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Objective: We investigated the relation between man papillomavirus (HPV) integration status and the immediate risk of cervical intraepithelial neoplasia (CIN), as well as the triage strategy based on HPV integration test. Methods: 4086 women aged 20 to 65 years in China were enrolled in 2015 for a prospective, population-based, clinical observational study to evaluate the triage performance of HPV integration. Cervical exfoliated cells were collected for HPV testing and cytologic test. If high-risk HPV was positive, HPV integration test was performed at baseline, 2-year and 5-year follow-up. Results: At baseline, HPV integration was positively correlated with the severity of cervical pathology, ranging from 5.0% (15/301) in normal diagnosis, 6.9% (4/58) in CIN1, 31.0% (9/29) in CIN2, 70% (14/20) in CIN3, and 100% (2/2) in cervical cancer (P < 0.001). Compared with cytology, HPV integration exhibits comparable sensitivity and negative predictive value for the diagnosis of CIN3+, higher specificity (92.8% [90.2%–95.4%] vs. 75.5% [71.2%–79.8%], P < 0.001) and higher positive predictive value (36.4% [22.1%–50.6%] vs. 15.2% [8.5%–21.8%], P < 0.001). HPV integration testing strategy yielded a significantly lower colposcopy referral rate than cytology strategy (10.7% [44/410] vs. 27.3% [112/410], P < 0.001). The HPV integration-negative group exhibited the lowest immediate risk for CIN3+ (1.6%) and accounted for the largest proportion of the total population (89.3%), when compared with the normal cytology group (risk, 1.7%; proportion, 72.7%). Conclusion: As a key molecular basis for the development of cervical cancer, HPV integration might be a promising triage strategy for HPV-positive patients.

ABSTRACT: Taste interaction is a well-known phenomenon in sensory studies, but how to quantify the magnitude of the effect of one tastant on other taste attribute(s) is still largely unsolved, let alone further explorations from a salivary biochemistry perspective. Upon acquiring the individual taste threshold and evaluating the just noticeable difference (JND), this study firstly established a quantitative method to assess the magnitude of taste interaction in a binary taste mixture by evaluating the concentration difference upon psychologically-comparable stimulation. The change of salty taste intensity (CSI) was therefore defined as the subtraction of JND using sour-salty taste stimulant from JND using pure salty taste stimulant, with a dimension of concentration in mmol/L. CSI was then used to demonstrate how citric acid affected salty taste perception in a salty - sour binary taste mixture in 16 young and healthy participants. Concentrations of citric acid used in the binary taste mixture were 0.05, 0.09, 0.14, 0.24 and 0.40 mmol/L, respectively, and results showed that salty taste perception was enhanced (average CSI of 0.93 mmol/L) when the citric acid concentration was low (at 0.05 and 0.09 mmol/L), but with an increasing concentration of citric acid ranging from 0.14 to 0.40 mmol/L, this effect gradually turned from enhancement to suppression of salty taste perception (correspondingly a continuously decreasing CSI all the way down to an average of –2.94 mmol/L). It was also found that cystatin SN concentration in participants’ unstimulated saliva samples was significantly negatively correlated with salty taste threshold (with and without the presence of citric acid), and it was one of the most significant factors affecting CSI, as shown in multiple regression analysis. Carbonic anhydrase VI concentration in participants’ unstimulated saliva samples was also found to be significantly negatively correlated with salty taste recognition (with and without presence of citric acid), but it did not pose significant effect on CSI. From these results, this study had not only demonstrated a citric acid concentration-dependent salty taste perception phenomenon based on a proposed methodology to quantitively assess the taste interaction in binary taste mixtures, but also showed how salivary biochemical properties (cystatin SN and carbonic anhydrase VI) might have been associated with salty taste perception during food oral processing.

Abstract Advanced pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Immunotherapy alone offers limited efficacy, but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor effects. This phase Ib/II study evaluated the safety and efficacy of combining toripalimab with the gemcitabine plus nab-paclitaxel (GnP) regimen as first-line treatment for locally advanced or metastatic PDAC and explored predictive biomarkers (ChiCTR2000032293). The primary endpoints were safety and overall survival (OS). The secondary outcomes were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Immune-related biomarkers including programmed death-ligand 1 (PD-L1) expression, genetic status, cytokine levels, and spatial features of the tumor immune microenviroment (TIME) were investigated. Neither serious treatment-related adverse events nor grade 4 immune-related adverse events were reported. Among the 72 patients, the median OS was 8.9 months, 12-month OS rate was 31.9%, with median PFS of 5.6 months, ORR of 33.3%, and DCR of 90.3%. Higher PD-L1 expression, without liver metastases were associated with higher ORR, however these factors could not effectively distinguish responders and non-responders. Importantly, dendritic cells - T helper cells - cytotoxic T lymphocytes (DC-Th-CTL) enriched immune niche and their spatial interactions were dominant predictors of response based on TIME analysis using a cyclic multiplex tissue staining assay, with an area under the curve value of 0.8. Overall, GnP plus toripalimab exhibited good safety and differentiated efficacy in selected population, and the spatial interactions of DC-Th-CTL represent promising predictors to efficacy of immunochemotherapy in locally advanced or metastatic PDAC.

Abstract Background Perinatal loss is a severe stressor that usually triggers distressing symptoms of acute grief. Moreover, acute grief can worsen with time and become a chronic debilitating state known as complicated grief. However, there is a lack of comprehensive reviews on this topic. This systematic review aims to synthesize the existing literature on complicated grief following the perinatal loss. Methods We systematically searched PubMed, Embase, Cochrane Library, CINAHL, ProQuest, and Web of Science to identify articles on complicated grief symptoms and influencing factors following perinatal loss. We performed a comprehensive, structured evaluation in full compliance with PRISMA guidelines. Results A systematic search produced 1163 results. Of these, 38 articles met the full-text screening criteria, and 10 pieces of literature met the inclusion criteria. Individuals may experience complicated grief following perinatal loss, manifesting in symptoms such as emotional reactions, physical responses, and social impairments. Furthermore, based on existing evidence, influencing factors include demographic characteristics, reproductive characteristics, marital relationships, social support, and coping strategies. Conclusions Complicated grief following perinatal loss is easily overlooked and has not been adequately studied. Further empirical research is needed to explore the symptoms and factors influencing this condition. A better understanding of complicated grief will help develop and optimize care strategies, informing future clinical practice and improving psychological support for individuals affected by perinatal loss. Trial registration PROSPERO registration number: CRD42023473510.

Abstract Previous reports showed that long non-coding RNA (lncRNA) participates in the development and progression of tumors. Nevertheless, the effect of LINC02139 and its mechanism on gastric cancer (GC) is still unknown. We revealed that LINC02139 is upregulated in GC cell lines and tissues and high LINC02139 expression was correlated with the advancement of GC in patients. Functionally, overexpression of LINC02139 promoted, while knockdown of LINC02139 impaired GC cell proliferation, migration, and invasion in vitro and impeded tumorigenesis in a tumor xenograft model in vivo. Mechanistically, LINC02139 directly bound to XIAP and increased the protein level by maintaining its protein stability through inhibition of the ubiquitination and proteasome-dependent degradation pathway. Importantly, the regulatory function of XIAP in LINC02139-mediated oncogenic effects was demonstrated. Both in vitro and in vivo experiments showed that LINC02139 and XIAP collaboratively modulate GC cell growth and apoptosis. Analysis of clinical GC tissues further confirmed the upregulation of XIAP and the positive association between LINC02139 and XIAP expression. These findings established LINC02139 as a driver of tumorigenesis and highlighted the crucial involvement of the LINC02139-XIAP axis in GC progression, suggesting its potential as a promising therapeutic target for combating GC advancement.

