Manipulation of magnetic beads for actively capturing Vibrio parahaemolyticus and nucleic acid based on microfluidic system.

Rapid biological detection of pathogen micro-organisms has attracted much attention for practical biomedical applications. Despite the development in this field, it is still challenging to achieve simple and rapid biological detection using the microfluidic method. Herein, we propose a novel strategy of biological detection that combines precise detection control of the capillary microfluidic chip and versatile manipulation of magnetic beads. The microfluidic chip was fabricated via laser cutting, which utilized capillary pressure to realize rapid passive injection of liquid samples. Under an external magnetic field, the aptamer-modified magnetic beads were actuated to mix with Vibrio parahaemolyticus (V. parahaemolyticus) and its nucleic acid in the capillary microfluidic chip for rapid selective capture and detection, which could be achieved within 40 min. The experimental results demonstrated that V. parahaemolyticus could be captured using on-chip immunomagnetic beads with a high efficiency and significantly enhanced detection value. Due to these superior performances, the capillary microfluidic system, based on the manipulation of magnetic beads, demonstrated great potential for automatic biological detection.

Discovery of novel biphenyl derivatives as androgen receptor degraders for the treatment of enzalutamide-resistant prostate cancer.

Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.

Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke.

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMTmean-AS: HR = 1.39, 95%CI = 1.09-1.78; cIMTmin-AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMTmax-AS: [Formula: see text]=0.23, P=9.44 × 10-5; cIMTmean-AS: [Formula: see text]=0.21, P=3.00 × 10-4; cIMTmin-AS: [Formula: see text]=0.16, P=6.30 × 10-3). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMTmax-AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMTmean-AS: OR=1.09, 95%CI=0.93-1.26; cIMTmin-AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMTmax: beta=0.07, 95%CI = 0.01-0.13; AS-cIMTmean: beta=0.08, 95%CI = 0.01-0.15; AS-cIMTmin: beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.

The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.

The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.

Risk factors for prostate cancer: An umbrella review of prospective observational studies and mendelian randomization analyses.

BACKGROUND: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. CONCLUSIONS: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.

Independent association of general and central adiposity with risk of gallstone disease: observational and genetic analyses.

Background: General obesity is a well-established risk factor for gallstone disease (GSD), but whether central obesity contributes additional independent risk remains controversial. We aimed to comprehensively clarify the effect of body fat distribution on GSD. Methods: We first investigated the observational association of central adiposity, characterized by waist-to-hip ratio (WHR), with GSD risk using data from UK Biobank (N=472,050). We then explored the genetic relationship using summary statistics from the largest genome-wide association study of GSD (ncase=43,639, ncontrol=506,798) as well as WHR, with and without adjusting for body mass index (BMI) (WHR: n=697,734; WHRadjBMI: n=694,649). Results: Observational analysis demonstrated an increased risk of GSD with one unit increase in WHR (HR=1.18, 95%CI=1.14-1.21). A positive WHR-GSD genetic correlation (rg =0.41, P=1.42×10-52) was observed, driven by yet independent of BMI (WHRadjBMI: rg =0.19, P=6.89×10-16). Cross-trait meta-analysis identified four novel pleiotropic loci underlying WHR and GSD with biological mechanisms outside of BMI. Mendelian randomization confirmed a robust WHR-GSD causal relationship (OR=1.50, 95%CI=1.35-1.65) which attenuated yet remained significant after adjusting for BMI (OR=1.17, 95%CI=1.09-1.26). Furthermore, observational analysis confirmed a positive association between general obesity and GSD, corroborated by a shared genetic basis (rg =0.40, P=2.16×10-43), multiple novel pleiotropic loci (N=11) and a causal relationship (OR=1.67, 95%CI=1.56-1.78). Conclusion: Both observational and genetic analyses consistently provide evidence on an association of central obesity with an increased risk of GSD, independent of general obesity. Our work highlights the need of considering both general and central obesity in the clinical management of GSD.

Design and Implementation of a Flexible Electromagnetic Actuator for Tunable Terahertz Metamaterials.

