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High glucose couples DJ-1 with PTEN to activate PDGFRβ for renal proximal tubular cell injury
High glucose milieu in diabetes induces proximal tubular epithelial cells in the kidney to undergo hypertrophy and matrix protein expansion via Akt/mTORC1 signaling, leading to renal fibrosis. The familial Parkinson’s disease protein DJ-1 acts as a driver of Ras-dependent tumorigenesis and protects dopaminergic neurons from apoptosis. But its function and mechanistic basis to regulate renal fibrosis is not clear. Here, we identify DJ-1 as a high glucose-promoted protein in renal proximal tubular epithelial cells. Mechanistic interrogation revealed that DJ-1 formed complex with the lipid phosphatase PTEN in high glucose-stimulated cells, resulting in phosphorylation/activation of Akt and mTORC1. siRNAs against DJ-1 decreased high glucose-stimulated Akt/mTORC1 activation. In contrast, overexpression of DJ-1 mimicked all effects of high glucose. Interestingly, inhibition of DJ-1 blocked high glucose-induced hypertrophy of proximal tubular epithelial cells and, matrix proteins fibronectin and collagen I (α2) expression while overexpression of DJ-1 mimicked the high glucose effects on these phenomena. Previously, we reported a role of PDGFRβ in proximal tubular cell injury. In exploring the mechanism of DJ-1 function, we found that siDJ-1 inhibited high glucose-induced activating and PI 3 kinase docking site tyrosine phosphorylation of PDGF receptor-β (PDGFRβ) to block phosphorylation of PI 3 kinase. Interestingly, overexpression of PTEN mimicked these effects of siDJ-1. Together, our results reveal an important role of DJ-1-PTEN nodal point for PDGFRβ activation during high glucose-induced proximal tubular epithelial cell injury.
A retrospective comparative study of the clinical and radiological outcomes of intertrochanteric fractures treated with proximal femoral nail antirotation (PFN-A) and INTERTAN nail
Background This study aimed to analyze the files of patients treated using PFN-A or INTERTAN intramedullary nails to reveal additional superiorities or disadvantageous factors for selecting the better intramedullary fixation method in patients presenting with intertrochanteric femur fractures. Methods In this retrospective study, the files of the patients who were operated on for intertrochanteric femur fractures using intramedullary fixation methods between September 2010 and June 2015 in the Orthopedics and Traumatology Clinic, Çukurova University Faculty of Medicine, were reviewed. The data including age, gender, chronic diseases, causes of fractures, fracture classification based on Arbeitsgemeinschaft für Osteosynthesefragen (AO), the nail type (long or short), the interval between trauma and surgery, duration of anesthesia and surgery, hospitalization duration, amount of blood transfusion, the Tip-Apex Distance (TAD) in postoperative radiographs, functional outcomes according to Harris Hip Score (HHS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), postoperative complications, need for revision, and mortality was noted. The data of the follow-up visits included physical examination findings in addition to the radiological assessment findings obtained using X-ray imaging involving the evaluation of the union in terms of the presence of infection, loss of reduction, implant failure, avascular necrosis, additional signs related to poor union formation, and the position data of the lag screw placement point according to Cleveland and Bosworth Quadrants. Results The records showed that 194 files were available for analysis. The mean age of the patients included in the study was 70.9±16.4 years; 100 patients (51.5%) were male, and 94 (48.5%) were female. There were 76 patients (39%) in the PFN-A group and 118 patients (61%) in the INTERTAN group. Analysis of the mean Harris Hip Scores in both nail groups showed that only the mean scores at the 1st follow-up were statistically significantly different (P = 0.025). Conclusion In conclusion, comparing the two nail types in terms of complication rates and clinical data, neither nail has proven superior to the other. Moreover, the temporary difference in the first follow-up HHS scores should not be considered an indicator of the overall functional outcome because long-term follow-up HHS scores did not differ.
