Paxillin facilitates timely neurite initiation on soft-substrate environments by interacting with the endocytic machinery.

Neurite initiation is the first step in neuronal development and occurs spontaneously in soft tissue environments. Although the mechanisms regulating the morphology of migratory cells on rigid substrates in cell culture are widely known, how soft environments modulate neurite initiation remains elusive. Using hydrogel cultures, pharmacologic inhibition, and genetic approaches, we reveal that paxillin-linked endocytosis and adhesion are components of a bistable switch controlling neurite initiation in a substrate modulus-dependent manner. On soft substrates, most paxillin binds to endocytic factors and facilitates vesicle invagination, elevating neuritogenic Rac1 activity and expression of genes encoding the endocytic machinery. By contrast, on rigid substrates, cells develop extensive adhesions, increase RhoA activity and sequester paxillin from the endocytic machinery, thereby delaying neurite initiation. Our results highlight paxillin as a core molecule in substrate modulus-controlled morphogenesis and define a mechanism whereby neuronal cells respond to environments exhibiting varying mechanical properties

Regular exercise and the trajectory of health-related quality of life among Taiwanese adults: a cohort study analysis 2006–2014

Abstract Background Physical activity is related to health-related quality of life, but little evidence from multiple waves of panel data in Asian countries area available. This study aims to explore the impacts of different degree of regular exercise on the trajectories of physical and mental dimensions of health-related quality of life (HRQOL) for community-dwelling Taiwanese adults during 2006–2014. Methods Data were derived from the “Landseed Integrated Outreaching Neighborhood Screening (LIONS)” study, with 6182 adults enrolled at the baseline and subsequently followed up to three times till 2014. Linear mixed-effects modeling approach was employed to evaluate the growth curve models of HRQOL (with 16,281 observations) by linear & quadratic time effects, regular exercise (5-level moderate-intensity physical activity), and major influential factors of HRQOL. Results Regular exercise showed significantly positive dose-response effects on physical HRQOL (β =1.27~2.54), and regular exercise of 150 min or more showed positive effects on mental HRQOL (β = 1.55~2.03). Besides, irregular exercise could also improve both physical and mental HRQOL (β = 1.27 & β = 0.87). However, such effects were not significant over time (at time slope) on HRQOL. In addition, physical and mental HRQOL improved across time (β = 1.01 and 1.49, respectively), but the time quadratic effect would significantly offset a little bit on physical dimension (β = − 0.22). Moreover, being female, increasing age, living alone, or poorer health status were related to lower physical HRQOL; and being younger, living alone, or poorer health status were associated with lower mental HRQOL. Conclusions The positive dose-response relationship between regular exercise and HRQOL or its domains was demonstrated for community-dwelling Taiwanese adults. Thus, a regular exercise habit (better ≧150 min per week) is advised for community-based healthcare professionals and the government to incorporate into health promotion strategies and plans.https://deepblue.lib.umich.edu/bitstream/2027.42/152207/1/12889_2019_Article_7662.pd

Mutation and Lineage Analysis of DNMT3A in BCR-ABL1-negative Chronic Myeloproliferative Neoplasms

SummaryIn addition to the JAK2 V617F mutation, somatic mutation in DNMT3A has been described in BCL-ABL1-negative myeloproliferative neoplasms (MPNs). We have screened for DNMT3A exon 23 mutations in 130 adult Taiwanese patients with chronic phase myeloproliferative neoplasms. Only one somatic DNMT3A R882H mutation was identified in one JAK2 V617F mutation-positive essential thrombocythemia patient (1/91, 1%). Both mutations were detected in the CD34+-, CD19+-, peripheral blood mononuclear cell- and granulocyte-enriched fractions, but were not detected in the CD3+-enriched fraction by lineage analysis. Our findings suggest that DNMT3A mutation is not prevalent in MPNs, and further study is needed to clarify its role in the molecular pathogenesis of myeloproliferative neoplasms

An iron detection system determines bacterial swarming initiation and biofilm formation