Actuators play a crucial role in microelectromechanical systems (MEMS) and hold substantial potential for applications in various domains, including reconfigurable metamaterials. This research aims to design, fabricate, and characterize structures for the actuation of the EMA. The electromagnetic actuator overcomes the lack of high drive voltage required by other actuators. The proposed actuator configuration comprises supporting cantilever beams with fixed ends, an integrated coil positioned above the cantilever's movable plate, and a permanent magnet located beneath the cantilever's movable plate to generate a static magnetic field. Utilizing flexible polyimide, the fabrication process of the EMA is simplified, overcoming limitations associated with silicon-based micromachining techniques. Furthermore, this approach potentially enables large-scale production of EMA, with displacement reaching up to 250 µm under a 100 mA current, thereby expanding their scope of applications in manufacturing. To demonstrate the function of the EMA, we integrated it with a metamaterial structure to form a compact, tunable terahertz absorber, demonstrating a potential for reconfigurable electromagnetic space.

Allosteric strand displacement isothermal amplification for the visual detection of Toxoplasma gondii in 30 minutes.

Early detection of Toxoplasma gondii (T. gondii) is critical due to a lack of effective treatment for toxoplasmosis.This study established a simple, cost-effective, and rapid colorimetric detection method for T. gondii. The entire testing process, from sample collection to results, takes only 0.5 h. These characteristics fulfill the demands of researchers seeking rapid target detection with minimal equipment reliance. For genomic extraction, this study evaluated the ability of two filter papers to capture genomes. A rapid genomic extraction device combined with the two filter papers was designed to simplify the genomic extraction process, which was completed within 10 min and increased the detection sensitivity tenfold. The method utilized a simplified primer design for isothermal amplification, namely allosteric strand displacement (ASD), and employed an underutilized commercial color indicator, Bromothymol Blue (BTB), for signal output. Compared with other reported indicators, BTB exhibited a more pronounced color change, shifting from blue to yellow in positive samples, facilitating easier visual differentiation. The reaction was completed in 20 min with a limit of detection (LOD) as low as 0.014 T. gondii per microliter.

Enhancing cartilage regeneration and repair through bioactive and biomechanical modification of 3D acellular dermal matrix.

Acellular dermal matrix (ADM) shows promise for cartilage regeneration and repair. However, an effective decellularization technique that removes cellular components while preserving the extracellular matrix, the transformation of 2D-ADM into a suitable 3D scaffold with porosity and the enhancement of bioactive and biomechanical properties in the 3D-ADM scaffold are yet to be fully addressed. In this study, we present an innovative decellularization method involving 0.125% trypsin and 0.5% SDS and a 1% Triton X-100 solution for preparing ADM and converting 2D-ADM into 3D-ADM scaffolds. These scaffolds exhibit favorable physicochemical properties, exceptional biocompatibility and significant potential for driving cartilage regeneration in vitro and in vivo. To further enhance the cartilage regeneration potential of 3D-ADM scaffolds, we incorporated porcine-derived small intestinal submucosa (SIS) for bioactivity and calcium sulfate hemihydrate (CSH) for biomechanical reinforcement. The resulting 3D-ADM+SIS scaffolds displayed heightened biological activity, while the 3D-ADM+CSH scaffolds notably bolstered biomechanical strength. Both scaffold types showed promise for cartilage regeneration and repair in vitro and in vivo, with considerable improvements observed in repairing cartilage defects within a rabbit articular cartilage model. In summary, this research introduces a versatile 3D-ADM scaffold with customizable bioactive and biomechanical properties, poised to revolutionize the field of cartilage regeneration.

Correspondence-based Generative Bayesian Deep Learning for semi-supervised volumetric medical image segmentation.

Automated medical image segmentation plays a crucial role in diverse clinical applications. The high annotation costs of fully-supervised medical segmentation methods have spurred a growing interest in semi-supervised methods. Existing semi-supervised medical segmentation methods train the teacher segmentation network using labeled data to establish pseudo labels for unlabeled data. The quality of these pseudo labels is constrained as these methods fail to effectively address the significant bias in the data distribution learned from the limited labeled data. To address these challenges, this paper introduces an innovative Correspondence-based Generative Bayesian Deep Learning (C-GBDL) model. Built upon the teacher-student architecture, we design a multi-scale semantic correspondence method to aid the teacher model in generating high-quality pseudo labels. Specifically, our teacher model, embedded with the multi-scale semantic correspondence, learns a better-generalized data distribution from input volumes by feature matching with the reference volumes. Additionally, a double uncertainty estimation schema is proposed to further rectify the noisy pseudo labels. The double uncertainty estimation takes the predictive entropy as the first uncertainty estimation and takes the structural similarity between the input volume and its corresponding reference volumes as the second uncertainty estimation. Four groups of comparative experiments conducted on two public medical datasets demonstrate the effectiveness and the superior performance of our proposed model. Our code is available on https://github.com/yumjoo/C-GBDL.