A new species of Proaphelinoides Girault, Proaphelinoides huangi Chen & Jiang, sp. nov., is reported from China. A key to all species of the genus is provided. DNA standard barcode COI and partial nuclear ribosomal 28S-D2 from two individuals of Proaphelinoides were sequenced, and 28S-D2 rDNA was included in a phylogenetic analysis, confirming Proaphelinoides as the sister group to Aphytis.

Abstract The study’s goals are to fabricate PLGA nanoparticles (PNPs) loaded with apigenin (AP) and adenosine (AD) using a microfluidic preparation method to a standard emulsification method and investigate the possible heart-protective effects of AP-AD PNPs made using the emulsification method. Compared to microfluidics, the emulsification method fabricated small-size nanoparticles, which are better at encapsulating drugs, retaining more drugs, and having a low viscosity for the myocardial infarction (MI) injection. TheMI model was developed using SD rats injected under the skin with 85 mg/kg doxorubicin (DOX) for 2 days. The metabolic results showed that our AP-AD PNPs accelerated the blood flow in rats with MI, which increased the amounts of AP and AD in the circulatory system. This led to significant improvements in the cardiac index and lower amounts of AST, LDH, and CK in the blood. A histopathological study using Hematoxylin&eosin, and TUNEL staining showed that cardiac function had improved and apoptosis had decreased. Moreover, tests that checked the amounts of IL-6, TNF-α, NO, GSH, MDA, and SOD showed that AP-AD PNPs may help treat MI by reducing oxidative stress and inflammation, making it a potentially useful therapeutic approach.

Rhinovirus (RV) is a common pathogen that causes respiratory tract infection and can cause outbreaks in hospitals and welfare institutions. A cluster of respiratory diseases occurred in a primary school in Shenyang City, Liaoning Province, China, in 2022. In this outbreak, a total of 31 students had symptoms similar to those of upper respiratory tract infection, mainly cough and sore throat. Among them, 27 throat swabs were collected and identified for respiratory pathogens by TaqMan low-density array (TLDA), quantitative real-time polymerase chain reaction (PCR), reverse transcription-nested PCR and whole-genome sequencing. Out of the 27 specimens, 24 tested positive for RV, and 21 RV viral protein 1 sequences were obtained, of which 15 (71.43%) were identified as RV-A49, while 2 RV-A20 and 4 sequences from 2 specimens were RV-A30 coinfected with RV-C15. In addition, one whole-genome sequence (WGS) of RV-A49 was obtained, and three unique amino acid mutations were found compared to 23 WGS of RV-A49 from GenBank. In conclusion, this outbreak of upper respiratory tract infection is caused by RV, mainly RV-A49.

BackgroundAdverse drug reactions (ADRs) to sodium dimercaptosulphonate (DMPS) mercury removal treatment have been reported in occupational mercury poisoning. In recent years, the number of cases of mercury poisoning due to mercury-containing cosmetics has been increasing, and ADRs to the use of DMPS are common in clinical practice.ObjectiveTo investigate the occurrence of ADRs and the influencing factors in patients with chronic mercury poisoning and mercury exposure treated with DMPS for mercury removal.MethodsPatients treated with DMPS due to mercury poisoning at the Occupational Disease Department of Nanjing Prevention and Treatment Center for Occupational Diseases from June 2017 to December 2023 were included in the study. Information on demographics, baseline characteristics, and treatment regimens was collected at admission. Information on secondhand smoke, place of residence, and blood groups not collected at admission was collected in follow-up. The patients were divided into two groups according to whether ADRs occurred after the use of DMPS and were compared for clinical characteristics, and the influencing factors related to the occurrence of ADRs after DMPS treatment were analyzed by binary logistic regression.ResultsA total of 72 patients were enrolled in the study, of which 26 reported ADRs during mercury removal. A total of 29 ADRs occurred, mainly rash in 11 cases (37.9%), fever in 5 cases (17.2%), and nausea in 4 cases (13.8%). Most ADRs occurred in the second course (7 cases, 26.9%) and the third course (9 cases, 34.6%). Of the 22 non-menopausal women who experienced ADRs, 13 (59.1%) used DMPS in the week prior to menstruation. The logistic regression analysis showed that smoking (OR=27.911, 95%CI: 2.835, 725.809) and blood type O (OR=6.885, 95%CI: 2.014, 26.896) were associated with elevated occurrence of ADRs after DMPS treatment.ConclusionsThe probability of ADRs after DMPS treatment is not low, but mild presentations are predominant and resolved with immediate treatment, with a favourable prognosis. The O blood group, smoking individuals, and female patients using DMPS one week before menstruation may be more prone to ADRs.

Abstract Two-dimensional (2D) materials, as adsorbents, have garnered great attention in removing heavy metal ions (HMIs) from drinking water due to their extensive exposed adsorption sites. Nevertheless, there remains a paucity of experimental research to remarkably unlock their adsorption capabilities and fully elucidate their adsorption mechanisms. In this work, exceptional lead ion (Pb2+) (a common HMI) removal capacity (up to 758 mg g−1) is achieved using our synthesized metallic 1T/1T′ phase 2D transition metal dichalcogenide (TMD, including MoS2, WS2, TaS2, and TiS2) nanosheets, which hold tremendous activated S chemisorption sites. The residual Pb2+ concentration can be reduced from 2 mg L−1 to 2 μg L−1 within 0.5 min, meeting the drinking water standards following World Health Organization guideline (Pb2+ concentrations

To further optimize the automotive AEB-P (autonomous emergency braking for pedestrian) control algorithm, an AEB-P hierarchical control strategy that integrates driving comfort and pedestrian injury risk was proposed. A braking safety distance model considering the driver′s comfort during braking was designed for the AEB-P evaluation standard of C-NCAP. The weight coefficient adjustment strategy was obtained by introducing fuzzy rules to comprehensively consider the risk of pedestrian injury and scenario working conditions. Based on this, the adaptive weight coefficient MPC (model predictive control) upper controller was designed, and the PID (proportion integration differentiation) lower controller was used to correct the actual deceleration of the auto-vehicle. The vehicle longitudinal dynamics model was established and the test scenario and control algorithm were constructed through CarSim and Matlab/Simulink, then the proposed method and the fixed TTC (time to collision) threshold algorithm were compared through hardware-in-the-loop experiments. The results show that the proposed control algorithm can effectively avoid collision in 93.4% of the test conditions, while the fixed TTC threshold algorithm has a successful rate of only 43.75% in obstacle avoidance. Compared with the traditional control strategy, the proposed method can maintain a more stable minimum distance between the vehicle and the pedestrian in front of it, with better robustness, which provides a reference basis for the AEB-P control theory.