Unveiling endothelial cell border heterogeneity: VE-cadherin adherens junction stratification by deep convolutional neural networks
Background Systemic diseases are often associated with endothelial cell (EC) dysfunction. A key function of ECs is to maintain the barrier between the blood and the interstitial space. The integrity of the endothelial cell barrier is maintained by VE-Cadherin homophilic interactions between adjacent cells. The morphology of these borders is highly dynamic and can be actively remodeled by numerous drivers in a (patho)physiologic context specific fashion. Objectives High-content screening of the impact of circulatory factors on the morphology of VE-Cadherin borders in endothelial monolayers in vitro will enable the assessment of the progression of systemic vascular disease. We therefore aimed to create an image analysis pipeline, capable of automatically analyzing images from large scale screenings, both capturing all VE-cadherin phenotypes present in a sample while preserving the higher-level 2D structure. Our pipeline is aimed at creating 1D tensor representations of the VE-cadherin adherence junction structure and negate the need for normalization. Method An image analysis pipeline, with at the center a convolution neural network was developed. The deep neural network was trained using examples of distinct VE-Cadherin morphologies from many experiments. The generalizability of the model was extensively tested in independent experiments, before further validation using ECs exposed ex vivo to plasma from patients with liver cirrhosis and proven vascular complications. Results Our workflow was able to detect and stratify many of the different VE-Cadherin morphologies present within the datasets and produced similar results within independent experiments, proving the generality of the model. Finally, by EC-cell border morphology profiling, our pipeline enabled the stratification of liver cirrhosis patients and associated patient-specific morphological cell border changes to responses elicited by known inflammatory factors. Conclusion We developed an image analysis pipeline, capable of intuitively and robustly stratifying all VE-Cadherin morphologies within a sample. Subsequent VE-Cadherin morphological profiles can be used to compare between stimuli, small molecule screenings, or assess disease progression.
Bifurcation analysis of an influenza A (H1N1) model with treatment and vaccination
This research uses numerical simulations and mathematical theories to simulate and analyze the spread of the influenza virus. The existence, uniqueness, positivity, and boundedness of the solution are established. We investigate the fundamental reproduction number guaranteeing the asymptotic stability of equilibrium points that are endemic and disease-free. We also examine the qualitative behavior of the models. Using the Lyapunov method, Routh-Hurwitz, and other criteria, we explore the local and global stability of these states and present our findings graphically. Our research assesses control policies and proposes alternatives, performing bifurcation analyses to establish prevention strategies. We investigate transcritical, Hopf, and backward bifurcations analytically and numerically to demonstrate disease transmission dynamics, which is novel to our study. Contour plots, box plots, and phase portraits highlight key characteristics for controlling epidemics. The disease’s persistence depends on its fundamental reproduction quantity. To validate our outcomes, we fit the model to clinical data from influenza cases in Mexico and Colombia (October 1, 2020, to March 31, 2023), aiming to analyze trends, identify critical factors, and forecast influenza trajectories at national levels. Additionally, we assess the efficacy of implemented control policies.
Barriers and missed opportunities in PrEP uptake, use and care among men who have sex with men with recent HIV infection in the Netherlands
Introduction Oral pre-exposure prophylaxis (PrEP) prevents Human Immunodeficiency Virus (HIV) acquisition. In the Netherlands, PrEP is accessible through the national PrEP program (NPP) or general practitioners (GP). Still, some men who have sex with men (MSM) entering HIV care indicated having PrEP experience prior to diagnosis. We aimed to identify barriers and missed opportunities in PrEP uptake, care and use among MSM with HIV and previous PrEP experience. Methods Between March 2022-March 2023, we conducted semi-structured in-depth interviews on PrEP among MSM diagnosed with HIV from 2019 onwards with previous PrEP experience. Interviewees were recruited through their HIV treatment centers and social media. Results Of the 11 included MSM, most reported significant PrEP-uptake delay because of the limited NPP capacity and high threshold of accessing PrEP from GPs (e.g. stigma, lack of sexual health expertise). Additional uptake or use barriers included anticipated/experienced side-effects, burden of daily pill-taking or event-driven regimen complexity, the latter leading to PrEP discontinuation. Missed opportunities in counseling on adherence and safer sex alternatives after discontinuation were reported. Most interviewees considered informal PrEP unsuitable. Conclusion PrEP uptake delay played a crucial role in context of HIV infection among MSM with HIV and previous PrEP experience. HIV diagnoses at or shortly after PrEP initiation emphasize the importance of ensuring rapid and timely PrEP access. Uptake barriers at GPs, stigma on sexuality, lack of expertise, and missed care opportunities need to be addressed. Early detection of PrEP protocol/user-mismatch and counseling on safer sex alternatives after discontinuation are pivotal for sustainable HIV prevention.