Unraveling the role of the FHL family in cardiac diseases: Mechanisms, implications, and future directions.

Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.

Hetero- and Homointerlocked Metal-Organic Cages.

Interlocked molecular assemblies constitute a captivating ensemble of chemical topologies, comprising two or more separate components that exhibit remarkably intricate structures. The interlocked molecular assemblies are typically identical, and heterointerlocked systems that comprise structurally distinct assemblies remain unexplored. Here, we demonstrate that metal-templated synthesis can be exploited to afford not only a homointerlocked cage but also a heterointerlocked cage. Treatment of a carboxylated 2,9-dimethyl-1,10-phenanthroline (dmp) or Cu(I) bis-dmp linker with a Ni4-p-tert-butylsulfonylcalix[4]arene cluster affords noninterlocked octahedron and quadruply interlocked double cages consisting of two identical tetragonal pyramids, respectively. In contrast, when a mixture of dmp and Cu(I) bis-dmp linkers is used, a quadruply heterointerlocked cage is produced, consisting of a tetragonal pyramid and an octahedron. With photoredox-active [Cu(dmp)2]+ in the structures, both interlocked cages exhibit remarkable performance as photocatalysts for atom transfer radical addition (ATRA) reactions of trifluoromethanesulfonyl chloride with alkenes or oxo-azidations of vinyl arenes. These interlocked structures serve the dual purpose of stabilizing photocatalytically active components against deactivation and encapsulating substrates within the cavity, resulting in yields comparable to or even surpassing those of their molecular counterparts. This work thus provides a new strategy that combines metal templating and nontemplating approaches to design new types of interlocked assemblies with intriguing architectures and properties.

Environmental Surveillance of Human Astroviruses in Jinan City of China, 2020-2021.

Human astroviruses (HAstVs) are a significant etiological agent of acute gastroenteritis in children. In order to investigate the circulation of HAstVs during the COVID-19 pandemic, a 2-year environmental surveillance was conducted in Jinan between 2020 and 2021. A total of 24 sewage samples were collected and concentrated. Real-time PCR indicated a positive rate of 83.3%, 79.2% (19/24), and 62.5% for classic, MLB, and VA types of HAstV in sewage samples, respectively, with genomic copies ranging from 6.4 × 103 to 3.7 × 107, 3.2 × 104 to 2.2 × 106, and 1.2 × 104 to 1.6 × 107 l-1. Next-generation sequencing (NGS) analysis on complete ORF2 amplicons from each sewage concentrate revealed the presence of 11 HAstV types, including HAstV-1, -2, -4, -5, MLB1, and VA1 to VA6, as well as non-human animal astroviruses. The most abundant HAstV types were HAstV-1, -4, and -5, which accounted for 70.3%, 12.6%, and 9.1% of total HAstV reads, respectively. Phylogenetic analysis revealed that the sequences obtained in this study were segregated into multiple transmission lineages, yet exhibited less genetic divergence among themselves than with foreign strains. These findings provide insight into the genotype diversity and genetic characterization of HAstVs during the COVID-19 pandemic, and highlight the effectiveness of utilizing NGS approaches to investigate sewage HAstVs.

Bidirectional relationship between type 2 diabetes mellitus and coronary artery disease: Prospective cohort study and genetic analyses.

BACKGROUND: While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD. METHODS: We evaluated phenotypic associations using data from the United Kingdom Biobank ( N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: Ncase / Ncontrol = 74,124/824,006; T2DM adjusted for BMI [T2DM adj BMI]: Ncase / Ncontrol = 50,409/523,897) and for CAD ( Ncase / Ncontrol = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM ( Ncase / Ncontrol = 180,834/1,159,055). RESULTS: Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DM→CAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01-2.24; CAD→T2DM: HR = 1.72, 95% CI: 1.63-1.81). A positive overall genetic correlation between T2DM and CAD was observed ( rg = 0.39, P = 1.43 × 10 -75 ), which was largely independent of BMI (T2DM adj BMI-CAD: rg = 0.31, P = 1.20 × 10 -36 ). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DM→CAD: odds ratio [OR] = 1.13, 95% CI: 1.11-1.16; CAD→T2DM: OR = 1.12, 95% CI: 1.07-1.18), which was confirmed in multiancestry individuals (T2DM→CAD: OR = 1.13, 95% CI: 1.10-1.16; CAD→T2DM: OR = 1.08, 95% CI: 1.04-1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9-83.4%) and 90.4% (95% CI: 29.3-151.5%), respectively. CONCLUSION: Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.

