Global, regional and national temporal trends in prevalence for musculoskeletal disorders in women of childbearing age, 1990-2019: an age-period-cohort analysis based on the Global Burden of Disease Study 2019.

OBJECTIVES: To provide an overview and in-depth analysis of temporal trends in prevalence of musculoskeletal (MSK) disorders in women of childbearing age (WCBA) at global, regional and national levels over the last 30 years, with a special focus on their associations with age, period and birth cohort. METHODS: Estimates and 95% uncertainty intervals (UIs) for MSK disorders prevalence in WCBA were extracted from the Global Burden of Diseases, Injuries and Risk Factors Study 2019. An age-period-cohort model was adopted to estimate the overall annual percentage change of prevalence (net drift, % per year), annual percentage change of prevalence within each age group (local drift, % per year), fitted longitudinal age-specific rates adjusted for period deviations (age effects) and period/cohort relative risks (period/cohort effects) from 1990 to 2019. RESULTS: In 2019, the global number of MSK disorders prevalence in WCBA was 354.57 million (95% UI: 322.64 to 387.68). Fifty countries had at least one million prevalence, with India, China, the USA, Indonesia and Brazil being the highest accounting for 51.03% of global prevalence. From 1990 to 2019, a global net drift of MSK disorders prevalence in WCBA was -0.06% (95% CI: -0.07% to -0.05%) per year, ranging from -0.09% (95% CI: -0.10% to -0.07%) in low-middle sociodemographic index (SDI) region to 0.10% (95% CI: 0.08% to 0.12%) in high-middle SDI region, with 138 countries presenting increasing trends, 24 presenting decreasing trends and 42 presenting relatively flat trends. As reflected by local drift, higher SDI regions had more age groups showing rising prevalence whereas lower SDI regions had more declining prevalence. Globally, an increasing occurrence of MSK disorders prevalence in WCBA beyond adolescent and towards the adult stage has been prominent. Age effects illustrated similar patterns across different SDI regions, with risk increasing with age. High SDI region showed generally lower period risks over time, whereas others showed more unfavourable period risks. High, high-middle and middle SDI regions presented unfavourable prevalence deteriorations, whereas others presented favourable prevalence improvements in successively birth cohorts. CONCLUSIONS: Although a favourable overall temporal trend (net drift) of MSK disorders prevalence in WCBA was observed over the last 30 years globally, there were 138 countries showing unfavourable rising trends, coupled with deteriorations in period/cohort risks in many countries, collectively raising concerns about timely realisation of the Targets of Sustainable Development Goal. Improvements in the MSK disorders-related prevention, management and treatment programmes in WCBA could decline the relative risk for successively younger birth cohorts and for all age groups over period progressing.

Cytoskeletal activation of NHE1 regulates cell volume and DNA methylation.

The regulation of mammalian cell volume is crucial for maintaining key cellular processes. Cells can rapidly respond to osmotic and hydrostatic pressure imbalances during environmental challenges, generating fluxes of water and ions that alter volume within minutes. While the role of ion pump and leak in cell volume regulation has been well-established, the role of the actomyosin cytoskeleton and its substantial interplay with ion transporters are still unclear. In this work, we discover a system of cell volume regulation controlled by cytoskeletal activation of ion transporters. Under hypotonic shock, NIH-3T3 and MCF-10A display a 20% secondary volume increase (SVI) following the initial regulatory volume decrease. We show that SVI is initiated by Ca 2+ influx through stretch activated channel Piezo1 and subsequent actomyosin remodeling. Rather than contracting cells, actomyosin triggers cell swelling by activating Na + -H + exchanger 1 (NHE1) through their co-binding partner ezrin. Cytoskeletal activation of NHE1 can be similarly triggered by mechanical stretch and attenuated by soft substrates. This mechanism is absent in certain cancer cell lines such as HT1080 and MDA-MB-231, where volume regulation is dominated by intrinsic response of ion transporters. Moreover, cytoskeletal activation of NHE1 during SVI induces nuclear deformation, leading to DNA demethylation and a significant, immediate transcriptomic response in 3T3 cells, a phenomenon that is absent in HT1080 cells. Overall, our findings reveal the central role of Ca 2+ and actomyosin-mediated mechanosensation in the regulation of ion transport, cell volume, DNA methylation, and transcriptomics.

Age-standardized incidence, prevalence, and mortality rates of autoimmune diseases in women of childbearing age from 1990 to 2019.

