrolytes with high ion conduction are critical in enabling the creation of advanced lithium batteries. However, known polymer electrolytes have much lower ionic conductivity than liquid/ceramics at room temperature, which limits their practical use in batteries. Here we show that precise positioning of designed repeating units in alternating polymer sequences lays the foundation for homogenized Li+ distribution, non-aggregated Li+-anion solvation and sequence-assisted site-to-site ion migration, facilitating the tuning of Li+ conductivity by up to three orders of magnitude. The assembled all-solid-state batteries facilitate reversible and dendrite-mitigated cycling against Li metal from ambient to elevated temperatures. This work demonstrates a powerful molecular engineering means to access highly ion-conductive solid-state materials for next-generation energy devices.

TIMP-3 Alleviates White Matter Injury After Subarachnoid Hemorrhage in Mice by Promoting Oligodendrocyte Precursor Cell Maturation.

Subarachnoid hemorrhage (SAH) is associated with high mortality and disability rates, and secondary white matter injury is an important cause of poor prognosis. However, whether brain capillary pericytes can directly affect the differentiation and maturation of oligodendrocyte precursor cells (OPCs) and subsequently affect white matter injury repair has still been revealed. This study was designed to investigate the effect of tissue inhibitor of metalloproteinase-3 (TIMP-3) for OPC differentiation and maturation. PDGFRßret/ret and wild-type C57B6J male mice were used to construct a mouse model of SAH via endovascular perforation in this study. Mice were also treated with vehicle, TIMP-3 RNAi or TIMP-3 RNAi + TIMP-3 after SAH. The effect of TIMP-3 on the differentiation and maturation of OPCs was determined using behavioral score, ELISA, transmission electron microscopy, immunofluorescence staining and cell culture. We found that TIMP-3 was secreted mainly by pericytes and that SAH and TIMP-3 RNAi caused a significant decrease in the TIMP-3 content, reaching a nadir at 24 h, followed by gradual recovery. In vitro, the myelin basic protein content of oligodendrocytes after oxyhemoglobin treatment was increased by TIMP-3 overexpression. The data indicates TIMP-3 could promote the differentiation and maturation of OPCs and subsequently improve neurological outcomes after SAH. Therefore, TIMP-3 could be beneficial for repair after white matter injury and could be a potential therapeutic target in SAH.

Electromagnetic field and cardiovascular diseases: A state-of-the-art review of diagnostic, therapeutic, and predictive values.

Despite encouraging advances in early diagnosis and treatment, cardiovascular diseases (CVDs) remained a leading cause of morbidity and mortality worldwide. Increasing evidence has shown that the electromagnetic field (EMF) influences many biological processes, which has attracted much attention for its potential therapeutic and diagnostic modalities in multiple diseases, such as musculoskeletal disorders and neurodegenerative diseases. Nonionizing EMF has been studied as a therapeutic or diagnostic tool in CVDs. In this review, we summarize the current literature ranging from in vitro to clinical studies focusing on the therapeutic potential (external EMF) and diagnostic potential (internal EMF generated from the heart) of EMF in CVDs. First, we provided an overview of the therapeutic potential of EMF and associated mechanisms in the context of CVDs, including cardiac arrhythmia, myocardial ischemia, atherosclerosis, and hypertension. Furthermore, we investigated the diagnostic and predictive value of magnetocardiography in CVDs. Finally, we discussed the critical steps necessary to translate this promising approach into clinical practice.

Transcatheter tricuspid valve replacement with LuX-valve device: Overview of key echocardiographic considerations.

Tricuspid regurgitation is a common valve disease with high incidence and poor prognosis. For elderly patients and those with a history of open heart surgery, second thoracotomy and valve replacement carry a high risk. Transcatheter tricuspid valve replacement (TTVR) has become an alternative treatment for patients with high surgical risk. LuX-Valve is a novel self-expandable valve that does not rely on radial force to anchor the valve annulus. The preliminary results have been satisfactory, and this technology is gradually being adopted in China and around the world. Successful implementation of this technique depends on echocardiographic preoperative screening, intraoperative guidance, and postoperative follow-up. The purpose of this article is to provide a state-of-the-art review of the key points and technical considerations for preoperative screening, intraoperative guidance, and postoperative follow-up for TTVR.

Five-year follow-up after percutaneous pulmonary valve implantation using the Venus P-valve system for patients with pulmonary regurgitation and an enlarged native right ventricular outflow tract.

