Activin A as a potential biomarker for preserved ratio impaired spirometry (PRISm) and clinical outcomes in community-dwelling adults.

INTRODUCTION: This study endeavors to decipher the association between Activin A and PRISm, thereby addressing the potential of Activin A as a serum biomarker for early detection and long-term clinical outcome prediction of PRISm and subsequent all-cause mortality. METHODS: The study sample comprised middle-aged and older adults from the I-Lan Longitudinal Aging Study. Pulmonary function including forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were measured. Demographic data and laboratory data (including serum Activin A levels) were also collected. Multivariate logistic regression and Cox proportional hazards models were used to identify independent predictors of PRISm and all-cause mortality, respectively. RESULTS: Among 711 eligible participants, 34 % had PRISm. The risk of PRISm elevated with Activin A levels in group quartiles (adjusted odds ratio (aOR), Q2: 1.606 [95 % CI 0.972-2.652], p = 0.064, Q3: 2.666 [1.635-4.348], p < 0.001, Q4: 3.225 [1.965-5.293], p < 0.001). On the other hand, lower hemoglobin (aOR: 1.122, p = 0.041) and higher blood urea nitrogen (BUN) levels (aOR: 1.033, p = 0.048) were associated with increased risk of PRISm. In addition, the PRISm group had a higher all-cause mortality rate (non-PRISm 4.5% vs. PRISm 8.3 %, p = 0.038). Multivariate Cox models also identify a higher level of Activin A as a risk factor of all-cause mortality (aHR: 1.001 [1.000-1.003], p = 0.042). CONCLUSIONS: Higher Activin A quartiles were linked to increased risk of PRISm, along with lower hemoglobin and higher BUN levels. Additonally, elevated Activin A was a significant risk factor of all-cause mortality.

The crosstalk between copper-induced oxidative stress and cuproptosis: a novel potential anticancer paradigm.

Copper is a crucial trace element that plays a role in various pathophysiological processes in the human body. Copper also acts as a transition metal involved in redox reactions, contributing to the generation of reactive oxygen species (ROS). Under prolonged and increased ROS levels, oxidative stress occurs, which has been implicated in different types of regulated cell death. The recent discovery of cuproptosis, a copper-dependent regulated cell death pathway that is distinct from other known regulated cell death forms, has raised interest to researchers in the field of cancer therapy. Herein, the present work aims to outline the current understanding of cuproptosis, with an emphasis on its anticancer activities through the interplay with copper-induced oxidative stress, thereby providing new ideas for therapeutic approaches targeting modes of cell death in the future.

Sex-specific implications of inflammation in covert cerebral small vessel disease.

BACKGROUND: The relationship between inflammation and covert cerebral small vessel disease (SVD) with regards to sex difference has received limited attention in research. We aim to unravel the intricate associations between inflammation and covert SVD, while also scrutinizing potential sex-based differences in these connections. METHODS: Non-stroke/dementia-free study population was from the I-Lan longitudinal Aging Study. Severity and etiology of SVD were assessed by 3T-MRI in each participant. Systemic and vascular inflammatory-status was determined by the circulatory levels of high-sensitivity C-reactive protein (hsCRP) and homocysteine, respectively. Sex-specific multivariate logistic regression to calculate odds ratios (ORs) and interaction models to scrutinize women-to-men ratios of ORs (RORs) were used to evaluate the potential impact of sex on the associations between inflammatory factors and SVD. RESULTS: Overall, 708 participants (62.19 ± 8.51 years; 392 women) were included. Only women had significant associations between homocysteine levels and covert SVD, particularly in arteriosclerosis/lipohyalinosis SVD (ORs[95%CI]: 1.14[1.03-1.27] and 1.15[1.05-1.27] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively). Furthermore, higher circulatory levels of homocysteine were associated with a greater risk of covert SVD in women compared to men, as evidenced by the RORs [95%CI]: 1.14[1.01-1.29] and 1.14[1.02-1.28] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively. No significant associations were found between circulatory hsCRP levels and SVD in either sex. CONCLUSION: Circulatory homocysteine is associated with covert SVD of arteriosclerosis/lipohyalinosis solely in women. The intricacies underlying the sex-specific effects of homocysteine on SVD at the preclinical stage warrant further investigations, potentially leading to personalized/tailored managements. TRIAL REGISTRATION: Not applicable.

