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1.
Article in English | MEDLINE | ID: mdl-38828789

ABSTRACT

The aim of this study was to validate the preventive effects of koumine (KM), a monoterpene indole alkaloid, on gouty arthritis (GA) and to explore its possible mechanisms. C57BL/6 mice were intraperitoneally administered KM (0.8, 2.4 or 7.2 mg/kg), colchicine (3.0 mg/kg) or sterile saline. One hour later, a monosodium urate (MSU) suspension was injected into the right hind paws of the mice to establish an acute gout model. Inflammation symptoms were evaluated at 0, 3, 6, 12 and 24 h, and the mechanical withdrawal threshold was evaluated at 0, 6 and 24 h. After 24 h, the mice were euthanized, and the joint tissue, kidney and blood were collected for subsequent experiments. Histological examination and antioxidant enzyme, kidney index and serum uric acid (UA) measurements were taken. The expression levels of the signalling pathway components were determined. KM effectively alleviated the symptoms of redness, swelling and pain; counteracted inflammatory cell infiltration; and increased antioxidant enzyme levels, reduced kidney index and seru UA levels through regulating UA excretion in MSU-induced mice. The expression of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB)/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) signalling pathway proteins and mRNA were reduced in the KM group. These results suggest that KM may be effective in alleviating GA through the TLR4/NF-κB/NLRP3 pathway.

2.
Carbohydr Polym ; 339: 122235, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-38823906

ABSTRACT

This study explored the physicochemical properties and structural characteristics of Agrocybe cylindracea polysaccharides at four developmental stages, as well as their dynamic evolution during maturation. Results showed that the polysaccharides from A. cylindracea water extract exhibited similar structural characteristics across all four maturity stages, despite a significant reduction in yields. Four water-soluble heteroglycans, including one high molecular weight (ACPM-Et50-I) and three low molecular weight (ACPM-Et50-II, ACPM-Et60, ACPM-Et80), were isolated from A. cylindracea at each maturity stage. ACPM-Et50-I was identified as branched heterogalactans, while ACPM-Et60 and ACPM-Et80 were branched heteroglucans. However, ACPM-Et50-II was characterized as a branched glucuronofucogalactoglucan at the tide-turning stage but a glucuronofucoglucogalactan at the pileus expansion stage due to the increase of its α-(1 â†’ 6)-D-Galp. In general, although the structural skeletons of most A. cylindracea heteroglycans were similar during maturation as shown by their highly consistent glycosyl linkages, there were still differences in the distribution of some heteroglucans. This work has for the first time reported a glucuronofucogalactoglucan in A. cylindracea and its dynamic evolution during maturation, which may facilitate the potential application of A. cylindracea in food and biomedicine industries.


Subject(s)
Agrocybe , Water , Water/chemistry , Agrocybe/chemistry , Glucans/chemistry , Polysaccharides/chemistry , Molecular Weight
3.
Geroscience ; 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38822946

ABSTRACT

Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.

4.
Biomater Adv ; 162: 213916, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38838618

ABSTRACT

The Ti6Al4V (TC4) alloy, a prevalent biomedical material in orthopedics, still faces limitation of the insufficient osseointegration. To improve the bioactivity of TC4, introducing the electric environment onto the TC4 surface may be an effective way in the view of the necessity of endogenous electric microenvironment in bone regeneration. Herein, a Volta potential pattern was engendered on the TC4 surface via parallel laser patterning, so as to promote the osteogenic differentiation of cells. A 15 W laser successfully transformed the original α + ß dual phase towards radially distributed lath-like martensite phase in the laser treated region. The atomic lattice distortion between the heterogeneous microstructures of the laser treated and untreated regions leads to a significant Volta potential fluctuation on the TC4 surface. The Volta potential pattern as well as the laser-engraved microgrooves respectively induced mutually orthogonal cell alignments. The hBMSCs osteogenic differentiation was significantly enhanced on the laser treated TC4 surfaces in comparison to the surface without the laser treatment. Moreover, a drastic Volta potential gradient on the TC4 surface (treated with 15 W power and 400 µm interval) resulted in the most pronounced osteogenic differentiation tendency compared to other groups. Modulating the electric environment on the TC4 surface by manipulating the phase transformation may provide an effective way in evoking favorable cell response of bone regeneration, thereby improving the bioactivity of TC4 implant.