AIM: To estimate the age-standardized incidence, prevalence, and mortality rates of autoimmune diseases including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), asthma, and psoriasis in women of childbearing age from 1990 to 2019, and to further analyze their changing trends, at global, regional, and national levels. METHODS: Women of childbearing age was defined as 15-49 years old. The estimates and 95% uncertainty intervals (UIs) for case number of RA, IBD, MS, T1DM, asthma and psoriasis in seven age groups (15-19, 20-24, 25-29, 30-34, 35-39, 40-44, 45-49 years) were extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Age standardization by direct method was adopted to estimate the age-standardized incidence, prevalence, and mortality rates of these autoimmune diseases in women of childbearing age. Joinpoint regression analysis was utilized to analyze the changing trends of estimated age-standardized incidence, prevalence, and mortality rates from 1990 to 2019 by calculating the average annual percentage change (AAPC) and its 95% confidence intervals (CIs). RESULTS: In 2019, the estimated global age-standardized incidence, prevalence, and mortality rates of RA in women of childbearing age was 17.13 (95% UI: 12.39 to 22.60), 215.86 (95% UI: 179.04 to 259.70), and 0.06 (95% UI: 0.04 to 0.08); of IBD was 5.85 (95% UI: 4.72 to 7.12), 63.54 (95% UI: 53.50 to 74.37), and 0.11 (95% UI: 0.08 to 0.13); of MS was 1.63 (95% UI: 1.05 to 2.28), 28.74 (95% UI: 23.80 to 34.46), and 0.17 (95% UI: 0.14 to 0.27); of T1DM was 6.22 (95% UI: 2.75 to 11.50), 290.51 (95% UI: 221.39 to 370.19), and 0.63 (95% UI: 0.48 to 0.78); of asthma was 291.14 (95% UI: 157.06 to 468.78), 2796.25 (95%UI: 1987.07 to 3842.97), and 1.42 (95% UI: 1.12 to 1.75), respectively. The estimated global age-standardized incidence and prevalence rates of psoriasis in women of childbearing age was 58.68 (95% UI: 51.04 to 66.85) and 477.20 (95% UI: 440.30 to 515.76). Highest disease burden generally exists in Region of the Americas and European Region. From 1990 to 2019, the estimated global age-standardized incidence and prevalence rates of RA (AAPC: 0.18, 95% CI: 0.11 to 0.24; AAPC: 0.24, 95% CI: 0.18 to 0.30) and T1DM (AAPC: 1.47, 95% CI: 1.40 to 1.54; AAPC: 0.83, 95% CI: 0.79 to 0.88) in women of childbearing age showed significantly increasing trends whereas those of IBD (AAPC: -0.76, 95% CI: -0.80 to -0.73; AAPC: -0.65, 95% CI: -0.70 to -0.60), MS (AAPC: -0.20, 95% CI: -0.23 to -0.16; AAPC: -0.25, 95% CI: -0.26 to -0.23), asthma (AAPC: -0.53, 95% CI: -0.60 to -0.47; AAPC: -0.74, 95% CI: -0.81 to -0.68), and psoriasis (AAPC: -0.83, 95% CI: -0.85 to -0.82; AAPC: -0.99, 95% CI: -1.02 to -0.96) showed significantly decreasing trends. Favorably, the estimated global age-standardized mortality rate of RA (AAPC: -1.32, 95% CI: -1.63 to -1.01), IBD (AAPC: -0.95, 95% CI: -1.06 to -0.84), MS (AAPC: -0.96, 95% CI: -1.12 to -0.80), T1DM (AAPC: -1.05, 95% CI: -1.21 to -0.89), and asthma (AAPC: -2.27, 95% CI: -2.34 to -2.19) in women of childbearing age all declined. The changing trends of estimated age-standardized incidence, prevalence, and mortality rates varied significantly across 204 countries and territories. CONCLUSIONS: Our study provides an accurate estimation on the age-standardization of disease indicators of autoimmune diseases in women of childbearing age. There are remarkable disparities in the incidence, prevalence, and mortality burden related to autoimmune diseases in women of childbearing age, as well as their changing trends across the world, suggesting that each individual government should establish flexible health policies and make reasonable source allocation to address different needs for autoimmune diseases in this population.

Temporal trends in the prevalence of autoimmune diseases from 1990 to 2019.