Objective To analyze the infectious indicators, HBV s gene mutations and changes in bioinformatics characteristics of HBV DNA+ /HBsAg- blood donor. Methods A sample of HBV DNA+ /HBsAg- was screened by PCR method, and HBsAg/HBsAb/HBeAg/HBeAb/HBcAb of HBV in the sample were detected by ELISA and chemiluminescence methods. The mutation of the HBVs gene fragment in the sample was sequenced and analyzed, and the bioinformatics analysis was performed using analysis software. Results The sample showed HBV DNA+, HBsAg-, HBsAb+, HBeAg+, HBeAb- and HBcAb+, with an amino acid unit point mutation (P151L) occurred in the HBV s gene, and the spatial structure changed. Conclusion The spatial structural changes in the gene sequence of HBVs may be the reason for the appearance of serological HBsAg-/HBsAb+ /HBV DNA+ in the test results.

Images and videos provide a wealth of information for people in production and life. Although most digital information is transmitted via optical fiber, the image acquisition and transmission processes still rely heavily on electronic circuits. The development of all-optical transmission networks and optical computing frameworks has pointed to the direction for the next generation of data transmission and information processing. Here, we propose a high-speed, low-cost, multiplexed parallel and one-piece all-fiber architecture for image acquisition, encoding, and transmission, called the Multicore Fiber Acquisition and Transmission Image System (MFAT). Based on different spatial and modal channels of the multicore fiber, fiber-coupled self-encoding, and digital aperture decoding technology, scenes can be observed directly from up to 1 km away. The expansion of capacity provides the possibility of parallel coded transmission of multimodal high-quality data. MFAT requires no additional signal transmitting and receiving equipment. The all-fiber processing saves the time traditionally spent on signal conversion and image pre-processing (compression, encoding, and modulation). Additionally, it provides an effective solution for 2D information acquisition and transmission tasks in extreme environments such as high temperatures and electromagnetic interference.

Abstract Background Evidence on the association between serum vitamin C (sVC) levels and obesity is limited. This study aimed to explore the relationship between sVC and body mass index (BMI) in adolescents aged 12 to 19 years. Methods We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2003–2006, with 3952 participants. sVC and BMI were independent variables and dependent variables, respectively. The associations of sVC with BMI were examined using multivariable linear regression models. Age, sex, and race/ethnicity were analyzed as subgroups. Then, we devised smooth curve fittings and saturation threshold analysis to address the nonlinear relationship. Results sVC had a negative correlation with BMI after adjusting for all covariates (β: -1.020, 95% CI: -1.359, -0.680). In the subgroup analysis by age, sex, and race/ethnicity, there was still a negative correlation between sVC and BMI (p

Abstract Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021–22 and 2022–23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021–22 and 12 out of 18 models in 2022–23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021–22 and the 5th most accurate in the 2022–23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

Abstract Exosomes derived from mesenchymal stem cells (MSCs) have been confirmed to enhance cell proliferation and improve tissue repair. Exosomes release their contents into the cytoplasmic solution of the recipient cell to mediate cell expression, which is the main pathway through which exosomes exert therapeutic effects. The corresponding process of exosome internalization mainly occurs in the early stage of treatment. However, the therapeutic effect of exosomes in the early stage remains to be further studied. We report that the three-dimensional cell traction force can intuitively reflect the ability of exosomes to enhance the cytoskeleton and cell contractility of recipient cells, serving as an effective method to characterize the therapeutic effect of exosomes. Compared with traditional biochemical methods, we can visualize the early therapeutic effect of exosomes in real time without damage by quantifying the cell traction force. Through quantitative analysis of traction forces, we found that endometrial stromal cells exhibit short-term cell roundness accompanied by greater traction force during the early stage of exosome therapy. Further experiments revealed that exosomes enhance the traction force and cytoskeleton by regulating the Rac1/RhoA signaling pathway, thereby promoting cell proliferation. This work provides an effective method for rapidly quantifying the therapeutic effects of exosomes and studying the underlying mechanisms involved.

BackgroundFGFR2 fusions or rearrangements occur in 13%–20% of patients with intrahepatic cholangiocarcinoma (iCCA). Pemigatinib, a representative FGFR inhibitor, is commonly used for targeted therapy in such patients. Additionally, brain metastasis (BM) is extremely rare in advanced iCCA, and there is currently no standard treatment strategy for advanced iCCA patients with BM. Stereotactic body radiation therapy (SBRT) combined with immune checkpoint inhibitors (ICIs) may exhibit synergistic antitumor effects, presenting a promising approach for advanced iCCA.Case presentationThe patient, a 58-year-old male, experienced a recurrence of iCCA following surgery and chemotherapy, with multiple metastases in the liver, lungs, and brain. Genetic testing revealed FGFR2-TXLNG-fusion, and the patient was treated with pemigatinib in combination with tislelizumab and SBRT for the BM, resulting in significant tumor shrinkage. Adverse events (AEs) such as liver dysfunction, nail loss, and dry mouth were observed during treatment, which were considered to be related to pemigatinib. These AEs were significantly alleviated after dose reduction and symptomatic treatment.ConclusionThis case presented a rare occurrence of FGFR2 fusion-positive iCCA with BM, with extremely limited data on treatment options and survival outcomes in such patients. Our study was the first to report the application of the treatment strategy combining pemigatinib with ICI and SBRT in this specific case. The combined therapy proved effective and well-tolerated, providing new insights for future treatment considerations.

The objective of this retrospective cohort study was to assess the relationship between Corona Disease 2019 (COVID-19) and Secukinumab treatment in patients with Spondylarthritis (SpA) in China during the omicron surge. Researchers retrieved 1018 medical records of Secukinumab-treated patients between January 2020 and January 2023 from the West China Hospital of Sichuan University. Out of these, 190 SpA patients from the rheumatology clinic were selected for the study. Guided phone questionnaires were administered by research staff to collect baseline characteristics, SpA disease status, and COVID-19 clinical outcomes. Cohabitants served as the control group and provided COVID-19 related data. Of the 190 potential SpA patients, 122 (66%) completed the questionnaire via phone, along with 259 cohabitants. 84.4% of SpA patients were diagnosed with Ankylosing Spondylitis (AS), and 15.6% were diagnosed with Psoriatic Arthritis (PsA). The rate of SARS-CoV-2 infection was 83.6% in the Secukinumab group and 88.8% in the cohabitants control group, with no significant difference (OR = 0.684, CI 0.366–1.275). One instance of severe COVID-19 was observed in the Secukinumab group, while two were identified in the cohabitants control group. Patients in the Secukinumab group had less time with fever caused by COVID-19 (p = 0.004). Discontinuing Secukinumab after SARS-CoV-2 infection did not significantly affect the course of COVID-19 or worsen SpA status according to our data. Our study suggests that administering Secukinumab to SpA patients does not increase their susceptibility to contracting SARS-CoV-2, and may have a positive effect on the course of SARS-CoV-2 infection.