A 5-day course of rTMS before pain onset ameliorates future pain and increases sensorimotor peak alpha frequency.

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine i) whether 5 consecutive days of rTMS delivered prior to experimentally-induced prolonged jaw pain could reduce future pain intensity and ii) whether any effects of rTMS on pain were mediated by changes in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from Day 0-4, forty healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. PAF and CME were assessed on Day 0 (before rTMS) and Day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor (NGF) in the right masseter muscle after the final rTMS session. From Days 5-25, participants completed twice-daily electronic dairies including pain on chewing and yawning (primary outcomes), as well as pain during other activities (e.g. talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Although active rTMS increased PAF, the effects of rTMS on pain were not mediated by changes in PAF or CME. This study is the first to show that rTMS delivered prior to pain onset can protect against future pain and associated functional impairment. Thus, rTMS may hold promise as a prophylactic intervention for persistent pain.

The Influence of Pain Hypersensitivity and Psychological Factors on Pain and Disability in the Transition From Acute to Chronic Low Back Pain: A Longitudinal Exploratory Investigation and Cluster Analysis.

Pain hypersensitivity is present in some people with acute low back pain (LBP) and thought to be involved in the development of chronic LBP. Early evidence suggests that pain hypersensitivity in acute LBP precedes poor long-term outcome. We aimed to examine whether the presence of pain hypersensitivity in acute LBP influenced recovery status at 6 months and differentiated how pain and disability changed over time. Participants with acute nonspecific LBP (<6 weeks after pain onset, N = 118) were included in this longitudinal study. Quantitative sensory testing, including pressure and heat pain thresholds, and conditioned pain modulation and questionnaires were compared at baseline and longitudinally (at 3 and 6 months) between recovered and unrecovered participants. Using k-means clustering, we identified subgroups based on baseline sensory measures alone, and in combination with psychological factors, and compared pain and disability outcomes between subgroups. Sensory measures did not differ at baseline or longitudinally between recovered (N = 50) and unrecovered (N = 68) participants. Subgrouping based on baseline sensory measures alone did not differentiate pain or disability outcomes at any timepoint. Participants with high psychological distress at baseline (N = 19) had greater disability, but not pain, at all timepoints than those with low psychological distress, regardless of the degrees of pain sensitivity. Our findings suggest that pain hypersensitivity in acute LBP does not precede poor recovery at 6 months or differentiate how pain and disability change over time. High psychological distress during acute LBP is associated with unremitting and pronounced disability, while pain severity is unaffected. PERSPECTIVE: Pain hypersensitivity is thought to be involved in the transition to chronic LBP. Contradictory to prevailing hypothesis, our findings suggest pain hypersensitivity alone in acute LBP does not precede poor recovery. High psychological distress in acute LBP has a stronger influence than pain hypersensitivity on long-term disability, but not pain outcomes.

Follistatin-respiratory connection predicting all-cause mortality among community-dwelling middle-to-old age individuals: Results from the I-Lan Longitudinal Study.

OBJECTIVES: The link between aging and pulmonary function decline is well-established, but the underlying mechanisms have yet to be fully revealed. Serum follistatin, a myokine implicated in muscle degeneration, may play a role in age-related pulmonary changes. This study aims to investigate the relationship between serum follistatin levels and pulmonary function decline in community-dwelling older adults, and evaluate their combined association with all-cause mortality. RESEARCH DESIGN AND METHODS: This longitudinal cohort study utilized data from 751 participants aged ≥50 years in the I-Lan Longitudinal Aging Study between 2018-2019. Serum follistatin levels, spirometry results, demographic and clinical data were retrieved. Participants were stratified based on their follistatin levels. Survival curves and group comparisons based on follistatin levels and decline in peak expiratory flow (PEF) using Kaplan-Meier analysis and log-rank tests. Multivariate Cox proportional hazards models were further used to identify independent predictors of all-cause mortality during the 52-month follow-up. RESULTS: Elevated follistatin levels significantly correlated with worse pulmonary function, particularly decreased PEF (p = 0.030). Kaplan-Meier analysis revealed the combination of elevated follistatin levels and decreased PEF was associated with increased risk of all-cause mortality (Log-rank p = 0.023). Cox proportional hazards models further identified that concurrent presence of higher follistatin levels and decreased PEF predicted higher risk of all-cause mortality (adjusted HR 3.58, 95% CI: 1.22-10.53, p = 0.020). CONCLUSION: Higher serum follistatin levels correlate with decreased pulmonary function, specifically PEF decline, in community-dwelling older adults. Furthermore, the coexistence of elevated follistatin levels and decreased PEF was associated with risk of all-cause mortality. Follistatin may serve as a biomarker for pulmonary aging and related adverse outcomes.

Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells.

Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell-state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing nongenetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupt acquired resistance in GBM.

Nailfold capillary measurements correlated to NOTCH3 R544C mutation in preclinical CADASIL patients.

BACKGROUND: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by NOTCH3 mutation. Nailfold capillaroscopy is a non-invasive technique typically used for rheumatic diseases. It has potential in other conditions linked to vascular pathology. However, capillaroscopy in CADASIL has not been explored. This study aims to investigate whether capillaroscopy measurements can correlate with brain vascular changes in preclinical CADASIL patients, specifically those with NOTCH3 mutation. METHODS: This study included 69 participants from the Taiwan Precision Medicine Initiative (TPMI) dataset who visited Taichung Veterans General Hospital from January to December 2022. All individuals underwent genetic studies, brain imaging and nailfold capillaroscopy. The Mann-Whitney U test was used to compare results of brain imaging between carriers and controls. It was also used to compare measurements in nailfold capillaroscopy within each group. Spearman Rank Correlation Analysis was used to explore the relationship between capillary measurements and brain MRI results. RESULTS: White matter hyperintensities (WMH) expression was positively correlated with capillary dimension and negatively correlated with density. Our results presented that R544C carriers exhibited a diffuse increase in WMH (p < 0.001) and a global reduction in gray matter volume but preserved in specific areas. The white matter lesion scores in all brain regions were higher in the mutation carriers than the controls. (p < 0.001). CONCLUSION: This research highlights the association of nailfold capillaroscopy findings with white matter lesions in preclinical CADASIL patients. Capillaroscopy guides an effective screening strategy in individuals with NOTCH3 mutations.

Safeguarding vitality and cognition: The role of sarcopenia in intrinsic capacity decline among octogenarians from multiple cohorts.

BACKGROUND: Sarcopenia and intrinsic capacity (IC) declines pose significant challenges to healthy aging, particularly in the rapidly growing octogenarian population. This study aimed to elucidate the relationship between sarcopenia and declines in IC across multiple cohorts of community-dwelling older adults. METHODS: Data from four Taiwanese cohorts were analyzed. Sarcopenia was diagnosed based on the Asian Working Group for Sarcopenia (AWGS) 2019 criteria (algorithm 1: categorized as either having possible sarcopenia or not (robust); algorithm 2: categorized as robust, possible sarcopenia or sarcopenia). IC was operationalized using the World Health Organization's Integrated Care for Older People (ICOPE) framework (step 1 and step 2), encompassing six domains: locomotion, vitality, vision, hearing, cognition, and psychological well-being. Multivariable logistic regression models were adopted to assess the association between sarcopenia and IC decline. RESULTS: Among 599 octogenarians (median age 82.2 years, 54.8% male), the prevalence of possible sarcopenia (algorithm 1) was 64.6%. When adopting algorithm 2, the prevalence of possible sarcopenia and sarcopenia was 46,2% and 32.1%, respectively. After adjusting for covariates, participants with possible sarcopenia or sarcopenia (algorithm 2) were more likely to exhibit declines in vitality (ICOPE Step 1: possible sarcopenia aOR 3.65, sarcopenia aOR 4.74; ICOPE Step 2: possible sarcopenia aOR 5.11, sarcopenia aOR 14.77) and cognition (ICOPE Step 1: possible sarcopenia aOR 2.40, sarcopenia aOR 2.12; ICOPE Step 2: possible sarcopenia aOR 2.02, sarcopenia aOR 2.51) compared to robust individuals. CONCLUSIONS: This study underscores the robust association between sarcopenia and declines in vitality and cognition among octogenarians, highlighting the importance of sarcopenia screening and management in promoting healthy longevity in this vulnerable population.