AIM: To describe current situation and analyze temporal trends of prevalence for four autoimmune diseases including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS) and psoriasis, at the global, continental, and national levels. METHODS: The estimates and 95% uncertainty interval (UI) for age-standardized prevalence rate (ASPR) of RA, IBD, MS and psoriasis were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. ASPR of RA, IBD, MS and psoriasis in 2019 was illustrated at the global, continental, and national levels. Joinpoint regression analysis was adopted to analyze the 1990-2019 temporal trends by calculating the annual percentage change (APC) and average APC (AAPC), as well as their 95% confidence interval (CI). RESULTS: In 2019, the global ASPR of RA, IBD, MS and psoriasis was 224.25 (95% UI: 204.94 to 245.99), 59.25 (95% UI: 52.78 to 66.47), 21.25 (95% UI: 18.52 to 23.91) and 503.62 (95% UI: 486.92 to 519.22), respectively, with ASPRs generally higher in Europe and America than in Africa and Asia. From 1990 to 2019, the global ASPR increased significantly for RA (AAPC = 0.27%, 95% CI: 0.24 to 0.30; P < 0.001) and decreased significantly for IBD (AAPC = -0.73%, 95% CI: -0.76 to -0.70; P < 0.001), MS (AAPC = -0.22%, 95% CI: -0.25 to -0.18; P < 0.001) and psoriasis (AAPC = -0.93%, 95% CI: -0.95 to -0.91; P < 0.001), with the most substantial changes occurring at different continents and periods. The trends of ASPR of these four autoimmune diseases varied significantly across 204 countries and territories. CONCLUSIONS: There is a strong heterogeneity in prevalence (2019), as well as their temporal trends (1990-2019) of autoimmune diseases across the world, highlighting the strong distributive inequities of autoimmune diseases worldwide, which may be instructive for better understanding the epidemiology of these diseases, appropriately allocating the medical resources, as well as making relevant health policies.

Emerging roles of air pollution and meteorological factors in autoimmune eye diseases.

Autoimmune eye diseases (AEDs), a collection of autoimmune inflammatory ocular conditions resulting from the dysregulation of immune system at the ocular level, can target both intraocular and periorbital structures leading to severe visual deficit and blindness globally. The roles of air pollution and meteorological factors in the initiation and progression of AEDs have been increasingly attractive, among which the systemic and local mechanisms are both involved in. Exposure to excessive air pollution and extreme meteorological conditions including PM2.5/PM0.1, environmental tobacco smoke, insufficient sunshine, and high temperature, etc., can disturb Th17/Treg balance, regulate macrophage polarization, activate neutrophils, induce systemic inflammation and oxidative stress, decrease retinal blood flow, promote tissue fibrosis, activate sympathetic nervous system, adversely affect nutrients synthetization, as well as induce heat stress, therefore may together deteriorate AEDs. The crosstalk among inflammation, oxidative stress and dysregulated immune system appeared to be prominent. In the present review, we will concern and summarize the potential mechanisms underlying linkages of air pollution and meteorological factors to ocular autoimmune and inflammatory responses. Moreover, we concentrate on the specific roles of air pollutants and meteorological factors in several major AEDs including uveitis, Graves' ophthalmopathy (GO), ocular allergic disease (OAD), glaucoma, diabetic retinopathy (DR), etc.

Myosin and [Formula: see text]-actinin regulation of stress fiber contractility under tensile stress.

Stress fibers are actomyosin bundles that regulate cellular mechanosensation and force transduction. Interacting with the extracellular matrix through focal adhesion complexes, stress fibers are highly dynamic structures regulated by myosin motors and crosslinking proteins. Under external mechanical stimuli such as tensile forces, the stress fiber remodels its architecture to adapt to external cues, displaying properties of viscoelastic materials. How the structural remodeling of stress fibers is related to the generation of contractile force is not well understood. In this work, we simulate mechanochemical dynamics and force generation of stress fibers using the molecular simulation platform MEDYAN. We model stress fiber as two connecting bipolar bundles attached at the ends to focal adhesion complexes. The simulated stress fibers generate contractile force that is regulated by myosin motors and [Formula: see text]-actinin crosslinkers. We find that stress fibers enhance contractility by reducing the distance between actin filaments to increase crosslinker binding, and this structural remodeling ability depends on the crosslinker turnover rate. Under tensile pulling force, the stress fiber shows an instantaneous increase of the contractile forces followed by a slow relaxation into a new steady state. While the new steady state contractility after pulling depends only on the overlap between actin bundles, the short-term contractility enhancement is sensitive to the tensile pulling distance. We further show that this mechanical response is also sensitive to the crosslinker turnover rate. Our results provide new insights into the stress fiber mechanics that have significant implications for understanding cellular adaptation to mechanical signaling.