The role of a novel mineralocorticoid receptor antagonist, finerenone, in chronic kidney disease: mechanisms and clinical advances.

BACKGROUND: Chronic kidney disease (CKD) poses a significant health risk in contemporary society. Current CKD treatments primarily involve renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, albeit associated with hyperkalemia risks. A novel selective mineralocorticoid receptor antagonist, finerenone, offers a promising, safer alternative for CKD therapy. This review comprehensively assesses the role and efficacy of finerenone in CKD treatment by analyzing clinical and animal studies. Emerging evidence consistently supports finerenone's ability to effectively slow the progression of CKD. By targeting the mineralocorticoid receptor, finerenone not only mitigates renal damage but also exhibits a favorable safety profile, minimizing hyperkalemia concerns. CONCLUSION: Finerenone emerges as a valuable addition to CKD therapy, demonstrating potential benefits in delaying CKD progression while minimizing side effects. Nevertheless, further clinical trials are necessary to provide a comprehensive understanding of its safety and efficacy.

Epidemiological and Genetic Analyses of Schizophrenia and Breast Cancer.

BACKGROUND AND HYPOTHESIS: While the phenotypic association between schizophrenia and breast cancer has been observed, the underlying intrinsic link is not adequately understood. We aim to conduct a comprehensive interrogation on both phenotypic and genetic relationships between schizophrenia and breast cancer. STUDY DESIGN: We first used data from UK Biobank to evaluate a phenotypic association and performed an updated meta-analysis incorporating existing cohort studies. We then leveraged genomic data to explore the shared genetic architecture through a genome-wide cross-trait design. STUDY RESULTS: Incorporating results of our observational analysis, meta-analysis of cohort studies suggested a significantly increased incidence of breast cancer among women with schizophrenia (RR = 1.30, 95% CIs = 1.14-1.48). A positive genomic correlation between schizophrenia and overall breast cancer was observed (rg = 0.12, P = 1.80 × 10-10), consistent across ER+ (rg  = 0.10, P = 5.74 × 10-7) and ER- subtypes (rg = 0.09, P = .003). This was further corroborated by four local signals. Cross-trait meta-analysis identified 23 pleiotropic loci between schizophrenia and breast cancer, including five novel loci. Gene-based analysis revealed 27 shared genes. Mendelian randomization demonstrated a significantly increased risk of overall breast cancer (OR = 1.07, P = 4.81 × 10-10) for genetically predisposed schizophrenia, which remained robust in subgroup analysis (ER+: OR = 1.10, P = 7.26 × 10-12; ER-: OR = 1.08, P = 3.50 × 10-6). No mediation effect and reverse causality was found. CONCLUSIONS: Our study demonstrates an intrinsic link underlying schizophrenia and breast cancer, which may inform tailored screening and management of breast cancer in schizophrenia.

A single atom cobalt anchored MXene bifunctional platform for rapid, label-free and high-throughput biomarker analysis and tissue imaging.

Few of single-atom materials have been served as platform to analyze small molecules for surface assisted laser desorption/ionization mass spectrometry (SALDI-MS). Herein, a novel single Co atom-anchored MXene (Co-N-Ti3C2) is prepared to achieve enhanced SALDI-MS and mass spectrometry imaging (MSI) performance for the first time. The Co-N-Ti3C2 films were prepared by a simple in situ self-assembly strategy to generate an efficient SALDI-MS platform. Compared to typical inorganic/organic matrices, Co-N-Ti3C2 films exhibit superior performance in small molecules detection with ultra-high sensitivity (LOD at amol level), excellent repeatability (CV <4%), clean background and wide analyte coverage, enabling accurate quantitative analysis of various low-concentration metabolites from 1 µL biofluid in seconds. Its usage efficiently enhanced SALDI-MS detection of various small-molecule biomarkers such as amino acids, succinic acid, itaconic acid, arachidonic acid, citrulline, prostaglandin E2, creatinine, uric acid, glutamine, D-mannose, cholesterol and inositol in positive ion mode. The blood glucose level in humans was successfully determined from a linearity concentration range (0.25-10 mM). Notably, the Co-N-Ti3C2 assisted SALDI-MSI enables study the spatial distribution of small molecules covering the range central to metabolomics at a high resolution on a tissue section. Furthermore, Co-N-Ti3C2 platform revealed a specific peak profile that distinguishes osteoarthritis (OA) from rheumatoid arthritis (RA) tissue. Density functional theory theoretical investigation revealed that single Co atoms anchored on Ti3C2 could highly enhanced the ionization ability of metabolites, resulting in high-sensitivity and heterogeneous metabolome coverage.