Metabolite changes during developmental transitions in Adonis amurensis Regel et Radde flowers: Insights from HPLC-MS analysis
Adonis amurensis Regel et Radde is a remarkable and important spring ephemeral plant and gained considerable attention because of its remarkable medicinal properties. Extensive research has been conducted on its therapeutic applications, physical characteristics, flowering patterns, reproductive, cultural and molecular biology. However, there is a lack of comprehensive understanding regarding the metabolic changes associated with flower developmental stages. This study was designed to investigate the changes in metabolites and their interrelationships at five distinct developmental stages of A . amurensis flower: Flower Primordium (FP), Sepal Stage (SE), Perianth Primordium (PE), Stamens Stage (SE), and Pistil Stage (PI). High-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) was utilized to investigate and characterize the metabolites associated with specific flower developmental stages. The various stages of flower development exerted a substantial influence on both the quantity and composition of metabolites present, signifying significant changes in the types and quantities of metabolites throughout the developmental progression of the flower. Metabolite Set Enrichment Analysis (MSEA) and annotation via the KEGG database highlighted enriched pathways such as flavonoid biosynthesis and plant hormone signal transduction, which are crucial for flower maturation. The highest number of differentially expressed metabolites was identified between the SE and PI stages, emphasizing a marked appreciation in metabolite expression linked to the development of reproductive organs. Key pathways such as flavonoid biosynthesis and plant hormone signal transduction were markedly enriched, underscoring their roles in flower maturation and potential pharmacological applications. Our research not only helps us in understanding the metabolomic dynamics during the flower development of A . amurensis but also emphasizes the potential pharmacological implication of stage-specific metabolites. Identifying these metabolites can help targeted bioprospecting and optimization of extraction methods to tackle the plant’s full therapeutic potential, particularly in the development of treatments for cardiac insufficiency, edema, and possibly cancer.
Correction: Wealthy individual investors and stock markets’ tail risk
Are companies responding to minimum wage increases by reducing corporate social responsibility?
Corporate social responsibility (CSR) has been widely discussed. However, the existing literature does not delve into the theoretical mechanism to show how companies adjust their CSR in the face of minimum wage increases. This may be due to the lack of a theoretical framework that clarifies the relationship between minimum wage increases and CSR adjustments. The objectives of this study is to fill this gap by investigating the impact of minimum wage increases on CSR, employing both cost stickiness and optimal distinctiveness theories. We use the data from the CSMAR database, the Human Resources and Social Security Administration, and Hexun rating system. The subject of this study is China’s A-share listed companies during 2010–2020. This study employs fixed-effects models for a panel data. The findings reveal that minimum wage increases are significantly associated with a reduction in both strategic CSR and responsive CSR. Notably, the decrease in responsive CSR outweighs that of strategic CSR. Furthermore, our results indicate that customer concentration or CSR sensitivity significantly moderates this relationship. More particularly, firms with higher customer concentration are less responsive to minimum wage increases in their CSR activities. Firms with higher sensitivity in CSR are more likely to mitigate the reducing effect of the minimum wage on CSR. By revealing how minimum wage increases affect CSR and its economic consequences, our study provides scientific recommendations for policymakers to measure the impact of minimum wage policies at the firm level.
ESG rating disagreement and bank loan availability: Evidence from China
Environmental, social, and governance (ESG) ratings are receiving increasing attention in credit markets. However, ESG rating disagreement erects obstacles for companies in obtaining capital resources. This study investigates the impact of ESG rating disagreement on bank loan availability uses data of Chinese listed firms from 2014 to 2022, and employs models with multiple regression analyses and fixed effects. We find that greater ESG rating disagreement leads to a decrease in newly obtained bank loans. The mechanism analysis confirms that ESG rating disagreement amplifies information asymmetry and increases operational uncertainty, thereby raising the information and credit risks faced by banks, leading to a decrease in bank loan availability. Heterogeneity analysis reveals that the negative effect of ESG rating disagreement on bank loan availability is more pronounced in firms with poor financing capabilities, poor information environments, and fierce competitive macro environments. Our findings contribute to the literature on ESG rating disagreement from credit markets, which are important for a more comprehensive and objective understanding of ESG rating disagreement.