5.
ACS Appl Bio Mater ; 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38833534

ABSTRACT

Nature continually refines its processes for optimal efficiency, especially within biological systems. This article explores the collaborative efforts of researchers worldwide, aiming to mimic nature's efficiency by developing smarter and more effective nanoscale technologies and biomaterials. Recent advancements highlight progress and prospects in leveraging engineered nucleic acids and proteins for specific tasks, drawing inspiration from natural functions. The focus is developing improved methods for characterizing, understanding, and reprogramming these materials to perform user-defined functions, including personalized therapeutics, targeted drug delivery approaches, engineered scaffolds, and reconfigurable nanodevices. Contributions from academia, government agencies, biotech, and medical settings offer diverse perspectives, promising a comprehensive approach to broad nanobiotechnology objectives. Encompassing topics from mRNA vaccine design to programmable protein-based nanocomputing agents, this work provides insightful perspectives on the trajectory of nanobiotechnology toward a future of enhanced biomimicry and technological innovation.

6.
Geroscience ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38837026

ABSTRACT

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.

7.
Article in English | MEDLINE | ID: mdl-38833147

ABSTRACT

PURPOSE: The objective of the study is to test the efficacy of cyclopentenyl cytosine (CPEC)-coated stents on blocking artery stenosis, promoting reendothelialization, and reducing thrombosis. METHODS: Scanning electron microscopy was employed to observe the morphological characteristics of stents coated with a mixture of CPEC and poly(lactic-co-glycolic acid) (PLGA) copolymer. PLGA has been used in various Food and Drug Administration (FDA)-approved therapeutic devices. In vitro release of CPEC was tested to measure the dynamic drug elution. Comparison between CPEC- and everolimus-coated stents on neointimal formation and thrombosis formation was conducted after being implanted into the human internal mammary artery and grafted to the mouse aorta. RESULTS: Optimization in stent coating resulted in uniform and consistent coating with minimal variation. In vitro drug release tests demonstrated a gradual and progressive discharge of CPEC. CPEC- or everolimus-coated stents caused much less stenosis than bare-metal stents. However, CPEC stent-implanted arteries exhibited enhanced reendothelialization compared to everolimus stents. Mechanistically, CPEC-coated stents reduced the proliferation of vascular smooth muscle cells while simultaneously promoting reendothelialization. More significantly, unlike everolimus-coated stents, CPEC-coated stents showed a significant reduction in thrombosis formation even in the absence of ongoing anticoagulant treatment. CONCLUSIONS: The study establishes CPEC-coated stent as a promising new device for cardiovascular interventions. By enhancing reendothelialization and preventing thrombosis, CPEC offers advantages over conventional approaches, including the elimination of the need for anti-clogging drugs, which pave the way for improved therapeutic outcomes and management of atherosclerosis-related medical procedures.