Discovery of (2S)-N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(6-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-hydroxy-2-methylpropanamide as a Highly Potent and Selective Topical Androgen Receptor Antagonist for Androgenetic Alopecia Treatment.

Androgenetic alopecia (AGA) is the most prevalent form of progressive hair loss disorder in both men and women, significantly impacting their appearance and overall quality of life. Overactivation of the AR signaling pathway in dermal papilla cells (DPCs) plays a crucial role in the development and progression of AGA. Considering the severe systemic side effects associated with oral AR antagonists, the idea of developing of topical AR antagonists with rapid metabolic deactivation properties emerged as a promising approach. Herein, through systematic structural optimization, we successfully identified compound 30a as a potent and selective AR antagonist with favorable pharmacokinetic properties, resulting in high skin exposure and low plasma exposure following topical administration. Importantly, in both hair-growth and AGA mouse models, compound 30a showed potent hair-growth-promoting effects without any noticeable toxicity. These findings suggest that compound 30a holds significant potential as a topical AR antagonist for treating AGA patients.

Observational and genetic analyses of the bidirectional relationship between depression and hypertension.

BACKGROUND: While the association between depression and hypertension has been extensively investigated, the pattern and nature of such association remain inconclusive. We sought to investigate the bidirectional relationship between depression and hypertension and its causal. METHODS: We first performed observational analyses using longitudinal data from the UK Biobank. We then performed genetic analyses leveraging summary statistics from large-scale genome-wide association studies (GWASs) conducted in European ancestry for depression and hypertension. RESULTS: Observational analysis suggested a significant bidirectional phenotypic association between depression and hypertension (Depression â†’ Hypertension: HR = 1.27, 95 % CI: 1.19, 1.36; Hypertension â†’ Depression: HR = 1.65, 95 % CI: 1.58, 1.72). Linkage disequilibrium score regression demonstrated a positive genetic correlation between the two conditions (rg=0.15, P = 5.75 × 10-10). Bidirectional two-sample Mendelian randomization (MR) suggested that genetic liability to depression was significantly associated with an increased risk of hypertension (OR = 1.27, 95 % CI: 1.12, 1.43), while the genetic liability to hypertension was not associated with the risk of depression (OR = 1.01, 95 % CI: 0.99, 1.03). Multivariate MR, after adjusting for smoking, drinking, and body mass index, further supported an independent causal effect of genetic liability to depression on hypertension risk (OR = 1.10, 95 % CI: 1.02, 1.18). LIMITATIONS: (1) interference of confounders, (2) absence of adequate statistical power, and (3) limitation to European populations. CONCLUSION: Our study indicates depression is a causal risk factor for hypertension, whereas the reverse maybe not. Findings support that prevention of depression might help in decreasing hypertension incidence.

Facile fabrication of diatomite biosilica-based nasal drug delivery vehicle for enhanced treatment of allergic rhinitis.

Nanostructured silica-based materials have great potential as drug delivery vehicles for precise and personalized medical applications. As natural nanostructured silica, diatomite biosilica (DB) is recognized as a novel carrier to construct oral/parenteral smart drug delivery systems due to high surface area, biocompatibility, and applicability at low cost, yet the related studies on its use in local delivery routes are still scarce. Herein, we proposed a novel strategy to develop multifunctional nasal drug delivery vehicles based on DB, and demonstrated their versatile performance for enhanced treatment of allergic rhinitis (AR). As a proof of concept, the purified DB microparticles were loaded with budesonide as an anti-inflammatory model drug, and further processed via surface modification to graft polydopamine and carboxymethyl chitosan layers. The synthesized microcapsules exhibited remarkable mucin binding capacity and antibacterial activity against Staphylococcus aureus. Besides, toxicity evaluation with human skin fibroblast cells and hemolysis tests indicated their high biocompatibility. Moreover, in vitro drug release results demonstrated pH-responsive release performance of the microcapsules under simulated AR environment (pH 5.0, 35 °C). Hence, this study provides a facile and reliable approach to construct DB-based mucoadhesive nasal drug delivery vehicles, showing great potential for treatment of allergic airway inflammatory diseases.