JNK/c-Jun pathway activation is essential for HBx-induced IL-35 elevation to promote persistent HBV infection.

BACKGROUND: Immunoregulation plays pivotal roles during chronic hepatitis B virus (HBV) infection. Studies have shown that Interleukin (IL)-35 is an important molecule associated with inadequate immune response against HBV. However, the mechanisms involved in the up-regulation of IL-35 expression during persistent HBV infection remain unknown. METHODS: In this study, we constructed a plasmid expressing the HBV X protein (pCMV-HBx) to evaluate the relationship between HBx and IL-35. Activation of the JNK/c-Jun pathway was analyzed and chromatin immunoprecipitation followed by sequencing and luciferase reporter assays were performed to determine whether c-Jun could regulate IL-35 transcription. RESULTS: HBx can significantly activate IL-35 promoter in both LO2 and HepG2 cells compared to the control plasmid (pCMV-Tag2) using the dual-luciferase assay. Whereas other viral proteins, such as S, preS1, the core protein, had no significant effect on IL-35 expression. Similarly, WB and qRT-PCR also showed that HBx can significantly promote IL-35 expression at protein and mRNA levels in the aforementioned cells. The relevant pathway mechanism showed that the expression of JNK and c-Jun genes was significantly higher in transfected cells carrying pCMV-HBx than in the pCMV-Tag2-transfected and -untransfected cells. WB analysis revealed that phosphorylated JNK and c-Jun were overexpressed after HBx action. Conversely, the addition of the JNK/c-Jun signaling pathway inhibitor could significantly suppress HBx-induced IL-35 expression in a dose-dependent manner. CONCLUSIONS: A novel molecular mechanism of HBV-induced IL-35 expression was revealed, which involves JNK/c-Jun signaling in up-regulating IL-35 expression via HBx, resulting in transactivation of the IL-35 subunit EBI3 and p35 promoter.

Genetic and Phenotypic Characteristics of Carbapenem-Resistant Klebsiella pneumoniae Isolates from a Tertiary Hospital in Beijing.

Objective: Klebsiella pneumoniae is a common multidrug-resistant pathogen that jeopardizes the health of hospitalized patients. We aimed to study the phenotypic and genotypic characteristics of carbapenem-resistant K. pneumoniae (CRKP) isolates from a hospital in Beijing. Methods: Twenty-four CRKP clinical isolates were collected within a half-year to investigate antimicrobial resistance and genomic characteristics. Illumina and Nanopore sequencing were performed to assemble and annotate genomes. Results: All strains were multi-drug resistant. Twenty-two strains carried the bla KPC-2 gene and two harbored bla NDM-5. Multilocus sequence type(MLST) analysis identified five sequence types; most isolates belonged to ST11. Three strains were isolated from the same patient; each carried a different plasmid replicon, either IncFII (pHN7A8), IncX, or IncFIB (K). Conclusion: This study furthers the understanding of CRKP antimicrobial resistance genotypes, and may facilitate the control of nosocomial infections caused by antimicrobial-resistant pathogens.

A tug of war between filament treadmilling and myosin induced contractility generates actin rings.

In most eukaryotic cells, actin filaments assemble into a shell-like actin cortex under the plasma membrane, controlling cellular morphology, mechanics, and signaling. The actin cortex is highly polymorphic, adopting diverse forms such as the ring-like structures found in podosomes, axonal rings, and immune synapses. The biophysical principles that underlie the formation of actin rings and cortices remain unknown. Using a molecular simulation platform called MEDYAN, we discovered that varying the filament treadmilling rate and myosin concentration induces a finite size phase transition in actomyosin network structures. We found that actomyosin networks condense into clusters at low treadmilling rates or high myosin concentrations but form ring-like or cortex-like structures at high treadmilling rates and low myosin concentrations. This mechanism is supported by our corroborating experiments on live T cells, which exhibit ring-like actin networks upon activation by stimulatory antibody. Upon disruption of filament treadmilling or enhancement of myosin activity, the pre-existing actin rings are disrupted into actin clusters or collapse towards the network center respectively. Our analyses suggest that the ring-like actin structure is a preferred state of low mechanical energy, which is, importantly, only reachable at sufficiently high treadmilling rates.

Extracellular Hydraulic Resistance Enhances Cell Migration.