8.
BMC Womens Health ; 24(1): 315, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824522

ABSTRACT

BACKGROUND: Sleep health and obesity may affect the risk of female infertility. However, few studies focused on the interaction of obesity and sleep health on the female infertility risk. This study aimed to evaluate the combined impact of trouble sleeping / sleep duration and overweight/obesity/ abdominal obesity on the risk of female infertility. METHODS: The data for this cross-sectional study was obtained from National Health and Nutritional Examination Survey, which provided information on trouble sleeping, sleep duration, overweight/obesity, abdominal obesity, and confounding factors. Adopted weighted univariate and multivariate logistic regression models to explore the relationship between trouble sleeping, sleep duration, overweight/obesity, abdominal obesity, and the risk of infertility, respectively, and the combined effect of trouble sleeping and overweight/obesity, trouble sleeping and abdominal obesity, sleep duration and overweight/obesity, sleep duration and abdominal obesity, on the female infertility risk. RESULTS: This study included a total of 1,577 women, and 191 were diagnosed with infertility. Women with infertility had a higher proportion of people with overweight/obesity, abdominal obesity, sleep duration ≤ 7 h and trouble sleeping than those with non-infertility. The result indicated that trouble sleeping [odds ratio (OR) = 2.25, 95% confidence intervals (CI): 1.49-3.39], sleep duration ≤ 7 h (OR = 1.59, 95% CI: 1.03-2.48), and the combined impact of abdominal obesity and trouble sleeping (OR = 2.18, 95% CI: 1.28-3.72), abdominal obesity and sleep duration ≤ 7 h (OR = 2.00, 95% CI: 1.17-3.40), overweight/obesity and trouble sleeping (OR = 2.29, 95% CI: 1.24-4.26), and overweight/obesity and sleep duration ≤ 7 h (OR = 1.88, 95% CI: 1.01-3.49) were associated with increased odds of infertility, respectively. CONCLUSION: There was combined effects of trouble sleeping/sleep duration ≤ 7 h and overweight/obesity/ abdominal obesity on increased odds of female infertility.


Subject(s)
Infertility, Female , Nutrition Surveys , Obesity, Abdominal , Obesity , Sleep Wake Disorders , Humans , Female , Adult , Infertility, Female/epidemiology , Infertility, Female/etiology , Cross-Sectional Studies , Obesity/epidemiology , Obesity/complications , Obesity, Abdominal/epidemiology , Obesity, Abdominal/complications , Sleep Wake Disorders/epidemiology , Sleep Wake Disorders/complications , Sleep/physiology , Overweight/epidemiology , Overweight/complications , Risk Factors , Young Adult , United States/epidemiology
9.
Acta Pharm Sin B ; 14(6): 2761-2772, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38828152

ABSTRACT

Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes, its therapeutic potential is compromised by its short half-life and narrow therapeutic index. Current long-acting insulin analogs, such as insulin-polymer conjugates, are mainly used to improve pharmacokinetics by reducing renal clearance. However, these conjugates are synthesized without sacrificing the bioactivity of insulin, thus retaining the narrow therapeutic index of native insulin, and exceeding the efficacious dose still leads to hypoglycemia. Here, we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance. By impairing the binding affinity to the receptor and the activation of the receptor, di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly, increases its maximum tolerated dose 10-fold. The target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high dose. This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.

10.
Anal Chim Acta ; 1306: 342612, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38692793

ABSTRACT

Despite the widespread utilization of variable valence metals in electrochemistry, it is still a formidable challenge to enhance the valence conversion efficiency to achieve excellent catalytic activity without introducing heterophase elements. Herein, the in-situ precipitation of Co particles on Co2VO4 not only enhanced the concentration of oxygen vacancies (Ov) but also generated a greater number of low-valence metals, thereby enabling efficient reduction towards Hg(II). The electroanalysis results demonstrate that the sensitivity of Co/Co2VO4 towards Hg(II) was measured at an impressive value of 1987.74 µA µM-1 cm-2, significantly surpassing previously reported results. Further research reveals that Ov acted as the main adsorption site to capture Hg(II). The redox reactions of Co2+/Co3+ and V3+/V4+ played a synergistic role in the reduction of Hg(II), accompanied by the continuous supply of electrons from zero-valent Co to expedite the valence cycle. The Co/Co2VO4/GCE presented remarkable selectivity towards Hg(II), with excellent stability, reproducibility, and anti-interference capability. The electrode also exhibited minimal sensitivity fluctuations towards Hg(II) in real water samples, underscoring its practicality for environmental applications. This study elucidates the mechanism underlying the surface redox reaction of metal oxides facilitated by zero-valent metals, providing us with new strategies for further design of efficient and practical sensors.