Agent-based simulation of trust networks and opportunistic behaviours of hydraulic infrastructure project participants
Opportunistic behaviour has become a research hotspot in hydraulic infrastructure project management owing to its serious damage to the cooperation efficiency of all participants in a project. The trust networks formed by each participant can restrain opportunistic behaviour, but due to the dynamic evolution of the networks, its research should adopt a dynamic paradigm. The structure and evolution of trust networks can be simulated using computer simulations and modelling. This study explores the influence mechanism of the structural characteristics of trust networks on the diffusion of opportunistic behaviour. The results show that trust network density has a positive effect on inhibiting the implementation tendency of opportunistic behaviour. However, the centralisation of trust networks has a negative correlation with the degree of inhibition of opportunistic behaviour.
Clade-1 Vap virulence proteins of Rhodococcus equi are associated with the cell surface and support intracellular growth in macrophages
The multi-host pathogen Rhodococcus equi is a parasite of macrophages preventing maturation of the phagolysosome, thus creating a hospitable environment supporting intracellular growth. Virulent R. equi isolated from foals, pigs and cattle harbor a host-specific virulence plasmid, pVAPA, pVAPB and pVAPN respectively, which encode a family of 17 Vap proteins belonging to seven monophyletic clades. We examined all 17 Vap proteins for their ability to complement intracellular growth of a R. equi ΔvapA strain, and show that only vapK1, vapK2 and vapN support growth in murine macrophages of this strain. We show that only the clade-1 proteins VapA, VapK1, VapK2 and VapN are located on the R. equi cell surface. The pVAPB plasmid encodes three clade-1 proteins: VapK1, VapK2 and VapB. The latter was not able to support intracellular growth and was not located on the cell surface. We previously showed that the unordered N-terminal VapA sequence is involved in cell surface localisation of VapA. We here show that although the unordered N-terminus of the 17 Vap proteins is highly variable in length and sequence, it is conserved within clades, which is consistent with our observation that the N-terminus of clade-1 Vap proteins plays a role in cell surface localisation.
Association between low fasting glucose of the living donor and risk of graft loss in the recipient after liver transplantation
The urban carbon unlocking effect of digital infrastructure construction: A spatial difference-in-difference analysis from “Broadband China” pilot policy
As the foundation and cornerstone of the digital economy, digital infrastructure construction is an indispensable engine for realizing China’s energy-saving and emission-reduction, innovation-driven and low-carbon transformation and development. Investigating the carbon unlocking effect of digital infrastructure construction might hasten the achievement of the dual-carbon goal and the “win-win” scenario of environmental protection and economic growth. However, there is still a gap between whether and how digital infrastructure construction can break the carbon lock-in (CLI). Based on the panel data of 266 prefecture-level cities from 2006 to 2019, this paper takes “Broadband China” policy (BCP) as a quasi-natural experiment, constructs a spatial difference-in-difference (SDID) model to explore its impact on CLI, and further analyzes its transmission mechanism, spatial spillover effect and heterogeneity. The results show that: (1) BCP can break the carbon lock-in in the pilot cities and remains valid after a series of robustness tests. (2) There is a lag in the carbon unlocking effect of BCP, and the effect is gradually significant after 3 years of policy implementation. (3) BCP has a spatial spillover impact on CLI, and it significantly contributes to both nearby and local cities. (4) By encouraging green technical advancement and upgrading industrial structure, BCP breaks the CLI. (5) There is regional heterogeneity and urban characteristic heterogeneity in the carbon unlocking effect of BCP. On this basis, we propose a series of policy recommendations to hasten the implementation of low-carbon transformation and sustainable urban development.