Cells migrating in vivo encounter microenvironments with varying physical properties. One such physical variable is the fluid viscosity surrounding the cell. Increased viscosity is expected to increase the hydraulic resistance experienced by the cell and decrease cell speed. The authors demonstrate that contrary to this expected result, cells migrate faster in high viscosity media on 2-dimensional substrates. Both actin dynamics and water dynamics driven by ion channel activity are examined. Results show that cells increase in area in high viscosity and actomyosin dynamics remain similar. Inhibiting ion channel fluxes in high viscosity media results in a large reduction in cell speed, suggesting that water flux contributes to the observed speed increase. Moreover, inhibiting actin-dependent vesicular trafficking that transports ion channels to the cell boundary changes ion channel spatial positioning and reduces cell speed in high viscosity media. Cells also display altered Ca2+ activity in high viscosity media, and when cytoplasmic Ca2+ is sequestered, cell speed reduction and altered ion channel positioning are observed. Taken together, it is found that the cytoplasmic actin-phase and water-phase are coupled to drive cell migration in high viscosity media, in agreement with physical modeling that also predicts the observed cell speedup in high viscosity environments.

Simulated actin reorganization mediated by motor proteins.

Cortical actin networks are highly dynamic and play critical roles in shaping the mechanical properties of cells. The actin cytoskeleton undergoes significant reorganization in many different contexts, including during directed cell migration and over the course of the cell cycle, when cortical actin can transition between different configurations such as open patched meshworks, homogeneous distributions, and aligned bundles. Several types of myosin motor proteins, characterized by different kinetic parameters, have been involved in this reorganization of actin filaments. Given the limitations in studying the interactions of actin with myosin in vivo, we propose stochastic agent-based models and develop a set of data analysis measures to assess how myosin motor proteins mediate various actin organizations. In particular, we identify individual motor parameters, such as motor binding rate and step size, that generate actin networks with different levels of contractility and different patterns of myosin motor localization, which have previously been observed experimentally. In simulations where two motor populations with distinct kinetic parameters interact with the same actin network, we find that motors may act in a complementary way, by tuning the actin network organization, or in an antagonistic way, where one motor emerges as dominant. This modeling and data analysis framework also uncovers parameter regimes where spatial segregation between motor populations is achieved. By allowing for changes in kinetic rates during the actin-myosin dynamic simulations, our work suggests that certain actin-myosin organizations may require additional regulation beyond mediation by motor proteins in order to reconfigure the cytoskeleton network on experimentally-observed timescales.

Transplantation of Human Umbilical Cord Mesenchymal Stem Cells-Derived Neural Stem Cells Pretreated with Neuregulin1ß Ameliorate Cerebral Ischemic Reperfusion Injury in Rats.

Ischemic stroke is a common cerebrovascular disease and recovering blood flow as early as possible is essential to reduce ischemic damage and maintain neuronal viability, but the reperfusion process usually causes additional damage to the brain tissue in the ischemic area, namely ischemia reperfusion injury. The accumulated studies have revealed that transplantation of exogenous neural stem cells (NSCs) is an ideal choice for the treatment of ischemia reperfusion injury. At present, the source and efficacy of exogenous NSCs after transplantation is still one of the key issues that need to be resolved. In this study, human umbilical cord mesenchymal stem cells (hUC-MSCs) were obtained and induced into NSCs byadding growth factor and neuregulin1ß (NRG1ß) was introduced during the differentiation process of NSCs. Then, the rat middle cerebral artery occlusion/reperfusion (MCAO/R) models were established, and the therapeutic effects were evaluated among groups treated by NRG1ß, NSCs and NSCs pretreated with 10 nM NRG1ß (NSCs-10 nM NRG1ß) achieved through intra-arterial injection. Our data show that the NSCs-10 nM NRG1ß group significantly improves neurobehavioral function and infarct volume after MCAO/R, as well as cerebral cortical neuron injury, ferroptosis-related indexes and mitochondrial injury. Additionally, NSCs-10 nM NRG1ß intervention may function through regulating the p53/GPX4/SLC7A11 pathway, and reducing the level of ferroptosis in cells, further enhance the neuroprotective effect on injured cells.

Body Temperature Monitoring for Regular COVID-19 Prevention Based on Human Daily Activity Recognition.