11.
Small ; : e2312124, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38751072

ABSTRACT

Rechargeable metal batteries have received widespread attention due to their high energy density by using pure metal as the anode. However, there are still many fundamental problems that need to be solved before approaching practical applications. The critical ones are low charge/discharge current due to slow ion transport, short cycle lifetime due to poor anode/cathode stability, and unsatisfied battery safety. To tackle these problems, various strategies have been suggested. Among them, electrolyte additive is one of the most widely used strategies. Most of the additives currently studied are soluble, but their reliability is questionable, and they can easily affect the electrochemical process, causing unwanted battery performance decline. On the contrary, insoluble additives with excellent chemical stability, high mechanical strength, and dimensional tunability have attracted considerable research exploration recently. However, there is no timely review on insoluble additives in metal batteries yet. This review summarizes various functions of insoluble additives: ion transport modulation, metal anode protection, cathode amelioration, as well as battery safety enhancement. Future research directions and challenges for insoluble solid additives are also proposed. It is expected this review will stimulate inspiration and arouse extensive studies on further improvement in the overall performance of metal batteries.

12.
J Clin Transl Hepatol ; 12(5): 457-468, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38779518

ABSTRACT

Background and Aims: Hepatitis B virus (HBV) reactivation is commonly observed in individuals with chronic HBV infection undergoing antineoplastic drug therapy. Paclitaxel (PTX) treatment has been identified as a potential trigger for HBV reactivation. This study aimed to uncover the mechanisms of PTX-induced HBV reactivation in vitro and in vivo, which may inform new strategies for HBV antiviral treatment. Methods: The impact of PTX on HBV replication was assessed through various methods including enzyme-linked immunosorbent assay, dual-luciferase reporter assay, quantitative real-time PCR, chromatin immunoprecipitation, and immunohistochemical staining. Transcriptome sequencing and 16S rRNA sequencing were employed to assess alterations in the transcriptome and microbial diversity in PTX-treated HBV transgenic mice. Results: PTX enhanced the levels of HBV 3.5-kb mRNA, HBV DNA, HBeAg, and HBsAg both in vitro and in vivo. PTX also promoted the activity of the HBV core promoter and transcription factor AP-1. Inhibition of AP-1 gene expression markedly suppressed PTX-induced HBV reactivation. Transcriptome sequencing revealed that PTX activated the immune-related signaling networks such as IL-17, NF-κB, and MAPK signaling pathways, with the pivotal common key molecule being AP-1. The 16S rRNA sequencing revealed that PTX induced dysbiosis of gut microbiota. Conclusions: PTX-induced HBV reactivation was likely a synergistic outcome of immune suppression and direct stimulation of HBV replication through the enhancement of HBV core promoter activity mediated by the transcription factor AP-1. These findings propose a novel molecular mechanism, underscoring the critical role of AP-1 in PTX-induced HBV reactivation.

13.
Sci Adv ; 10(21): eadj8184, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38781332

ABSTRACT

Sinking particles are a critical conduit for the transport of surface microbes to the ocean's interior. Vertical connectivity of phylogenetic composition has been shown; however, the functional vertical connectivity of microbial communities has not yet been explored in detail. We investigated protein and taxa profiles of both free-living and particle-attached microbial communities from the surface to 3000 m depth using a combined metaproteomic and 16S rRNA amplicon sequencing approach. A clear compositional and functional vertical connectivity of microbial communities was observed throughout the water column with Oceanospirillales, Alteromonadales, and Rhodobacterales as key taxa. The surface-derived particle-associated microbes increased the expression of proteins involved in basic metabolism, organic matter processing, and environmental stress response in deep waters. This study highlights the functional vertical connectivity between surface and deep-sea microbial communities via sinking particles and reveals that a considerable proportion of the deep-sea microbes might originate from surface waters and have a major impact on the biogeochemical cycles in the deep sea.