Abstract In the context of drilling operations, the study investigated the ability of a combination of rigid mineral particles and composite plugging agents to seal simulated cracks effectively. The study used a neural network model to predict the outcomes of experiments using this combination, based on data collected during the research. Initially, a backpropagation (BP) neural network was used to establish the prediction model, which was later optimized using the particle swarm optimization (PSO) algorithm to improve its accuracy, stability, and learning abilities. As a result, the optimized prediction model was found to be capable of providing accurate and compliant drilling plugging formulas quickly. This feature helped guide targeted formula experiments and significantly reduced experimental time and costs. In five practices in a well area in the southern Sichuan region of China, the application success rate was as high as 60%, and the time spent on plugging was reduced by an average of 36%. Overall, this study contributes to the development of effective and efficient drilling techniques, which are essential in the exploration and production of hydrocarbon resources.

BackgroundRecently, the clinical benefits of neoadjuvant chemotherapy combined with immunotherapy have been observed in patients with locally advanced gastric or gastroesophageal junction (G/GEJ) cancer; however, the pathological complete response (pCR) and long-term survival rates are still unsatisfactory. The aim of this study is to investigate the efficacy and safety of chemotherapy combined with tislelizumab and low-dose radiation therapy (LDRT) for the neoadjuvant treatment of locally advanced G/GEJ cancer.MethodsThis is a prospective, multicenter, single-arm, phase Ib/II trial. In the phase Ib study, 5 patients will be enrolled in each treatment group with different radiation doses. In the phase II study, a total of 44 patients will be enrolled. Eligible patients will be registered and receive three cycles of SOX regimen chemotherapy (S-1: 40-60 mg Bid, d1-14, q3w; oxaliplatin: 130 mg/m2, iv drip, d1, q3w) plus tislelizumab (200 mg, iv drip, d1, q3w). Simultaneously, LDRT will be planned and administered after the first cycle of systemic therapy. Radical D2 gastrectomy will be performed 4-6 weeks after the last administration of chemotherapy plus tislelizumab. The primary endpoint of phase Ib study is to determine the optimal radiation dose for phase II study. The primary endpoint of phase II is the pCR rate. The secondary endpoints include R0 resection rate, major pathological response (MPR) rate, 2-year event-free survival (EFS) rate, 2-year overall survival (OS) rate and safety profile. Moreover, we will also explore potential molecular markers for predicting the benefit and safety of this neoadjuvant regimen. Written informed consent should be provided by all patients enrolled in the study. The study protocol was approved by the independent ethics committee at each institution.DiscussionThis is the first study to explore the efficacy and safety of neoadjuvant chemotherapy combined with tislelizumab and LDRT in G/GEJ cancer patients, the results of which may provide novel treatment strategy for patients with locally advanced G/GEJ adenocarcinoma.Clinical trial registrationClinicalTrials.Gov, identifier NCT06266871.

Background Increased vascular CaV1.2 channel function causes enhanced arterial tone during hypertension. This is mediated by elevations in angiotensin II/protein kinase C signaling. Yet, the mechanisms underlying these changes are unclear. We hypothesize that α1C phosphorylation at serine 1928 (S1928) is a key event mediating increased CaV1.2 channel function and vascular reactivity during angiotensin II signaling and hypertension. Methods and Results The hypothesis was examined in freshly isolated mesenteric arteries and arterial myocytes from control and angiotensin II‐infused mice. Specific techniques include superresolution imaging, proximity ligation assay, patch‐clamp electrophysiology, Ca2+ imaging, pressure myography, laser speckle imaging, and blood pressure telemetry. Hierarchical “nested” and appropriate parametric or nonparametric t test and ANOVAs were used to assess statistical differences. We found that angiotensin II redistributed the CaV1.2 pore‐forming α1C subunit into larger clusters. This was correlated with elevated CaV1.2 channel activity and cooperativity, global intracellular Ca2+ and contraction of arterial myocytes, enhanced myogenic tone, and altered blood flow in wild‐type mice. These angiotensin II‐induced changes were prevented/ameliorated in cells/arteries from S1928 mutated to alanine knockin mice, which contain a negative modulation of the α1C S1928 phosphorylation site. In angiotensin II‐induced hypertension, increased α1C clustering, CaV1.2 activity and cooperativity, myogenic tone, and blood pressure in wild‐type cells/tissue/mice were averted/reduced in S1928 mutated to alanine samples. Conclusions Results suggest an essential role for α1C S1928 phosphorylation in regulating channel distribution, activity and gating modality, and vascular function during angiotensin II signaling and hypertension. Phosphorylation of this single vascular α1C amino acid could be a risk factor for hypertension that may be targeted for therapeutic intervention.

Abstract To identify different patterns of neurogenic lower urinary tract dysfunction management among Chinese community-dwelling individuals with spinal cord injury and explore the factors associated with latent classes. This was a cross-sectional study conducted in communities throughout China Mainland. Participants were recruited through the China Association of Persons with Physical Disability and a total of 2582 participants was included in the analysis. The data were collected by a questionnaire consisting of socio-demographic factors, disease-related factors, and a list of 8 bladder management methods. Latent class analysis was used to identify different latent classes of neurogenic lower urinary tract dysfunction management. Then the multinomial logistic regression was applied to analyze the relationship between neurogenic lower urinary tract dysfunction management patterns and socio-demographic and disease-related factors. Neurogenic lower urinary tract dysfunction management pattern among community-dwelling individuals with spinal cord injury was divided into four latent classes: “urinal collecting apparatus dominated pattern” (40.3%), “bladder compression dominated pattern” (30.7%), “intermittent catheterization dominated pattern” (19.3%) and “urethral indwelling catheterization dominated pattern” (9.6%). Multinomial logistic regression analysis found that the employment status, residential region, nursing need, payment method for catheterization products, hand function, time since spinal cord injury, urinary incontinence and concerns about social interaction affected by urination problems were significantly associated with latent classes. Only 19.3% of people used the intermittent catheterization as their main neurogenic lower urinary tract dysfunction management method. More attention needs to be paid to the promotion of the standardization process of intermittent catheterization in community-dwelling individuals with spinal cord injury. The associated factors of the four classes can be used for tailored and targeted interventions to increase the use of intermittent catheterization.

Abstract To assess the effectiveness and safety of combining Saccharomyces boulardii powder with triple therapy as a primary approach for eradicating H. pylori infection, a total of 144 patients who tested positive for H. pylori and diagnosed with non-ulcer dyspepsia underwent endoscopy at two national centers between June 2017 and March 2019 were included. The patients were categorized into three groups using a subsection randomization method and received initial H. pylori eradication treatments. Microbial composition, eradication rates, symptom alleviation, and adverse reactions were monitored on the 14th and 44th days post-treatment. According to PP analysis showed the eradication rates for the SRAC group was 75%, BRAC was 93.18% and RAC was 65.2%. Group BRAC exhibited a marginally higher eradication rate compared to other groups. However, patients receiving Saccharomyces boulardii treatment exhibited an overall reduction in initial dyspepsia symptoms by the end of the treatment period. When employed as a primary strategy, the combination of Saccharomyces boulardii powder with triple therapy displayed notable efficacy and smaller gastrointestinal side effects in eradicating initial H. pylori infections among non-ulcer dyspepsia patients. Moreover, this approach demonstrated advantages in alleviating symptoms, exhibited favorable tolerance, and maintained a high level of clinical safety.