Existing wearable systems that use G-sensors to identify daily activities have been widely applied for medical, sports and military applications, while body temperature as an obvious physical characteristic that has rarely been considered in the system design and relative applications of HAR. In the context of the normalization of COVID-19, the prevention and control of the epidemic has become a top priority. Temperature monitoring plays an important role in the preliminary screening of the population for fever. Therefore, this paper proposes a wearable device embedded with inertial and temperature sensors that is used to apply human behavior recognition (HAR) to body surface temperature detection for body temperature monitoring and adjustment by evaluating recognition algorithms. The sensing system consists of an STM 32-based microcontroller, a 6-axis (accelerometer and gyroscope) sensor, and a temperature sensor to capture the original data from 10 individual participants under 4 different daily activity scenarios. Then, the collected raw data are pre-processed by signal standardization, data stacking and resampling. For HAR, several machine learning (ML) and deep learning (DL) algorithms are implemented to classify the activities. To compare the performance of different classifiers on the seven-dimensional dataset with temperature sensing signals, evaluation metrics and the algorithm running time are considered, and random forest (RF) is found to be the best-performing classifier with 88.78% recognition accuracy, which is higher than the case of the absence of temperature data (<78%). In addition, the experimental results show that participants' body surface temperature in dynamic activities was lower compared to sitting, which can be associated with the possible missing fever population due to temperature deviations in COVID-19 prevention. According to different individual activities, epidemic prevention workers are supposed to infer the corresponding standard normal body temperature of a patient by referring to the specific values of the mean expectation and variance in the normal distribution curve provided in this paper.

Dietary pectin caused great changes in bile acid profiles of Pelteobagrus fulvidraco.

To reveal the impact of dietary fiber (DF) on the bile acid (BA) profiles of fish, yellow catfish (Pelteobagrus fulvidraco) were fed a diet containing 300 g kg-1 dextrin (CON diet, control) or pectin (a type of soluble DF, PEC diet) for 7 days, and then the BA profiles were analyzed by UHPLC-MS/MS. A total of 26 individuals of BAs were detected in the fish body, with 8, 10, 14, and 22 individuals of BAs detected in the liver, serum, bile, and hindgut digesta, respectively. The conjugated BAs (CBAs) of fish were dominated by taurine CBAs (TCBAs). The concentrations of free BAs (FBAs) and the value of FBAs/CBAs in the bile of fish fed the PEC diet were nearly 5 and 7 times higher, respectively than those in fish fed the CON diet. The value of glycine CBAs/TCBAs in the liver, serum and bile of fish fed the PEC diet was significantly lower, and in the hindgut digesta was higher than that of fish fed the CON diet (P < 0.05). These results suggested that dietary pectin greatly changed the BA profiles of Pelteobagrus fulvidraco, attributed to inhibition of reabsorption of BAs. Therefore, attention should be paid to the impact on BA homeostasis when replacing fishmeal with DF-rich plant ingredients in the fish diet.

Distinct Bile Acid Profiles in Patients With Chronic Hepatitis B Virus Infection Reveal Metabolic Interplay Between Host, Virus and Gut Microbiome.

Hepatitis B virus (HBV) can hijack the host bile acids (BAs) metabolic pathway during infection in cell and animal models. Additionally, microbiome was known to play critical role in the enterohepatic cycle of BAs. However, the impact of HBV infection and associated gut microbiota on the BA metabolism in chronic hepatitis B (CHB) patients is unknown. This study aimed to unveil the distinct BA profiles in chronic HBV infection (CHB) patients with no or mild hepatic injury, and to explore the relationship between HBV, microbiome and BA metabolism with clinical implications. Methods: Serum BA profiles were compared between CHB patients with normal ALT (CHB-NALT, n = 92), with abnormal ALT (CHB-AALT, n = 34) and healthy controls (HCs, n = 28) using UPLC-MS measurement. Hepatic gene expression in CHB patients were explored using previously published transcriptomic data. Fecal microbiome was compared between 30 CHB-NALT and 30 HCs using 16S rRNA sequencing, and key microbial function was predicted by PICRUSt analysis. Results: Significant higher percentage of conjugated BAs and primary BAs was found in CHB patients even without apparent liver injury. Combinatory BA features can discriminate CHB patients and HCs with high accuracy (AUC = 0.838). Up-regulation of BA importer Na+ taurocholate co-transporting peptide (NTCP) and down-regulation of bile salt export pump (BSEP) was found in CHB-NALT patients. The microbial diversity and abundance of Lactobacillus, Clostridium, Bifidobacterium were lower in CHB-NALT patients compared to healthy controls. Suppressed microbial bile salt hydrolases (BSH), 7-alpha-hydroxysteroid dehydrogenase (hdhA) and 3-dehydro-bile acid Delta 4, 6-reductase (BaiN) activity were found in CHB-NALT patients. Conclusion: This study provides new insight into the BA metabolism influenced both by HBV infection and associated gut microbiome modulations, and may lead to novel strategy for clinical management for chronic HBV infection.