Iron availability affects swarming and biofilm formation in various bacterial species. However, how bacteria sense iron and coordinate swarming and biofilm formation remains unclear. Using Serratia marcescens as a model organism, we identify here a stage-specific iron-regulatory machinery comprising a two-component system (TCS) and the TCS-regulated iron chelator 2-isocyano-6,7-dihydroxycoumarin (ICDH-Coumarin) that directly senses and modulates environmental ferric iron (Fe3+) availability to determine swarming initiation and biofilm formation. We demonstrate that the two-component system RssA-RssB (RssAB) directly senses environmental ferric iron (Fe3+) and transcriptionally modulates biosynthesis of flagella and the iron chelator ICDH-Coumarin whose production requires the pvc cluster. Addition of Fe3+, or loss of ICDH-Coumarin due to pvc deletion results in prolonged RssAB signaling activation, leading to delayed swarming initiation and increased biofilm formation. We further show that ICDH-Coumarin is able to chelate Fe3+ to switch off RssAB signaling, triggering swarming initiation and biofilm reduction. Our findings reveal a novel cellular system that senses iron levels to regulate bacterial surface lifestyle

PTIGS-IdIt, a system for species identification by DNA sequences of the psbA-trnH intergenic spacer region

Abstract Background DNA barcoding technology, which uses a short piece of DNA sequence to identify species, has wide ranges of applications. Until today, a universal DNA barcode marker for plants remains elusive. The rbcL and matK regions have been proposed as the “core barcode” for plants and the ITS2 and psbA-trnH intergenic spacer (PTIGS) regions were later added as supplemental barcodes. The use of PTIGS region as a supplemental barcode has been limited by the lack of computational tools that can handle significant insertions and deletions in the PTIGS sequences. Here, we compared the most commonly used alignment-based and alignment-free methods and developed a web server to allow the biologists to carry out PTIGS-based DNA barcoding analyses. Results First, we compared several alignment-based methods such as BLAST and those calculating P distance and Edit distance, alignment-free methods Di-Nucleotide Frequency Profile (DNFP) and their combinations. We found that the DNFP and Edit-distance methods increased the identification success rate to ~80%, 20% higher than the most commonly used BLAST method. Second, the combined methods showed overall better success rate and performance. Last, we have developed a web server that allows (1) retrieving various sub-regions and the consensus sequences of PTIGS, (2) annotating novel PTIGS sequences, (3) determining species identity by PTIGS sequences using eight methods, and (4) examining identification efficiency and performance of the eight methods for various taxonomy groups. Conclusions The Edit distance and the DNFP methods have the highest discrimination powers. Hybrid methods can be used to achieve significant improvement in performance. These methods can be extended to applications using the core barcodes and the other supplemental DNA barcode ITS2. To our knowledge, the web server developed here is the only one that allows species determination based on PTIGS sequences. The web server can be accessed at http://psba-trnh-plantidit.dnsalias.org

Prospective cohort study evaluating efficacy and safety of efgartigimod in Chinese generalized myasthenia gravis patients

BackgroundDespite the efficacy of efgartigimod demonstrated in ADAPT phase 3 trial, data specifically derived from Chinese participants are not available. Therefore, we aimed to evaluate the efficacy and safety of efgartigimod in Chinese patients with generalized myasthenia gravis (gMG).MethodsThis is a prospective cohort study conducted in 8 hospitals across China. gMG patients received weekly intravenous infusions of efgartigimod (10 mg/kg) under a named patient program (NPP). The present study is an 8-week study, consisting of 4 consecutive doses of efgartigimod administered over 3 weeks (one cycle), followed by a 5-week follow-up period to assess the tolerability of efgartigimod’s therapeutic effects. The primary outcome was the mean change in MG activities of daily living (MG-ADL) total score from baseline to 4 weeks. MG-ADL responder was defined as a ≥ 2-point improvement that persisted for 4 weeks, starting by week 4. Safety evaluations encompassed the monitoring of adverse events (AE) and serious AE (SAE) throughout the study.ResultsBetween 5 July 2022 and 25 August 2023, a total of 14 gMG patients were included. The mean age was 57.7 years, with a mean MG-ADL score of 10.86 ± 3.32. At week 4, MG-ADL scores showed a mean reduction of 6 points, reaching a maximum decline of 13 points. Among the patients, 85.7% (12/14) achieved MG-ADL responder status after one cycle of treatment. The most significant reduction in quantitative MG (QMG) scores also occurred at week 4, with a mean decrease of 7 points. Notably, the improvements in MG-ADL and QMG scores persisted until week 8. During treatment and follow-up period, only two mild neck rashes occurred and resolved promptly. No infections or SAE were reported.DiscussionA single cycle of efgartigimod treatment demonstrates effectiveness and the tolerability through week 8, with no new safety signals observed in Chinese gMG patients