Subject(s)
Microbiota , Oceans and Seas , Phylogeny , RNA, Ribosomal, 16S , Seawater , RNA, Ribosomal, 16S/genetics , Seawater/microbiology , Bacteria/genetics , Bacteria/classification
14.
PLoS One ; 19(5): e0299316, 2024.
Article in English | MEDLINE | ID: mdl-38787866

ABSTRACT

OBJECTIVES: Diabetes is associated with decline of cognitive function. Exploring different trajectories of cognitive function occurring in people with diabetes is important to improved prognosis. This study aimed to investigate differential patterns of trajectories of cognitive function and baseline determinants of trajectory group membership utilizing data from middle-aged and older Chinese adults with diabetes. METHODS: Participants of the Chinese Health And Retirement Longitudinal Study (CHARLS) aged 45 years and above received biennial assessments between 2011 and 2018. The primary outcome was overall cognitive function score operationalized as sum of mental intactness and episodic memory scores derived from the Telephone Interview of Cognitive Status (TICS). A weighted growth mixture model was used to estimate cognitive function trajectories of CHARLS participants with diabetes, and baseline factors associated with trajectory group membership were investigated with weighted multinomial logistic regression. RESULTS: Data from 1,463 participants with diabetes aged 45 years and above were analyzed, a three-group trajectory model showed the best fit for overall cognitive scores: low baseline, linear declining (22.1%); moderate baseline, linear declining (37.5%) and high-stable (40.3%). Older participants, females, participants with low education, with nighttime sleep <6 h, without daytime napping habits, and with depressive symptoms were at a higher risk of unfavorable cognitive function trajectories. CONCLUSIONS: We identified heterogeneous trajectories of cognitive function among middle-aged and older people living with diabetes in China. Socially vulnerable groups including females, rural residents, and those with low education were at a higher risk for unfavorable trajectories. In health programs aimed at preventing and mitigating cognitive decline in individuals with diabetes more attention should be given to vulnerable groups. Reduced nighttime sleep, lack of daytime napping, and depressive symptoms appear to be modifiable risk factors.


Subject(s)
Cognition , Diabetes Mellitus , Humans , Female , Male , China/epidemiology , Longitudinal Studies , Middle Aged , Aged , Cognition/physiology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/physiopathology , Diabetes Mellitus/psychology , Cognitive Dysfunction/epidemiology , Risk Factors , Aged, 80 and over
15.
Cell Death Differ ; 2024 May 30.
Article in English | MEDLINE | ID: mdl-38816580

ABSTRACT

Sterol regulatory element binding transcription factors (SREBPs) play a crucial role in lipid homeostasis. They are processed and transported to the nucleus via COPII, where they induce the expression of lipogenic genes. COPII maintains the homeostasis of organelles and plays an essential role in the protein secretion pathways in eukaryotes. The formation of COPII begins at endoplasmic reticulum exit sites (ERES), and is regulated by SEC16A, which provides a platform for the assembly of COPII. However, there have been few studies on the changes in SEC16A protein levels. The repetitive expansion of the hexanucleotide sequence GGGGCC within the chromosome 9 open reading frame 72 (C9orf72) gene is a prevalent factor in the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we found that the absence of C9orf72 leads to a decrease in SEC16A protein levels, resulting in reduced localization of the guanine nucleotide exchange factor SEC12 at the ERES. Consequently, the small GTP binding protein SAR1 is unable to bind the endoplasmic reticulum normally, impairing the assembly of COPII. Ultimately, the disruption of SREBPs transport decreases de novo lipogenesis. These results suggest that C9orf72 acts as a novel role in regulating lipid homeostasis and may serve as a potential therapeutic target for obesity.