BACKGROUND: Percutaneous pulmonary valve implantation (PPVI) with the self-expandable Venus P-valve system is a promising treatment for patients with pulmonary regurgitation (PR) and a native right ventricular outflow tract (RVOT). However, limited data is available regarding its midterm outcomes. This study assessed the midterm clinical and echocardiographic outcomes following Venus P-valve implantation. METHODS: From 2013 to 2018, 55 patients with moderate or severe PR after surgical RVOT repair with a transannular or RVOT patch were consecutively enrolled from six hospitals in China. Five-year clinical and echocardiographic outcomes were collected and evaluated. The primary endpoint was a freedom from all-cause mortality and reintervention. RESULTS: At 5 years, the primary endpoint was met for 96% of patients, corresponding to a freedom from all-cause mortality of 96% (95% confidence interval [CI]: 86%-99%) and freedom from reintervention of 98% (95% CI: 87%-100%). Endocarditis was reported in five patients (four patients within 1 year and one patient at 5 years) following PPVI. Transpulmonary gradient and stent orifice diameter remained stable compared to at discharge (p＞0.05). No paravalvular leak was reported while only 1 patient gradually increased to moderate PR during follow-up. Significant improvement of RV diameter and LVEF (p＜0.001) sustained over the 5-year follow-up, in consistent with remarked improved New York Heart Association(NYHA) functional class (p＜0.001). CONCLUSION: The 5-year results of the China VenusP Study demonstrated the midterm benefits of Venus P-valve implantation in the management of patients with severe PR with an enlarged native RVOT by providing sustained symptomatic and hemodynamic improvement.

Risk stratification by systemic manifestations secondary to hemodynamic disorders of patients with severe tricuspid regurgitation.

BACKGROUND: Tricuspid regurgitation (TR) is a prevalent disease that triggers systemic pathological changes including cardiac, respiratory, hepatic and digestive, hematopoietic, renal and skin issues. The burden of extra-cardiac manifestations has not been well described in TR patients and the clinical impact is unknown. METHODS: Patients with severe or more-than-severe TR during hospitalization, who did not have any previous cardiac procedures, hemodynamically significant congenital heart disease or concomitant severe aortic or mitral valve disease, were retrospectively analyzed. Pre-specified criteria and diagnosis of baseline characteristics were used to evaluate the presence of extra-cardiac manifestations secondary to TR after excluding comorbidities that may also lead to corresponding abnormalities. Extra-cardiac involvements encompass respiratory, hepatic and, digestive, renal, hematopoietic and dermatic system. Staging criteria are defined as no extra-cardiac system involvement in Stage 1, one in Stage 2, at least two extra-cardiac involvements in Stage 3 and any end-stage organ failure in Stage 4. A telephone follow-up was conducted to record the composite endpoint namely all-cause death or cardiac rehospitalization after the index hospitalization. RESULTS: A total of 258 patients were identified with a median age of 73 (interquartile range [IQR]: 62-83) years and 52.3% were female. Severe TR and more-than-severe TR patients accounted for 92.6% and 7.4% of the cohort. There were 20.5%, 27.5%, 37.6% and 14.3% of patients from Stage 1 to 4 respectively. The follow-up time was at a median of 251 (IQR: 183-324) days. TR Patients in Stage 3&4 were at an increased risk with borderline statistical significance to experience the composite endpoint compared to patients in Stage 1&2 (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.0 to 3.7, P = 0.049). CONCLUSIONS: Approximately half of patients with at least severe TR presented with two or more extra-cardiac systemic manifestations, which may incur a 1.9-fold higher risk of all-cause death or cardiac rehospitalization than TR patients with one or less extra-cardiac involvement.

Voltage-gated sodium channel gene mutation and P450 gene expression are associated with the resistance of Aphis spiraecola Patch (Hemiptera: Aphididae) to lambda-cyhalothrin.