Survey of hepatitis B virus infection status after 35 years of universal vaccination implementation in Taiwan.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination. METHODS: A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated. RESULTS: After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed. CONCLUSION: The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV.

Can non-invasive brain stimulation modulate peak alpha frequency in the human brain? A systematic review and meta-analysis.

Peak alpha frequency (PAF), the dominant oscillatory frequency within the alpha range (8-12 Hz), is associated with cognitive function and several neurological conditions, including chronic pain. Manipulating PAF could offer valuable insight into the relationship between PAF and various functions and conditions, potentially providing new treatment avenues. This systematic review aimed to comprehensively synthesise effects of non-invasive brain stimulation (NIBS) on PAF speed. Relevant studies assessing PAF pre- and post-NIBS in healthy adults were identified through systematic searches of electronic databases (Embase, PubMed, PsychINFO, Scopus, The Cochrane Library) and trial registers. The Cochrane risk-of-bias tool was employed for assessing study quality. Quantitative analysis was conducted through pairwise meta-analysis when possible; otherwise, qualitative synthesis was performed. The review protocol was registered with PROSPERO (CRD42020190512) and the Open Science Framework (https://osf.io/2yaxz/). Eleven NIBS studies were included, all with a low risk-of-bias, comprising seven transcranial alternating current stimulation (tACS), three repetitive transcranial magnetic stimulation (rTMS), and one transcranial direct current stimulation (tDCS) study. Meta-analysis of active tACS conditions (eight conditions from five studies) revealed no significant effects on PAF (mean difference [MD] = -0.12, 95% CI = -0.32 to 0.08, p = 0.24). Qualitative synthesis provided no evidence that tDCS altered PAF and moderate evidence for transient increases in PAF with 10 Hz rTMS. However, it is crucial to note that small sample sizes were used, there was substantial variation in stimulation protocols, and most studies did not specifically target PAF alteration. Further studies are needed to determine NIBS's potential for modulating PAF.

The Epidemiology, Management and Therapeutic Outcomes of Subdural Empyema in Neonates with Acute Bacterial Meningitis.

Background: Subdural empyema is one of the more serious complications of bacterial meningitis and therapeutic challenges to clinicians. We aimed to evaluate the clinical characteristics, treatment, and outcome of subdural empyema in neonates with bacterial meningitis. Methods: A retrospective cohort study was conducted in two medical centers in Taiwan that enrolled all cases of neonates with subdural empyema after bacterial meningitis between 2003 and 2020. Results: Subdural empyema was diagnosed in 27 of 153 (17.6%) neonates with acute bacterial meningitis compared with cases of meningitis without subdural empyema. The demographics and pathogen distributions were comparable between the study group and the controls, but neonates with subdural empyema were significantly more likely to have clinical manifestations of fever (85.2%) and seizure (81.5%) (both p values < 0.05). The cerebrospinal fluid results of neonates with subdural empyema showed significantly higher white blood cell counts, lower glucose levels and higher protein levels (p = 0.011, 0.003 and 0.006, respectively). Neonates with subdural empyema had a significantly higher rate of neurological complications, especially subdural effusions and periventricular leukomalacia. Although the final mortality rate was not increased in neonates with subdural empyema when compared with the controls, they were often treated much longer and had a high rate of long-term neurological sequelae. Conclusions: Subdural empyema is not uncommon in neonates with acute bacterial meningitis and was associated with a high risk of neurological complications, although it does not significantly increase the final mortality rate. Close monitoring of the occurrence of subdural empyema is required, and appropriate long-term antibiotic treatment after surgical intervention may lead to optimized outcomes.

Numb positively regulates Hedgehog signaling at the ciliary pocket.

Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identify Numb as a ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impedes Sonic hedgehog (Shh)-induced Ptch1 exit from the cilium, resulting in reduced Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into cell fates reliant on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.

Carbon Dot-Stabilized Hydrogel Composite: A New Adsorbent for Efficient and Sustainable Pb(II) Removal.