Abstract To explore altered patterns of static and dynamic functional brain network connectivity (sFNC and dFNC) in Primary angle-closure glaucoma (PACG) patients. Clinically confirmed 34 PACG patients and 33 age- and gender-matched healthy controls (HCs) underwent evaluation using T1 anatomical and functional MRI on a 3 T scanner. Independent component analysis, sliding window, and the K-means clustering method were employed to investigate the functional network connectivity (FNC) and temporal metrics based on eight resting-state networks. Differences in FNC and temporal metrics were identified and subsequently correlated with clinical variables. For sFNC, compared with HCs, PACG patients showed three decreased interactions, including SMN-AN, SMN-VN and VN-AN pairs. For dFNC, we derived four highly structured states of FC that occurred repeatedly between individual scans and subjects, and the results are highly congruent with sFNC. In addition, PACG patients had a decreased fraction of time in state 3 and negatively correlated with IOP (p

Abstract Light-induced spin currents with the faster response is essential for the more efficient information transmission and processing. Herein, we systematically explore the effect of light illumination energy and direction on the light-induced spin currents in the W/Y3Fe5O12 heterojunction. Light-induced spin currents can be clearly categorized into two types. One is excited by the low light intensity, which mainly involves the photo-generated spin current from spin photovoltaic effect. The other is caused by the high light intensity, which is the light-thermally induced spin current and mainly excited by spin Seebeck effect. Under low light-intensity illumination, light-thermally induced temperature gradient is very small so that spin Seebeck effect can be neglected. Furthermore, the mechanism on spin photovoltaic effect is fully elucidated, where the photo-generated spin current in Y3Fe5O12 mainly originates from the process of spin precession induced by photons. These findings provide some deep insights into the origin of light-induced spin current.

Abstract Vitamin A plays a pivotal role in health, particularly in regulating fat metabolism. Despite its significance, research into the direct relationship between vitamin A levels and obesity, especially among adolescents, is sparse. This study aims to explore this association within the adolescent population in the United States. This cross-sectional study analyzed the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2006, with 8218 participants. The levels of vitamin A in the serum were determined based on utilizing high-performance liquid chromatography with photodiode array detection. The relationship between serum vitamin A concentrations and body mass index (BMI) was evaluated using weighted multiple linear regression models, incorporating subgroup analyses by sex and race/ethnicity to provide nuanced insights. A positive correlation was observed between serum vitamin A levels and BMI, with BMI increasing progressively across vitamin A quartiles (P

Abstract The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.

Although current policies discourage the use of corporal punishment (CP), its use is still widespread in the US. The objective of this study was to assess the proportion of parents who used CP during the pandemic and identify related risk and protective factors. We analyzed results of a nationwide cross-sectional internet panel survey of 9000 US caregivers who responded in three waves from November 2020 to July 2021. One in six respondents reported having spanked their child in the past week. Spanking was associated with intimate partner violence and the use of multiple discipline strategies and not significantly associated with region or racial self-identification. Parents who spanked sought out more kinds of support, suggesting an opportunity to reduce spanking through more effective parenting resources. Additionally, these results suggest that parents who report using CP may be at risk for concurrent domestic violence.

Abstract Objective To compare the similarities and differences between patients with Coronavirus Disease 2019 (COVID-19) and those with other community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU), utilizing propensity score matching (PSM), regarding hospitalization expenses, treatment options, and prognostic outcomes, aiming to inform the diagnosis and treatment of COVID-19. Methods Patients admitted to the ICU of the Third People’s Hospital of Datong City, diagnosed with COVID-19 from December 2022 to February 2023, constituted the observation group, while those with other CAP admitted from January to November 2022 formed the control group. Basic information, clinical data at admission, and time from symptom onset to admission were matched using PSM. Results A total of 70 patients were included in the COVID-19 group and 119 in the CAP group. The patients were matched by the propensity matching method, and 37 patients were included in each of the last two groups. After matching, COVID-19 had a higher failure rate than CAP, but the difference was not statistically significant (73% vs. 51%, p = 0.055). The utilization rate of antiviral drugs (40% vs. 11%, p = 0.003), γ-globulin (19% vs. 0%, p = 0.011) and prone position ventilation (PPV) (27% vs. 0%, p

Abstract Microstructures and mechanical properties of Mg-12Gd-0.8Zn-0.4Zr (GZ1208K, wt.%) alloy under different treatments (as-cast: signed as nonHIP-GZ1208K, hot isostatic pressing (HIP): signed as HIP-GZ1208K) were characterized. Based on microstructure characterization, two prismatic precipitates, β′ and β1 precipitates, and one basal precipitate, γ′ precipitate, formed in both of nonHIP-GZ1208K and HIP-GZ1208K alloy. According to analysis, the area number density and the size of β′ precipitate could be adjusted through HIP treatment. The area number density of β′ precipitate increased after HIP treatment when aged at 32 h, and the size of β′ precipitate refined in both of the HIP-GZ1208K alloy aged at 8 h and 32 h. Except the influence of HIP treatment on microstructures, the ultimate tensile strength (UTS) and elongation of nonHIP-GZ1208K alloy also improved after HIP treatment. The UTS of the GZ1208K alloy aged at 8 h increased from 348 MPa (nonHIP-) to 371 MPa (HIP-) and the elongation increased from 2.6% to 4.7%. The density of the nonHIP-GZ1208K alloy increased after HIP treatment, that is to say the casting defects could be eliminated and the compactness of microstructures could be increased under the high pressure of HIP treatment.

Abstract Eye tracking techniques enable high-efficient, natural, and effortless human-machine interaction by detecting users’ eye movements and decoding their attention and intentions. Here, a miniature, imperceptible, and biocompatible smart contact lens is proposed for in situ eye tracking and wireless eye-machine interaction. Employing the frequency encoding strategy, the chip-free and battery-free lens successes in detecting eye movement and closure. Using a time-sequential eye tracking algorithm, the lens has a great angular accuracy of

Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis. Objectives: To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis. Methods: The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments. Results: We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation. Conclusion: Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases.

The incidence rate of prostate cancer (PCa) has risen by 3% per year from 2014 through 2019 in the United States. An estimated 34,700 people will die from PCa in 2023, corresponding to 95 deaths per day. Castration resistant prostate cancer (CRPC) is the leading cause of deaths among men with PCa. Androgen receptor (AR) plays a critical role in the development of CRPC. N-terminal domain (NTD) is the essential functional domain for AR transcriptional activation, in which modular activation function-1 (AF-1) is important for gene regulation and protein interactions. Over last 2 decades drug discovery against NTD has attracted interest for CRPC treatment. However, NTD is an intrinsically disordered domain without stable three-dimensional structure, which has so far hampered the development of drugs targeting this highly dynamic structure. Employing high throughput cell-based assays, small-molecule NTD inhibitors exhibit a variety of unexpected properties, ranging from specific binding to NTD, blocking AR transactivation, and suppressing oncogenic proliferation, which prompts its evaluation in clinical trials. Furthermore, molecular dynamics simulations reveal that compounds can induce the formation of collapsed helical states. Nevertheless, our knowledge of NTD structure has been limited to the primary sequence of amino acid chain and a few secondary structure motif, acting as a barrier for computational and pharmaceutical analysis to decipher dynamic conformation and drug-target interaction. In this review, we provide an overview on the sequence-structure-function relationships of NTD, including the polymorphism of mono-amino acid repeats, functional elements for transcription regulation, and modeled tertiary structure of NTD. Moreover, we summarize the activities and therapeutic potential of current NTD-targeting inhibitors and outline different experimental methods contributing to screening novel compounds. Finally, we discuss current directions for structure-based drug design and potential breakthroughs for exploring pharmacological motifs and pockets in NTD, which could contribute to the discovery of new NTD inhibitors.