Aphis spiraecola Patch is one of the most economically important tree fruit pests worldwide. The pyrethroid insecticide lambda-cyhalothrin is commonly used to control A. spiraecola. In this 2-year study, we quantified the resistance level of A. spiraecola to lambda-cyhalothrin in different regions of the Shaanxi province, China. The results showed that A. spiraecola had reached extremely high resistance levels with a 174-fold resistance ratio (RR) found in the Xunyi region. In addition, we compared the enzymatic activity and expression level of P450 genes among eight A. spiraecola populations. The P450 activity of A. spiraecola was significantly increased in five regions (Xunyi, Liquan, Fengxiang, Luochuan, and Xinping) compared to susceptible strain (SS). The expression levels of CYP6CY7, CYP6CY14, CYP6CY22, P4504C1-like, P4506a13, CYP4CZ1, CYP380C47, and CYP4CJ2 genes were significantly increased under lambda-cyhalothrin treatment and in the resistant field populations. A L1014F mutation in the sodium channel gene was found and the mutation rate was positively correlated with the LC50 of lambda-cyhalothrin. In conclusion, the levels of lambda-cyhalothrin resistance of A. spiraecola field populations were associated with P450s and L1014F mutations. Our combined findings provide evidence on the resistance mechanism of A. spiraecola to lambda-cyhalothrin and give a theoretical basis for rational and effective control of this pest species.

[Rapamycin and HPPH Co-Loaded Nanodrug Delivered via Dissolvable Microneedles to Treat Port-Wine Stains]. / å ±è½½é›·å¸•éœ‰ç´ å’Œå ‰å ‹æ´›çš„çº³ç±³è¯ç‰©å¤åˆå¯æº¶è§£å¾®é’ˆæ²»ç–—é²œçº¢æ–‘ç—£çš„å®žéªŒç ”ç©¶.

Objective: Port-wine stains are a kind of dermatological disease of congenital capillary malformation. Based on the biological characteristics of port-wine stains and the advantages of microneedle transdermal administration, we intend to construct a nanodrug co-loaded with rapamycin (RPM), an anti-angiogenesis drug, and photochlor (HPPH), a photosensitizer, and integrate the nanodrug with dissolvable microneedles (MN) to achieve anti-angiogenesis and photodynamic combination therapy for port-wine stains. Methods: First, RPM and HPPH co-loaded nanoparticles (RPM-HPPH NP) were prepared by the emulsification solvent-volatilization method, and its ability to generate reactive oxygen species (ROS) was investigated under 660 nm laser irradiation. Mouse hemangioendothelioma endothelial cells (EOMA) were used as the subjects of the study. The cellular uptake behaviors were examined by fluorescence microscopy and flow cytometry. The cytotoxicity effects of RPM-HPPH NP with or without 660 nm laser irradiation on EOMA cells were examined by MTT assays (with free RPM serving as the control). Then, hyaluronic acid (HA) dissolvable microneedles loaded with RPM-HPPH NP (RPM-HPPH NP@HA MN) were obtained by compounding the nanodrug with HA dissolvable microneedle system through the molding method. The morphological characteristics and mechanical properties of RPM-HPPH NP@HA MN were investigated by scanning electron microscope and electronic universal testing machine. The penetration ability of RPM-HPPH NP@HA MN on the skin of nude mice was evaluated by trypan blue staining and H&E staining experiment. Results: The RPM-HPPH NP prepared in the study had a particle size of 150 nm and generated large amounts of ROS under laser irradiation. At the cellular level, RPM-HPPH NP was taken up by EOMA cells in a time-dependent manner. The cytotoxicity of RPM-HPPH NP was higher than that of free RPM with or without laser irradiation. Under laser irradiation, RPM-HPPH NP exhibited stronger cytotoxic effects and the difference was statistically significant (P<0.05). The height of the needle tip of RPM-HPPH NP@HA MN was 600 µm and the mechanical property of a single needle was 0.75048 N. Trypan blue staining and HE staining showed that pressing on the microneedles could produce pores on the skin surface and penetration of the stratum corneum. Conclusion: RPM-HPPH NP@HA MN can deliver RPM-HPPH NP percutaneously to the lesion tissue and realize the synergistic treatment of port-wine stains with anti-angiogenic therapy and photodynamic therapy, providing a new strategy for the construction of nanodrug-loaded microneedle delivery system and the clinical treatment of port-wine stains.

[Mechanism of total saponins of Panax japonicus against liver injury induced by acetaminophen in mice based on ERK/NF-κB/COX-2 signaling pathway].

This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1ß), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1ß, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1ß, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1ß, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.

Organocatalyzed Photo-Controlled Synthesis of Ultrahigh-Molecular-Weight Fluorinated Alternating Copolymers.