In this paper, a carbon dot hydrogel composite (CDs-Hy) capable of efficiently removing Pb(II) was prepared by hydrogen bonding self-assembly in combination with carbon dots and a hydrogel. CDs-Hy was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS), and the effect of the adsorption conditions on the adsorption efficiency of CDs-Hy was studied. The results of the study showed that the incorporation of carbon dots, on the one hand, significantly increased the adsorption capacity of the material. On the other hand, it can increase the stability of hydrogels in aqueous solution. The possible adsorption mechanisms were further verified as ion exchange and coordination. CDs-Hy is a novel adsorbent material capable of removing Pb2+ efficiently, which can be reused several times with high stability.

Optimization of Mother-to-Child Hepatitis B Virus Prevention Program: Integration of Maternal Screening and Infant Post-vaccination Serologic Testing.

BACKGROUND: Evaluation of the impact on mother-to-child transmission (MTCT) of a HBV-prevention program that incorporates maternal antiviral prophylaxis is hindered by the limited availability of real-world data. METHODS: This study analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for HBsAg among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 01/01/2008-31/12/2022. Through linkage with the National Health Insurance Database, information of maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies. RESULTS: Totally, 2,460,218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and HBeAg seropositivity rates among native pregnant women aged 15-49 years decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (p for both trends < 0.0001). Among the 22,859 at-risk infants undergoing PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; p < 0.001). The MTCT rate was 1.72% (11/641) for infants born to HBeAg-positive mothers with antiviral prophylaxis. MTCT risk increased with maternal HBeAg-positivity (OR 9.29, 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR 0.28, 0.16-0.49). For infants with maternal HBeAg-positivity, MTCT risk was associated with mothers born in the immunization era (OR 1.40, 1.17-1.67). CONCLUSIONS: MTCT was related to maternal HBeAg-positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk.

Different Splice Isoforms of Peripheral Triggering Receptor Expressed on Myeloid Cells 2 mRNA Expressions are Associated With Cognitive Decline in Mild Dementia Due to Alzheimer's Disease and Reflect Central Neuroinflammation.

Triggering receptor expressed on myeloid cells 2 (TREM2) is upregulated in activated microglia and may be related to cognitive decline in patients with Alzheimer's disease (AD). There is conflicting evidence regarding the association of peripheral TREM2 mRNA expression/soluble TREM2 (the extracellular domain of TREM2) with cognitive function/neuroinflammation in patients with AD. Herein, we studied the TREM2 and TREM2alt mRNA expression and their association with the cognitive performance in subjects with mild dementia due to AD and healthy controls. In a subgroup of patients with AD, magnetic resonance spectroscopy was used to measure the myo-inositol level in the posterior cingulate cortex, a surrogate marker for neuroinflammation. The results showed that increased TREM2 and TREM2alt mRNA expression is associated with AD pathogenesis at the mild dementia stage, thereby serving as a potential biomarker for early symptomatic stage of AD. TREM2 may exert protective effects on both cognition and central neuroinflammation.

Shengu granules ameliorate ovariectomy-induced osteoporosis by the gut-bone-immune axis.

Introduction: Postmenopausal osteoporosis (PMOP) is a common chronic disease, and the loss of bone density and bone strength after menopause are its main symptoms. Effective treatments for PMOP are still uncertain, but Chinese medicine has some advantages in slowing down bone loss. Shengu granules are often used clinically to treat PMOP. It has been shown to be an effective prescription for the treatment of PMOP, and there is evidence that gut flora may play an important role. However, whether Shengu granules attenuate PMOP by modulating gut flora and related mechanisms remains unclear. Methods: In this study, we mainly examined the bone strength of the femur, the structure of the intestinal microbiota, SCFAs in the feces and the level of FOXP3 cells in the colon. To further learn about the inflammation response, the condition of the mucosa and the level of cytokines in the serum also included in the testing. In addition, to get the information of the protein expression, the protein expression of OPG and RANKL in the femur and the protein expression of ZO-1 and Occludin in the colon were taken into account. Results: The osteoporosis was significantly improved in the SG group compared with the OVX group, and the diversity of intestinal flora, the secretion level of SCFAs and the expression level of FOXP3 were significantly increased compared with the OVX group. In terms of inflammatory indicators, the intestinal inflammation scores of the SG group was significantly lower than those in the OVX group. Additionally, the serum expression levels of IL-10 and TGF-ß in the SG group were significantly increased compared with the OVX group, and the expression levels of IL-17 and TNF-α were significantly decreased compared with the OVX group. In terms of protein expression, the expression levels of ZO-1, Occluding and OPG were significantly increased in the SG group compared with the OVX group, and the expression level of RANKL was significantly decreased compared with the OVX group. Discussion: Shengu granules treatment can improve the imbalance of intestinal flora, increase the secretion of SCFAs and the expression of FOXP3, which reduces the inflammatory response and repairs the intestinal barrier, as well as regulates the expression of OPG/RANKL signaling axis. Overall, Shengu granules ameliorate ovariectomy-induced osteoporosis by the gut-bone-immune axis.