16.
Front Genet ; 15: 1375019, 2024.
Article in English | MEDLINE | ID: mdl-38808330

ABSTRACT

Background: The etiology of gallstone disease (GSD) has not been fully elucidated. Consequently, the primary objective of this study was to scrutinize and provisionally authenticate the distinctive expression profiles of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in GSD. Methods: RiboNucleic Acid (RNA) sequencing was used on four paired human gallbladder samples for the purpose of this study. Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were identified and subjected to analysis of their biological functions. The Pearson's correlation coefficients between DElncRNAs and DEmRNAs were computed to construct a co-expression network delineating their associations. Furthermore, both cis- and trans-regulatory networks of selected lncRNAs were established and visualized. Additionally, a competing endogenous RNA (ceRNA) regulatory network was constructed. To validate the RNA-sequencing data, we performed a Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) on 10 paired human gallbladder samples, assessing the expressions of the top 4 DEmRNAs and DElncRNAs in gallstone and control samples. Results: A total of 934 DEmRNAs and 304DElncRNAs were successfully identified. Functional enrichment analysis indicated a predominant involvement in metabolic-related biological functions. Correlation analysis revealed a strong association between the expressions of 597 DEmRNAs and 194 DElncRNAs. Subsequently, both a cis-lncRNA-mRNA and a trans-lncRNA-Transcription Factor (TF)-mRNA regulatory network were meticulously constructed. Additionally, a ceRNA network, comprising of 24 DElncRNAs, 201 DEmRNAs, and 120 predicted miRNAs, was established. Furthermore, using RT-qPCR, we observed significant upregulation of AC004692.4, HECW1-IT1, SFRP4, and COMP, while LINC01564, SLC26A3, RP1-27K12.2, and GSTA2 exhibited marked downregulation in gallstone samples. Importantly, these findings were consistent with the sequencing. Conclusion: We conducted a screening process to identify DElncRNAs and DEmRNAs in GSD. This approach contributes to a deeper understanding of the genetic factors involved in the etiology of gallstones.

17.
bioRxiv ; 2024 May 02.
Article in English | MEDLINE | ID: mdl-38746227

ABSTRACT

The CRISPR/Cas nucleases system is widely considered the most important tool in genome engineering. However, current methods for predicting on/off-target effects and designing guide RNA (gRNA) rely on purely data-driven approaches or focus solely on the system's thermal equilibrium properties. Nonetheless, experimental evidence suggests that the process is kinetically controlled rather than being in equilibrium. In this study, we utilized a vast amount of available data and combined random forest, a supervised ensemble learning algorithm, and free energy landscape analysis to investigate the kinetic pathways of R-loop formation in the CRISPR/Cas9 system and the intricate molecular interactions between DNA and the Cas9 RuvC and HNH domains. The study revealed (a) a novel three-state kinetic mechanism, (b) the unfolding of the activation state of the R-loop being the most crucial kinetic determinant and the key predictor for on- and off-target cleavage efficiencies, and (c) the nucleotides from positions +13 to +16 being the kinetically critical nucleotides. The results provide a biophysical rationale for the design of a kinetic strategy for enhancing CRISPR/Cas9 gene editing accuracy and efficiency.

18.
PLoS One ; 19(5): e0301984, 2024.
Article in English | MEDLINE | ID: mdl-38771833

ABSTRACT

BACKGROUND: The prevalence of burnout among live streamers remains largely unknown. This study aims to investigate the prevalence and factors associated with burnout among Chinese live streamers. METHODS: A cross-sectional study recruited 343 full-time live streamers from 3 companies in Changsha city. Socio-demographic and occupational characteristics were collected using self-designed items. Job stress was assessed using the Job Content Questionnaire (JCQ-22), while supervisor and coworker support were evaluated using the last 8 items of the JCQ-22. Burnout was assessed using the 17-item Chinese version of the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). RESULTS: Our findings revealed that 30.6% of live streamers experienced burnout. Lower levels of education (OR = 2.65 and 3.37, p = 0,005 and 0.003), higher monthly income (OR = 10.56 and 11.25, both p = 0.003), being an entertainment-oriented streamer (OR = 2.13, p = 0.028), continuous walking during live streams (OR = 2.81, p = 0.006), significant drop in follower count (OR = 2.65, P = 0.006), live streaming during the daytime (OR = 3.75, p = 0.001), and higher support from supervisors and coworkers (OR = 3.66, p = 0.001) were positively associated with burnout. However, the effects of education and drop in followers on burnout were not significant in the multivariate logistic models (p = 0.321 and 0.988). CONCLUSIONS: Burnout among Chinese live streamers is associated with income, being an entertainment streamer, engaging in continuous walking during live streams, conducting live streams during the daytime, and experiencing excessive support from supervisors and coworkers.