The mechanisms underlying the actions of Xuefu Zhuyu decoction pretreatment against neurological deficits after ischemic stroke in mice: The mediation of glymphatic function by aquaporin-4 and its anchoring proteins

Ischemic stroke (IS) has been associated with an impairment in glymphatic function. Xuefu Zhuyu Decoction (XFZYD) is widely used in the prevention and treatment of ischemic stroke. We hypothesized that Xuefu Zhuyu decoction pretreatment could attenuate early neurological deficits after ischemic stroke by enhancing the function of the glymphatic system. To prove our hypothesis, we carried out temporary middle cerebral artery occlusion and reperfusion surgery on C57BL/6 mice and then measured neurological score, infarct size and performed hematoxylin-eosin staining to assess stroke outcomes after 24 h of reperfusion. Subsequently, we injected fluorescent tracers in to the cisterna magna and evaluated tracer distribution in coronal brain sections. The polarization of aquaporin-4 (AQP4), colocalization of aquaporin-4, α-dystroglycan, β-dystroglycan and agrin were determined by immunofluorescence. Our research showed that pretreatment with Xuefu Zhuyu decoction significantly alleviated neurological scores, neurological deficits and pathological abnormalities in a mouse model of ischemic stroke. Importantly, Xuefu Zhuyu decoction pretreatment enhanced cerebrospinal fluid influx, protected aquaporin-4 depolarization and promoted the colocalization of aquaporin-4 with its anchoring proteins in the brain. Our findings highlight novel mechanisms underlying the neuroprotective effect of Xuefu Zhuyu decoction pretreatment on ischemic stroke-induced brain damage through the glymphatic system. Xuefu Zhuyu decoction pretreatment may offer a promising approach to slow the onset and progression of ischemic stroke

Natural products modulate NLRP3 in ulcerative colitis

Ulcerative colitis (UC) is a clinically common, progressive, devastating, chronic inflammatory disease of the intestine that is recurrent and difficult to treat. Nod-like receptor protein 3 (NLRP3) is a protein complex composed of multiple proteins whose formation activates cysteine aspartate protease-1 (caspase-1) to induce the maturation and secretion of inflammatory mediators such as interleukin (IL)-1β and IL-18, promoting the development of inflammatory responses. Recent studies have shown that NLRP3 is associated with UC susceptibility, and that it maintains a stable intestinal environment by responding to a wide range of pathogenic microorganisms. The mainstay of treatment for UC is to control inflammation and relieve symptoms. Despite a certain curative effect, there are problems such as easy recurrence after drug withdrawal and many side effects associated with long-term medication. NLRP3 serves as a core link in the inflammatory response. If the relationship between NLRP3 and gut microbes and inflammation-associated factors can be analyzed concerning its related inflammatory signaling pathways, its expression status as well as specific mechanism in the course of IBD can be elucidated and further considered for clinical diagnosis and treatment of IBD, it is expected that the development of lead compounds targeting the NLRP3 inflammasome can be developed for the treatment of IBD. Research into the prevention and treatment of UC, which has become a hotbed of research in recent years, has shown that natural products are rich in therapeutic means, and multi-targets, with fewer adverse effects. Natural products have shown promise in treating UC in numerous basic and clinical trials over the past few years. This paper describes the regulatory role of the NLRP3 inflammasome in UC and the mechanism of recent natural products targeting NLRP3 against UC, which provides a reference for the clinical treatment of this disease