Sex differences in the frailty phenotype and mortality in the I-Lan longitudinal aging study cohort.

BACKGROUND: Frailty is a common geriatric syndrome related to multiple adverse outcomes. Sex differences in its prevalence and impact on mortality remain incompletely understood. METHODS: This study was conducted with data from the I-Lan Longitudinal Aging Study, in which community-dwelling subjects aged > 50 years without coronary artery disease or diabetes were enrolled. Sex disparities in phenotypically defined frailty and sex-morality predictor interactions were evaluated. Sex- and frailty-stratified analyses of mortality were performed. RESULTS: The sample comprised 1371 subjects (51.4% women, median age 61 years). The median follow-up period was 6.3 (interquartile range, 5.8-7.0) years. The frailty prevalence did not differ between men (5.3%) and women (5.8%). Frail individuals were older and less educated and had poorer renal function than did non-frail individuals. Body composition trends differed between sexes, regardless of frailty. Relative to non-frail men, frail men had significantly lower body mass indices (BMIs; 24.5 vs. 23.4 kg/m2, p = 0.04) and relative appendicular skeletal muscle masses (7.87 vs. 7.05 kg/m2, p < 0.001). Frail women had significantly higher BMIs (25.2 vs. 23.9 kg/m2, p = 0.02) and waist circumferences (88 vs. 80 cm, p < 0.001) than did non-frail women. Frailty was an independent mortality predictor for men only [hazard ratio (95% confidence interval) = 3.395 (1.809-6.371), psex-frailty interaction = 0.03]. CONCLUSION: Frailty reflected poorer health in men than in women in the present cohort. This study revealed sex disparities in the impact of frailty on mortality among relatively healthy community-dwelling older adults.

Intrinsic capacity and multimorbidity predicting incident disability-Insights from the I-Lan Longitudinal Aging Study.

OBJECTIVES: This longitudinal cohort study aimed to examine the effect of intrinsic capacity (IC) and multimorbidity on the development of new disabilities. METHODS: The study utilized data from 1,009 participants without disabilities from the I-Lan Longitudinal Aging Study. Multivariable logistic regressions were employed to assess the predictive capability of IC (ranging from 0 to 100) and multimorbidity for incident disability over a 7-year follow-up period. RESULTS: Both low IC (OR 4.9, 95 % CI 2.1-11.1, p < 0.001) and multimorbidity (OR 4.5, 95 % CI 2.2-9.2, p < 0.001) significantly predicted incident disability over the 7-year period. A one-point increase in IC reduced the risk of incident disability by 10 % (OR 0.9, 95 % CI 0.8-0.9, p < 0.001). Among IC subdomains, both better locomotion (OR 0.96, 95 % CI 0.94-0.99, p = 0.014) and psychology (OR 0.97, 95 %CI 0.94-1.00, p = 0.049) significantly reduced the risk of incident disability. Rapid declines in IC significantly predicted incident disability (OR 4.1, 95 % CI 1.8-9.3, p = 0.001), whereas the onset of new multimorbidity or changes in the number of chronic conditions did not demonstrate a significant association with incident disability. The interaction terms between IC and multimorbidity, both categorically (low IC * multimorbidity, p = 0.959) and numerically (IC (per point) * multimorbidity, p = 0.660) were all statistically insignificant. CONCLUSIONS: IC exhibited better predictive capacity for 7-year incident disability compared to multimorbidity, so health care services targeting older adults should adopt an integrated care approach that combines both function- and disease-centric strategies.

Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells.

Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing non-genetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupts acquired resistance in GBM.