Subject(s)
Burnout, Professional , Humans , Female , Male , Adult , China/epidemiology , Cross-Sectional Studies , Prevalence , Burnout, Professional/epidemiology , Burnout, Professional/psychology , Middle Aged , Surveys and Questionnaires
19.
ACS Nano ; 18(20): 12808-12819, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38717026

ABSTRACT

Considerable progress has already been made in sweat sensors based on electrochemical methods to realize real-time monitoring of biomarkers. However, realizing long-term monitoring of multiple targets at the atomic level remains extremely challenging, in terms of designing stable solid contact (SC) interfaces and fully integrating multiple modules for large-scale applications of sweat sensors. Herein, a fully integrated wristwatch was designed using mass-manufactured sensor arrays based on hierarchical multilayer-pore cross-linked N-doped porous carbon coated by reduced graphene oxide (NPCs@rGO-950) microspheres with high hydrophobicity as core SC, and highly selective monitoring simultaneously for K+, Na+, and Ca2+ ions in human sweat was achieved, exhibiting near-Nernst responses almost without forming an interfacial water layer. Combined with computed tomography, solid-solid interface potential diffusion simulation results reveal extremely low interface diffusion potential and high interface capacitance (598 µF), ensuring the excellent potential stability, reversibility, repeatability, and selectivity of sensor arrays. The developed highly integrated-multiplexed wristwatch with multiple modules, including SC, sensor array, microfluidic chip, signal transduction, signal processing, and data visualization, achieved reliable real-time monitoring for K+, Na+, and Ca2+ ion concentrations in sweat. Ingenious material design, scalable sensor fabrication, and electrical integration of multimodule wearables lay the foundation for developing reliable sweat-sensing systems for health monitoring.


Subject(s)
Electrolytes , Graphite , Sweat , Wearable Electronic Devices , Sweat/chemistry , Humans , Graphite/chemistry , Electrolytes/chemistry , Ions/analysis , Calcium/analysis , Sodium/analysis , Sodium/chemistry , Biosensing Techniques/instrumentation , Electrochemical Techniques/instrumentation , Electrochemical Techniques/methods , Potassium/analysis
20.
Chem Sci ; 15(21): 7811-7823, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38817563

ABSTRACT

Complex diseases and diverse clinical needs necessitate drug delivery systems (DDSs), yet the current performance of DDSs is far from ideal. Supramolecular interactions play a pivotal role in various aspects of drug delivery, encompassing biocompatibility, drug loading, stability, crossing biological barriers, targeting, and controlled release. Nevertheless, despite having some understanding of the role of supramolecular interactions in drug delivery, their incorporation is frequently overlooked in the design and development of DDSs. This perspective provides a brief analysis of the involved supramolecular interactions in the action of drug delivery, with a primary emphasis on the DDSs employed in the clinic, mainly liposomes and polymers, and recognized phenomena in research, such as the protein corona. The supramolecular interactions implicated in various aspects of drug delivery systems, including biocompatibility, drug loading, stability, spatiotemporal distribution, and controlled release, were individually analyzed and discussed. This perspective aims to trigger a comprehensive and systematic consideration of supramolecular interactions in the further development of DDSs. Supramolecular interactions embody the true essence of the interplay between the majority of DDSs and biological systems.

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