Different translation dynamics of ß- and γ-actin regulates cell migration.

ß- and γ-cytoplasmic actins are ubiquitously expressed in every cell type and are nearly identical at the amino acid level but play vastly different roles in vivo. Their essential roles in embryogenesis and mesenchymal cell migration critically depend on the nucleotide sequences of their genes, rather than their amino acid sequences; however, it is unclear which gene elements underlie this effect. Here we address the specific role of the coding sequence in ß- and γ-cytoplasmic actins' intracellular functions, using stable polyclonal populations of immortalized mouse embryonic fibroblasts with exogenously expressed actin isoforms and their 'codon-switched' variants. When targeted to the cell periphery using ß-actin 3'UTR; ß-actin and γ-actin have differential effects on cell migration. These effects directly depend on the coding sequence. Single-molecule measurements of actin isoform translation, combined with fluorescence recovery after photobleaching, demonstrate a pronounced difference in ß- and γ-actins' translation elongation rates in cells, leading to changes in their dynamics at focal adhesions, impairments in actin bundle formation, and reduced cell anchoring to the substrate during migration. Our results demonstrate that coding sequence-mediated differences in actin translation play a key role in cell migration.

Most mammalian cells make both ß- and γ-actin, two proteins which shape the cell's internal skeleton and its ability to migrate. The molecules share over 99% of their sequence, yet they play distinct roles. In fact, deleting the ß-actin gene in mice causes death in the womb, while the animals can survive with comparatively milder issues without their γ-actin gene. How two similar proteins can have such different biological roles is a long-standing mystery. A closer look could hold some clues: ß- and γ-actin may contain the same blocks (or amino acids), but the genetic sequences that encode these proteins differ by about 13%. This is because different units of genetic information ­ known as synonymous codons ­ can encode the same amino acid. These 'silent substitutions' have no effect on the sequence of the proteins, yet a cell reads synonymous codons (and therefore produces proteins) at different speeds. To find out the impact of silent substitutions, Vedula et al. swapped the codons for the two proteins, forcing mouse cells to produce ß-actin using γ-actin codons, and vice versa. Cells with non-manipulated γ-actin and those with ß-actin made using γ-actin codons could move much faster than cells with ß-actin. This suggested that silent substitutions were indeed affecting the role of the protein. Vedula et al. found that cells read γ-codons ­ and therefore made γ-actin ­ much more slowly than ß-codons: this also affected how quickly the protein could be dispatched where it was needed in the cell. Slower production meant that bundles of γ-actin were shorter, which allowed cells to move faster by providing a weaker anchoring system. Overall, this work provides new links between silent substitutions and protein behavior, a relatively new research area which is likely to shed light on other protein families.

Clinical efficacy of methylprednisolone and the combined use of lopinavir/ritonavir with arbidol in treatment of coronavirus disease 2019.

This study aims to comparatively analyze the therapeutic efficacy upon multiple medication plans over lopinavir/ritonavir (LPV/r), arbidol (ARB), and methylprednisolone on patients with coronavirus disease 2019 (COVID-19). Totally, 75 COVID-19 patients admitted to The First Affiliated Hospital, Zhejiang University School of Medicine from January 22, 2020 to February 29, 2020 were recruited and grouped based on whether or not LPV/r and ARB were jointly used and whether or not methylprednisolone was used. Indexes including body temperature, time for nucleic acid negative conversion, hospital stays, and laboratory indexes were examined and compared. For all patients, there were no significant differences in the change of body temperature, the time for negative conversion, and hospital stays whether LPV/r and ARB were jointly used or not. While for severe and critically severe patients, methylprednisolone noticeably reduced the time for negative conversion. Meanwhile, the clinical efficacy was superior on patients receiving methylprednisolone within 3 days upon admission, and the duration of hospital stays was much shorter when methylprednisolone was given at a total dose of 0-400 mg than a higher dose of >400 mg if all patients received a similar dose per day. Nonetheless, no significant changes across hepatic, renal, and myocardial function indexes were observed. LPV/r combined with ARB produced no noticeably better effect on COVID-19 patients relative to the single-agent treatment. Additionally, methylprednisolone was efficient in severe and critically severe cases, and superior efficacy could be realized upon its early, appropriate, and short-term application.

Effect of Corticosteroid Therapy on the Duration of SARS-CoV-2 Clearance in Patients with Mild COVID-19: A Retrospective Cohort Study.