Our previous studies have shown that the novel selective RNA polymerase I inhibitor CX-5461 suppresses proliferation of vascular smooth muscle cells, mainly by inducing DNA damage response (DDR), including activations of ataxia telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) and p53. Currently, there is no information about the molecular mechanism(s) underlying CX-5461-induced DDR in vascular cells, while the results obtained in cancer cells and immortalized cell lines are controversial. In this study, we examined the responses of various DDR pathways to CX-5461 treatment in primary aortic smooth muscle cells isolated from normal adult Sprague Dawley rats. We demonstrated that CX-5461-induced DDR was not associated with activations of the nucleotide excision repair, DNA mismatch repair, or the non-homologous end joining pathways, while the homologous recombination pathway was activated. However, the alkaline comet assay did not show massive DNA double strand breaks in CX-5461-treated cells. Instead, CX-5461-induced DDR appeared to be related to induction of DNA replication stress, which was not attributable to increased formation of G-quadruplex or R-loop structures, but might be explained by the increased replication-transcription conflict. CX-5461-induced DDR was not exclusively confined to rDNA within the nucleolar compartment; the extra-nucleolar DDR might represent a distinct secondary response related to the downregulated Rad51 expression in CX-5461-treated cells. In summary, we suggest that DNA replication stress may be the primary molecular event leading to downstream ATM/ATR and p53 activations in CX-5461-treated vascular smooth muscle cells. Our results provide further insights into the molecular basis of the beneficial effects of CX-5461 in proliferative vascular diseases.

Background The tcdA gene codes for an important toxin produced by Clostridioides difficile (C. difficile), but there is currently no simple and cost-effective method of detecting it. This article establishes and validates a rapid and visual loop-mediated isothermal amplification (LAMP) assay for the detection of the tcdA gene. Methods Three sets of primers were designed and optimized to amplify the tcdA gene in C. difficile using a LAMP assay. To evaluate the specificity of the LAMP assay, C. difficile VPI10463 was used as a positive control, while 26 pathogenic bacterial strains lacking the tcdA gene and distilled water were utilized as negative controls. For sensitivity analysis, the LAMP assay was compared to PCR using ten-fold serial dilutions of DNA from C. difficile VPI10463, ranging from 207 ng/µl to 0.000207 pg/µl. The tcdA gene of C.difficile was detected in 164 stool specimens using both LAMP and polymerase chain reaction (PCR). Positive and negative results were distinguished using real-time monitoring of turbidity and chromogenic reaction. Results At a temperature of 66 °C, the target DNA was successfully amplified with a set of primers designated, and visualized within 60 min. Under the same conditions, the target DNA was not amplified with the tcdA12 primers for 26 pathogenic bacterial strains that do not carry the tcdA gene. The detection limit of LAMP was 20.700 pg/µl, which was 10 times more sensitive than that of conventional PCR. The detection rate of tcdA in 164 stool specimens using the LAMP method was 17% (28/164), significantly higher than the 10% (16/164) detection rate of the PCR method (X2 = 47, p < 0.01). Conclusion LAMP method is an effective technique for the rapid and visual detection of the tcdA gene of C. difficile, and shows potential advantages over PCR in terms of speed, simplicity, and sensitivity. The tcdA-LAMP assay is particularly suitable for medical diagnostic environments with limited resources and is a promising diagnostic strategy for the screening and detection of C. difficile infection in populations at high risk.

Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has been linked to an increased risk of intestinal fibrosis in patients of Crohn’s disease (CD). In this study, oral administration of either live F. prausnitzii or its extracellular vesicles (FEVs) can markedly mitigate the severity of fibrosis in mice induced by repetitive administration of DSS. In vitro experiment revealed that FEVs were capable of directing the polarization of peripheral blood mononuclear cells (PBMCs) towards an M2b macrophage phenotype, which has been associated with anti-fibrotic activities. This effect of FEV was found to be stable under various conditions that promote the development of pro-fibrotic M1/M2a/M2c macrophages. Proteomics and RNA sequencing were performed to uncover the molecular modulation of macrophages by FEVs. Notably, we found that FEVs reprogramed every metabolism of macrophages by damaging the mitochondria, and inhibited oxidative phosphorylation and glycolysis. Moreover, FEV-treated macrophages showed a decreased expression of PPARγ and an altered lipid processing phenotype characterized by decreased cholesterol efflux, which may promote energy reprogramming. Taken together, these findings identify FEV as a driver of macrophage reprogramming, suggesting that triggering M2b macrophage polarization by oral admiration of FEV may serve as strategy to alleviate hyperfibrotic intestine conditions in CD.

Accumulating oxidative damage is a primary driver of ovarian reserve decline along with aging. However, the mechanism behind the imbalance in reactive oxygen species (ROS) is not yet fully understood. Here we investigated changes in iron metabolism and its relationship with ROS disorder in aging ovaries of mice. We found increased iron content in aging ovaries and oocytes, along with abnormal expression of iron metabolic proteins, including heme oxygenase 1 (HO-1), ferritin heavy chain (FTH), ferritin light chain (FTL), mitochondrial ferritin (FTMT), divalent metal transporter 1 (DMT1), ferroportin1(FPN1), iron regulatory proteins (IRP1 and IRP2) and transferrin receptor 1 (TFR1). Notably, aging oocytes exhibited enhanced ferritinophagy and mitophagy, and consistently, there was an increase in cytosolic Fe2+, elevated lipid peroxidation, mitochondrial dysfunction, and augmented lysosome activity. Additionally, the ovarian expression of p53, p21, p16 and microtubule-associated protein tau (Tau) were also found to be upregulated. These alterations could be phenocopied with in vitro Fe2+ administration in oocytes from 2-month-old mice but were alleviated by deferoxamine (DFO). In vivo application of DFO improved ovarian iron metabolism and redox status in 12-month-old mice, and corrected the alterations in cytosolic Fe2+, ferritinophagy and mitophagy, as well as related degenerative changes in oocytes. Thereby in the whole, DFO delayed the decline in ovarian reserve and significantly increased the number of superovulated oocytes with reduced fragmentation and aneuploidy. Together, our findings suggest that aging-related disturbance in ovarian iron homeostasis contributes to excessive ROS production and that iron chelation may improve ovarian redox status, and efficiently delay the decline in ovarian reserve and oocyte quality in aging mice. These data propose a novel intervention strategy for preserving the ovarian reserve function in elderly women.