Ultrahigh-molecular-weight (UHMW) polymers with tailored structures are highly desirable for the outstanding properties. In this work, we developed a novel photoorganocatalyzed controlled radical alternating copolymerizations of fluoroalkyl maleimide and diverse vinyl comonomers, enabling efficient preparation of fluorinated copolymers of predetermined UHMWs and well-defined structures at high conversions. Versatility of this method was demonstrated by expanding to controlled terpolymerization, which allows facial access toward fluorinated terpolymers of UHMWs and functional pendants. The obtained copolymers exhibited attractive physical properties and furnished thermoplastic, anticorrosive and (super)hydrophobic attributes as coatings on different substrates. Molecular simulations provided insights into the coating morphology, which unveiled a fluorous protective layer on the top surface with polar groups attached to the bottom substrate, resulting in good adhesion and hydrophobicity, simultaneously. This synthetic method and customized copolymers shed light on the design of high-performance coatings by macromolecular engineering.

Controlled Radical Copolymerization toward Tailored F/N Hybrid Polymers by Using Light-Driven Organocatalysis.

Controlled radical copolymerizations present attractive avenues to obtain polymers with complicated compositions and sequences. In this work, we report the development of a visible-light-driven organocatalyzed controlled copolymerization of fluoroalkenes and acyclic N-vinylamides for the first time. The approach enables the on-demand synthesis of a broad scope of amide-functionalized main-chain fluoropolymers via novel fluorinated thiocarbamates, facilitating regulations over chemical compositions and alternating fractions by rationally selecting comonomer pairs and ratios. This method allows temporally controlled chain-growth by external light, and maintains high chain-end fidelity that promotes facile preparation of block sequences. Notably, the obtained F/N hybrid polymers, upon hydrolysis, afford free amino-substituted fluoropolymers versatile for post modifications toward various functionalities (e.g., amide, sulfonamide, carbamide, thiocarbamide). We further demonstrate the in-situ formation of polymer networks with desirable properties as protective layers on lithium metal anodes, presenting a promising avenue for advancing lithium metal batteries.

Reactive Solid Polymer Layer: From a Single Fluoropolymer to Divergent Fluorinated Interface.

Controlling the structure and chemistry of solid electrolyte interphase (SEI) underpins the stability of electrolyte-electrode interface, and is crucial for advancing rechargeable lithium metal batteries (LMBs). Here, we utilized photo-controlled copolymerization to achieve the on-demand synthesis of fluorosulfonyl fluoropolymers as unprecedented artificial SEI layers on Li metal anodes. This work not only enables instant formation of a hybrid polymer-inorganic interphase that consists of a polymer-enriched top layer and a LiF-fortified bottom layer, originating from a single polymeric component, but also imparts various desirable physical properties (e.g., good mechanical strength and flexibility, high ion conductivity, low overpotential) to SEI via a single-to-divergent strategy. Model reactions and structural characterizations supported the formation of a divergent fluorinated interphase, which furnished prolonged stabilization of Li deposition, high coulombic efficiency and improved cycling behavior in electrochemical experiments. This work highlights the great potential of exploring reactive polymers as versatile coatings to stabilize Li metal anodes, providing a promising avenue to solve electrode-electrolyte interfacial problems for LMBs.

Antinuclear antibody (ANA) status predicts immune-related adverse events in liver cancer patients undergoing anti-PD-1 therapy.

Immune-related adverse events (irAEs) clinically resemble autoimmune diseases, indicating autoantibodies could be potential biomarkers for the prediction of irAEs. This study aimed to assess the predictive value of peripheral blood antinuclear antibody (ANA) status for irAEs, considering the time and severity of irAEs, as well as treatment outcome in liver cancer patients administered anti-PD-1 therapy. Ninety-three patients with advanced primary liver cancer administered anti-PD-1 treatment were analyzed retrospectively. They were divided into the ANA positive (ANA+, titer ≥ 1:100) and negative (ANA-, titer < 1:100) groups. Development of irAEs, progression-free survival (PFS), and overall survival (OS) were assessed. Compared with ANA- patients, ANA+ cases were more prone to develop irAEs (43.3% vs. 19.2%, P = 0.031). With the increase of ANA titers, the frequency of irAEs increased. The time interval between anti-PD-1 therapy and the onset of irAEs was significantly shorter in ANA+ patients compared with the ANA- group (median, 1.7 months vs. 5.0 months, P = 0.022). Moreover, the time between anti-PD-1 therapy and irAE occurrence decreased with increasing ANA titer. In addition, PFS and OS were decreased in ANA+ patients compared with the ANA- group (median PFS, 2.8 months vs. 4.2 months, P = 0.043; median OS, 21.1 months vs. not reached, P = 0.041). IrAEs occur at higher frequency in ANA+ liver cancer patients undergoing anti-PD-1 therapy. ANA titer could help predict irAE development and treatment outcome in these patients.

Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.

The influence of biological sex in human skeletal muscle transcriptome during ageing.

Sex is a crucial biological variable, and influence of biological sex on the change of gene expression in ageing skeletal muscle has not yet been fully revealed. In this study, the mRNA expression profiles were obtained from the Gene Expression Omnibus database. Key genes were identified by differential expression analysis and weighted gene co-expression network analysis. The gene set enrichment analysis software and Molecular Signatures Database were used for functional and enrichment analysis. A protein-protein interaction network was constructed using STRING and visualized in Cytoscape. The results were compared between female and male subgroups. Differentially expressed genes and enriched pathways in different sex subgroups shared only limited similarities. The pathways enriched in the female subgroup were more similar to the pathways enriched in the older groups without taking sex difference into consideration. The pathways enriched in the female subgroup were more similar to the pathways enriched in the older groups without taking sex difference into consideration. The muscle myosin filament pathways were downregulated in the both aged female and male samples whereas transforming growth factor beta pathway and extracellular matrix-related pathways were upregulated. With muscle ageing, the metabolism-related pathways, protein synthesis and degradation pathways, results of predicted immune cell infiltration, and gene cluster associated with slow-type myofibers drastically different between the female and male subgroups. This finding may indicate that changes in muscle type with ageing may differ between the sexes in vastus lateralis muscle.

Molecular mechanism of engineered Zymomonas mobilis to furfural and acetic acid stress.

Acetic acid and furfural (AF) are two major inhibitors of microorganisms during lignocellulosic ethanol production. In our previous study, we successfully engineered Zymomonas mobilis 532 (ZM532) strain by genome shuffling, but the molecular mechanisms of tolerance to inhibitors were still unknown. Therefore, this study investigated the responses of ZM532 and its wild-type Z. mobilis (ZM4) to AF using multi-omics approaches (transcriptomics, genomics, and label free quantitative proteomics). Based on RNA-Seq data, two differentially expressed genes, ZMO_RS02740 (up-regulated) and ZMO_RS06525 (down-regulated) were knocked out and over-expressed through CRISPR-Cas technology to investigate their roles in AF tolerance. Overall, we identified 1865 and 14 novel DEGs in ZM532 and wild-type ZM4. In contrast, 1532 proteins were identified in ZM532 and wild-type ZM4. Among these, we found 96 important genes in ZM532 involving acid resistance mechanisms and survival rates against stressors. Furthermore, our knockout results demonstrated that growth activity and glucose consumption of mutant strains ZM532∆ZMO_RS02740 and ZM4∆ZMO_RS02740 decreased with increased fermentation time from 42 to 55 h and ethanol production up to 58% in ZM532 than that in ZM532∆ZMO_RS02740. Hence, these findings suggest ZMO_RS02740 as a protective strategy for ZM ethanol production under stressful conditions.

Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Significant Mitral Stenosis-a Preliminary Meta-Analysis.

INTRODUCTION: Patients with atrial fibrillation (AF) and concomitant moderate-to-severe mitral stenosis (MS) are listed as a contraindicated population to direct oral anticoagulant (DOAC) because of the traditional tenet of high stroke risk, despite scarce evidence. With accumulating data, we sought to conduct a systematic meta-analysis to preliminarily explore the efficacy and safety of DOAC versus warfarin in patients with AF and concomitant significant MS. METHODS: We searched the Medline, Embase databases, and the Cochrane Library (assessed October 10th, 2022) for eligible studies. Risk ratios (RRs) and 95% confidence intervals (CIs) were synthesized in Stata 16.1 (StataCorp). RESULTS: In random-effects meta-analyses, DOACs demonstrated a similar risk of stroke or systemic embolism (RR 0.51; 95% CI 0.09-2.96), all-cause death (RR 0.81; 95% CI 0.35-1.87), major or clinically relevant non-major bleeding (RR 0.57; 95% CI 0.24-1.39), and silent cerebral ischemia (RR 1.01; 95% CI 0.64-1.58) when compared with warfarin. CONCLUSIONS: DOACs were similar to warfarin in the efficacy and safety profiles in patients with AF and concomitant significant MS. Future evidence is expected from other large trials.