INTRODUCTION: In December, 2019, an outbreak of the coronavirus disease 2019 (COVID-19), which was caused by a novel coronavirus, started in Wuhan, China. So far, there is limited clinical evidence on the effect of corticosteroid therapy for this disease. This study aims to investigate the association between corticosteroid therapy and the duration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance among patients with mild COVID-19. METHODS: Patients with mild COVID-19 were enrolled from two medical centers in China between January 13, 2020 and February 29, 2020. Baseline characteristics and durations of RNA clearance were compared between the corticosteroid and non-corticosteroid therapy groups. The independent effects of corticosteroid therapy on the duration of RNA clearance were estimated by generalized linear models. RESULTS: Of 82 patients with a mild infection, 40 patients were male (48.8%), with a median age of 49 years (interquartile range, IQR 36-61). Among those patients, 36 patients (43.9%) received corticosteroid therapy. The adjusted multivariate models showed that the effects of corticosteroids were non-significant on the durations of onset to first RNA clearance [ß 2.48, 95% CI (95% confidence interval) - 0.42 to 5.38, P = 0.0926] and to persistent RNA clearance (ß 1.54, 95% CI - 1.41 to 4.48, P = 0.3016), and durations of therapy to first RNA clearance (ß 2.16, 95% CI - 0.56 to 4.89, P = 0.1184) and to persistent RNA clearance (ß 1.22, 95% CI - 1.52 to 3.95, P = 0.3787). CONCLUSIONS: Corticosteroid therapy in patients with mild COVID-19 was not associated with the duration of SARS-CoV-2 clearance, suggesting that the use of corticosteroids may not be beneficial for patients with mild COVID-19 and should be prudently recommended in clinical practice. However, further studies are needed to verify the findings.

Leveraging Wearable Sensors for Human Daily Activity Recognition with Stacked Denoising Autoencoders.

Activity recognition has received considerable attention in many research fields, such as industrial and healthcare fields. However, many researches about activity recognition have focused on static activities and dynamic activities in current literature, while, the transitional activities, such as stand-to-sit and sit-to-stand, are more difficult to recognize than both of them. Consider that it may be important in real applications. Thus, a novel framework is proposed in this paper to recognize static activities, dynamic activities, and transitional activities by utilizing stacked denoising autoencoders (SDAE), which is able to extract features automatically as a deep learning model rather than utilize manual features extracted by conventional machine learning methods. Moreover, the resampling technique (random oversampling) is used to improve problem of unbalanced samples due to relatively short duration characteristic of transitional activity. The experiment protocol is designed to collect twelve daily activities (three types) by using wearable sensors from 10 adults in smart lab of Ulster University, the experiment results show the significant performance on transitional activity recognition and achieve the overall accuracy of 94.88% on three types of activities. The results obtained by comparing with other methods and performances on other three public datasets verify the feasibility and priority of our framework. This paper also explores the effect of multiple sensors (accelerometer and gyroscope) to determine the optimal combination for activity recognition.

A Deep Learning System to Screen Novel Coronavirus Disease 2019 Pneumonia.

The real-time reverse transcription-polymerase chain reaction (RT-PCR) detection of viral RNA from sputum or nasopharyngeal swab had a relatively low positive rate in the early stage of coronavirus disease 2019 (COVID-19). Meanwhile, the manifestations of COVID-19 as seen through computed tomography (CT) imaging show individual characteristics that differ from those of other types of viral pneumonia such as influenza-A viral pneumonia (IAVP). This study aimed to establish an early screening model to distinguish COVID-19 from IAVP and healthy cases through pulmonary CT images using deep learning techniques. A total of 618 CT samples were collected: 219 samples from 110 patients with COVID-19 (mean age 50 years; 63 (57.3%) male patients); 224 samples from 224 patients with IAVP (mean age 61 years; 156 (69.6%) male patients); and 175 samples from 175 healthy cases (mean age 39 years; 97 (55.4%) male patients). All CT samples were contributed from three COVID-19-designated hospitals in Zhejiang Province, China. First, the candidate infection regions were segmented out from the pulmonary CT image set using a 3D deep learning model. These separated images were then categorized into the COVID-19, IAVP, and irrelevant to infection (ITI) groups, together with the corresponding confidence scores, using a location-attention classification model. Finally, the infection type and overall confidence score for each CT case were calculated using the Noisy-OR Bayesian function. The experimental result of the benchmark dataset showed that the overall accuracy rate was 86.7% in terms of all the CT cases taken together. The deep learning models established in this study were effective for the early screening of COVID-19 patients and were demonstrated to be a promising supplementary diagnostic method for frontline clinical doctors.