Abstract Background China has implemented policies to make rare diseases more affordable. While previous studies evaluated overall affordability, few have examined affordability differences across regions and disease types. Given the vastness of China and varying medical policies across cities, this study assesses the affordability of rare diseases based on China’s First List of Rare Diseases (CFLRD), National Reimbursement Drug List (NRDL), and outpatient chronic and special disease policies in each prefecture. Method Six rare diseases were selected and the average annual treatment cost of all relevant drugs in NRDL was calculated for each disease. Based on the WHO/HAI standardized approach, the study analyzed 289 cities with outpatient chronic and special disease policies, measured the security levels by the actual reimbursement ratio of Basic Medical Insurance (BMI) and affordability by the ratio of individual expenses after reimbursement to the annual disposable income of urban residents in the province. The security levels and affordability differences across disease types and provinces were analyzed using the Mann-Whitney U test and the K-W test. Result The affordability of rare diseases varied significantly on the disease types and annual treatment cost. Diseases with an annual treatment cost below 100 000 yuan are affordable to all prefectures even with low reimbursement rates, while those with a higher treatment cost were not affordable in at least 80% of prefectures even though the reimbursement ratio is high. The affordability of the same disease varies significantly across provinces and municipalities. Outpatient chronic and special diseases insurance and critical illness insurance, and the inconsistencies between them, result in regional differences. Conclusion Although China has made progress in improving the affordability of rare diseases, significant differences persist between cities and diseases. The study suggests the optimization of the BMI system and explores independent funds and innovative insurance models to enhance the affordability of rare diseases, particularly those with extremely high treatment costs.

Abstract Translation elongation is essential for maintaining cellular proteostasis, and alterations in the translational landscape are associated with a range of diseases. Ribosome profiling allows detailed measurements of translation at the genome scale. However, it remains unclear how to disentangle biological variations from technical artifacts in these data and identify sequence determinants of translation dysregulation. Here we present Riboformer, a deep learning-based framework for modeling context-dependent changes in translation dynamics. Riboformer leverages the transformer architecture to accurately predict ribosome densities at codon resolution. When trained on an unbiased dataset, Riboformer corrects experimental artifacts in previously unseen datasets, which reveals subtle differences in synonymous codon translation and uncovers a bottleneck in translation elongation. Further, we show that Riboformer can be combined with in silico mutagenesis to identify sequence motifs that contribute to ribosome stalling across various biological contexts, including aging and viral infection. Our tool offers a context-aware and interpretable approach for standardizing ribosome profiling datasets and elucidating the regulatory basis of translation kinetics.

Abstract Background Owing to an increase in life expectancy, it is common for the older adults to suffer from chronic diseases that can result in disability and a low quality of life. This study aimed to explore the influence of chronic diseases and multimorbidities on activities of daily living (ADLs) and instrumental ADLs (IADLs) in an older Chinese population. Methods Based on the Chinese Longitudinal Healthy Longevity Survey (2018), 9,155 older adults aged 65 years and above were included in the study. A self-administered questionnaire was used to collect information on demographic characteristics, chronic diseases, ADLs, and IADLs. The impact of factors affecting ADL and IADL impairment in older adults was analysed using binary logistic regression. Results In total, 66.3% participants had chronic diseases. Hypertension, heart disease, arthritis, diabetes and cerebrovascular disease were among the top chronic diseases. Of these, 33.7% participants had multimorbidities. The most common combination of the two chronic diseases was hypertension and heart disease (11.2%), whereas the most common combination of the three chronic diseases was hypertension, heart disease, and diabetes (3.18%). After categorising the older adults into four age groups, dementia, visual impairment, and hearing impairment were found to be more prevalent with increasing age. The prevalence of hypertension, heart disease, cerebrovascular disease, gastrointestinal ulcers, arthritis and chronic nephritis gradually increased with age until the age of 75 years, peaked in the 75–84 years age group, and then showed a decreasing trend with age. Multimorbidity prevalence followed a similar pattern. Regression analysis indicated that the increase in age group and the number of chronic diseases independently correlated with impairments in ADL as well as IADL. Additionally, gender, physical activity, educational background, obesity, depressive symptoms, and falls also had an impact on ADLs or IADLs. Conclusion Chronic diseases and multimorbidities are common in older adults, and it is important to note that aging, multimorbidity, obesity, and unhealthy lifestyle choices may interfere with ADLs or IADLs in older adults. Therefore, it is imperative that primary healthcare providers pay special attention to older adults and improve screening for multimorbidity and follow-up needs.

Abstract On February 6, a successive rupture of major faults in the Eastern Anatolian Fault Zone and Cardak-Surgu fault triggered a strong mainshock (Mw 7.7) and a major aftershock (Mw 7.6) in Kahramanmaras. The successive earthquake sequence hit southern provinces in Türkiye and northern regions in Syria, causing severe fatality and economic loss. After the earthquakes, the International Consortium on Geo-disaster Reduction (ICGdR) organized an investigation team, involving specialists from China, Japan and Türkiye, to conduct a primary field reconnaissance on seismic damage of infrastructure and ground failures. The 10-day reconnaissance, including a mini-symposium at the Istanbul Technical University (ITU), was conducted from 25 March to 3 April and specifically focused on fault ruptures, liquefaction, landslide, rockfall and lateral spreading along the major ruptured faults from Antakya in Hatay to Goksun in Kahramanmaras, passing through provinces of Gaziantep, Adıyaman and Malatya. By this reconnaissance, a large amount of original seismic data was collected and a primary understanding was established for further steps on mitigation and reduction of seismic damages and its secondary geohazards.

Abstract Systemic immune monitoring is a crucial clinical tool for disease early diagnosis, prognosis and treatment planning by quantitative analysis of immune cells. However, conventional immune monitoring using flow cytometry faces huge challenges in large-scale sample testing, especially in mass health screenings, because of time-consuming, technical-sensitive and high-cost features. However, the lack of high-performance detection platforms hinders the development of high-throughput immune monitoring technology. To address this bottleneck, we constructed a generally applicable DNA framework signal amplification platform (DSAP) based on post-systematic evolution of ligands by exponential enrichment and DNA tetrahedral framework-structured probe design to achieve high-sensitive detection for diverse immune cells, including CD4+, CD8+ T-lymphocytes, and monocytes (down to 1/100 μl). Based on this advanced detection platform, we present a novel high-throughput immune-cell phenotyping system, DSAP, achieving 30-min one-step immune-cell phenotyping without cell washing and subset analysis and showing comparable accuracy with flow cytometry while significantly reducing detection time and cost. As a proof-of-concept, DSAP demonstrates excellent diagnostic accuracy in immunodeficiency staging for 107 HIV patients (AUC > 0.97) within 30 min, which can be applied in HIV infection monitoring and screening. Therefore, we initially introduced promising DSAP to achieve high-throughput immune monitoring and open robust routes for point-of-care device development.

The heart and brain are important organs of human body, which are closely related in genetic, structural and functional aspects. It is of great significance to elucidate the correlation between heart and brain and its mechanism for prevention and treatment of cardiovascular and cerebrovascular diseases. This paper reviews the genetic, structural and functional correlations between heart and brain, and discusses mechanisms of correlations from the perspective of common clinical heart diseases and brain diseases, so as to provide theoretical basis for the research and treatment of brain and heart comorbidity.

We propose and demonstrate a high-quality ($Q$) bound state in the continuum (BIC) cavity based on a hexagonal lattice photonic crystal (PhC) slab with $C_{6}$ symmetry, which carries high-order topological charges of $q=-\text{2}$. By combining the lateral photonic bandgap and high-order topological charge, we realize a $Q$ of $\text{7}\times \text{10}^{4}$ in the experiment which is several times higher than traditional BIC cavities with topological charge of $q=\pm\text{1}$. Specifically, we found that the boundary orientation would significantly influence the performance of lateral confinement. In contrast to an X direction boundary, a gradient J direction boundary can best alleviate the shortcoming of lateral leakage due to incomplete bandgap and the scattering because of momentum mismatching, and relax the strict constraints on wafer thickness. Our findings could broaden the application of BIC cavities from bio-sensing to on-chip telecommunication.

This study explores an obstacle avoidance control approach that takes into account both actuator dead zones and unpredictable disturbances in environments with moving obstacles. Initially, we enhance a Barrier Lyapunov Function (BLF) by introducing the concept of an equivalent safe distance. This innovation broadens the safety perimeter around obstacles by considering their velocity and movement duration, thereby simplifying the intricacies associated with moving obstacle models in avoidance strategies. Furthermore, we refine the auxiliary function within the obstacle avoidance control laws by incorporating exponential and saturation functions. This refinement ensures that as the directional error increases, the velocity of the Automated Guided Vehicle (AGV) decreases. Similarly, it guarantees a reduction in speed as the AGV nears obstacles, resulting in a smoother auxiliary function that prevents excessive speeding when approaching obstacles. Subsequently, we propose an obstacle avoidance control method for AGVs with dead zones, leveraging the enhanced BLF alongside the introduction of a fixed-time disturbance observer. This integration facilitates the estimation of disturbances within a predetermined timeframe. Unlike existing fixed-time disturbance observers, our method incorporates command filtering to mitigate the risk of computational overload. Ultimately, the efficacy of our proposed approach is validated through rigorous experimental simulations conducted on the Matlab platform.

Abstract Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors have been identified for alphavirus entry; however, they cannot explain the broad host range and tissue tropism of certain alphaviruses, such as Getah virus (GETV), indicating the existence of additional receptors. Here we identify the evolutionarily conserved low-density lipoprotein receptor (LDLR) as a new cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV) and Bebaru virus (BEBV). Ectopic expression of LDLR facilitates cellular binding and internalization of GETV, which is mediated by the interaction between the E2-E1 spike of GETV and the ligand-binding domain (LBD) of LDLR. Antibodies against LBD block GETV infection in cultured cells. In addition, the GST-LBD fusion protein inhibits GETV infection both in vitro and in vivo. Notably, we identify the key amino acids in LDLR-LBD that played a crucial role in viral entry; specific mutations in the CR4 and CR5 domain of LDLR-LBD reduce viral entry to cells by more than 20-fold. These findings suggest that targeting the LDLR-LBD could be a potential strategy for the development of antivirals against multiple alphaviruses.

Abstract Background Combined antihypertensive therapy has obvious advantages over single drug therapy. Hypertension guidelines fully affirm the efficacy of dual combination in initial antihypertensive therapy. Recent studies have also pointed out that the quadruple combination of very low-dose antihypertensive drugs is superior to single drugs. However, whether low-dose quadruple therapy is better than dual combination is unknown. Methods/design A randomized double-blind crossover clinical trial will be conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg) in the initial treatment of patients with mild to moderate hypertension (140–179/90–109 mmHg). Ninety patients are required and will be recruited and randomly assigned in a 1:1 ratio to two crossover groups. Two groups will receive a different combination therapy for 4 weeks, then switch to the other combination therapy for 4 weeks, with a 2-week wash-out. Antihypertensive effects and related adverse effects of the two antihypertensive combination treatments will be compared. The primary outcome, i.e., mean 24-h systolic blood pressure in ambulatory blood pressure monitoring, will be assessed via linear mixed-effects model. Discussion This statistical analysis plan will be confirmed prior to blind review and data lock before un-blinding and is sought to increase the validity of the QUADUAL trial. Trial registration ClinicalTrials.gov, NCT05377203. Registered May 11, 2022, https://clinicaltrials.gov/study/NCT05377203 .

Large-scale and multi-sample datasets have revealed that microbial diversity and geographic distribution patterns are distinct across various habitats, particularly between hydrothermal vent and cold seep ecosystems. To date, our understanding of the effects of spatial and geochemical gradients on marine microbial communities remains limited. Here, we report the microbial diversity and metabolic versatility of a remote seafloor sediment ecosystem at different sites (GC-2, -4, -5, -6, -8) in the Mid-Okinawa Trough (Mid-OT) using high-throughput metagenomic sequencing technology. Desulfobacteraceae (3.1%) were detected in a high abundance at GC-2 with intense methane concentrations (353 μL/L), which showed a clear correlation with cold seeping. Whereas Candidatus Brocadiaceae (1.7%), Rhodobacteraceae (0.9%), and Rhodospirillaceae (0.7%), which are commonly involved in denitrification and sulfur oxidation, were enriched at GC-8. Concurrently investigating the potential of deep-sea microbial metabolism, we gained insights into the adaptive capabilities and metabolic mechanisms of microorganisms within seafloor environments. Utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, the analysis of functional modules revealed a significant enrichment (71–74%) of genes associated with metabolic pathways. These results expand our knowledge of the relationship between microbial biodiversity and metabolic versatility in deep-sea extreme environments.

The evaluation and prediction of ecological benefits are significant for regional resource development planning and path designing. This study established a novel ecological benefits evaluation system by integrating macro-ecosystem structure, Ecosystem service index (ESI), and ecological quality index (EQI). Based on this system, this study evaluated the spatiotemporal characteristics and changing trend of ecological benefits in Song-Liao River Basin (SRB) from 1990 to 2020. The results show that the macro-ecosystem structure in Song-Liao River Basin remains stable, and the ecosystem service and ecological quality generally show a trend of first decline and then increase. The average growth rates of ESI and EQI were 0.6% and 0.4%, respectively, during 1990–2020. The ecological benefits of natural areas with widely distributed forest areas are higher, while those of areas with frequent human activities are lower. The prediction model based on machine learning has achieved good modeling effect, which shows that the ecological benefits of SRB will be on the rise in the future. Based on the evaluation results, we suggest that more environmental protection policies on the basis of maintaining the existing development plan should be promoted to reduce the contradiction between human and nature in the development process. For the abundant natural forests in this area, reasonable forest management should be carried out to improve the carbon-fixation capacity of vegetation, and a Methodology for managing natural forests should be constructed to make full use of the existing carbon sinks. For the new afforestation project being promoted, carbon-sink afforestation projects of CCER (Chinese Certified Emission Reduction) should be promoted to realize the synergy between economic development and environmental protection.