A study on Pufferfish privacy algorithm based on Gaussian mixture models
The influence of cognitive reserve on ERP measures of selective visual attentional processing in older adults after mild traumatic brain injury
Objective Older adults have an increased risk of developing persistent cognitive complaints after mild traumatic brain injury (mTBI). Yet, studies exploring which factors protect older adults with mTBI from developing such complaints are rare. It has been suggested that one such factor may be cognitive reserve (CR), but it is unknown how CR influences cognition in this patient category. Here, we therefore study how CR influences brain processes during a task that taps into attention, an important cognitive function. Methods We studied 17 older adults (13 males, mean 68.18 (SD 5.08) years old) at the subacute stage after mTBI and 19 age- and CR-matched participants without mTBI; 9 males, mean 67.79 (SD 5.36) years old) performing a selective visual attentional processing task while recording EEG. The P2 brain event-related potential component was obtained by averaging over electrodes in the fronto-central region of interest and its amplitude and latency were derived as neural correlates of attentional processing. The inverse efficiency score (IES) was derived from accuracy and reaction times as a measure of performance. To investigate the effect of CR on performance and P2 component characteristics, three separate mixed model repeated measures analyses of covariance (RM-ANCOVA) were performed. Results Performance did not significantly differ across groups or task conditions, nor was it significantly influenced by CR. Main effects of CR illustrated that the P2 latency was delayed (p = .03) and the P2 amplitude increased (p = .02) with higher CR across groups. Furthermore, CR correlated positively with P2 latency in both groups (older adults without mTBI: r = .370, p = .005, older adults with mTBI: r = .287, p = 0.041), and with P2 amplitude in the older adults with mTBI (r = .595-.636, p<0.001-.011). We found no main or interaction effects of group or task condition on P2 characteristics. Conclusion Older adults with mTBI with higher CR employ more brain resources than older adults with mTBI with lower CR, accompanied by slower processing, suggesting that it may have resulted in similar performance at a selective visual attentional processing task. To better interpret these findings in the context of persistent complaints and establish that higher CR in these patients may result in better performance, our study needs to be repeated with more participants.
Role of miR-16, 146a, 19b and 720 gene expressions in the pathogenesis and diagnosis of vitiligo
AbstractVitiligo is a common long-term depigmenting skin disorder that is characterized by patches of skin losing their pigment. To evaluate serum/tissue levels of miR-16, 146a, 19b and 720 in vitiligo patients and healthy controls, also analyzing the correlations between all biomarkers to indicate whether those can be used to early diagnose vitiligo patients. Forty-subjects were included, divided into two equal groups, 20 healthy matched individuals and 20 vitiligo patients. For all groups a 5 mL venous blood sample for serum isolation was taken and analyzed for the serum level of miRNAs. For tissue analysis, 3 mm biopsy was taken. For all patients Vitiligo area scoring index (VASI), vitiligo disease activity (VIDA), disease duration and extent percentages were calculated. No significant difference was observed in age and sex ratio among the two groups (p > 0.05). Serum, expression levels for miR-16, 146a, and 19b were overexpressed in vitiligo patients as compared to healthy controls with p-value 0.000 for all biomarkers. While miR-720 was reported low in vitiligo patients compared to controls (p = 0.000). For tissue samples, miR-16, 146a, 19b were overexpressed in vitiligo patients with p-values 0.000, 0.000 and < 0.001 respectively, while for the expression level of miR-720 in tissue, the level was low compared to controls (p = 0.000). There are positive correlations between VASI and miR-16, 146a in serum and miR-146a in tissue. Also positive correlations between disease extent and both miR-16 and miR-146a in serum and in tissue was found. A negative correlation between VIDA and miR-720 in serum was found. Various correlations between the selected miRNAs were reported. Based upon the expression levels of miR-16, 146a, 19b and 720 in both serum and tissue, these biomarkers can be used as early indicators for vitiligo.
Estimating the accumulation and re-accumulation of commercial tobacco, electronic cigarette, and cannabis waste based on a stratified random sample of census blocks
We investigated the amount and distribution of waste generated by commercial tobacco, electronic cigarette, and cannabis (TEC) use to inform policy options aimed at mitigating the environmental harm caused by these products. Using disproportionate stratified random sampling, we selected 60 census blocks from the eight largest cities in San Diego County, California. We twice surveyed publicly accessible areas in these blocks to quantify TEC waste accumulation and its re-accumulation. All collected items were photographed, classified, geocoded, counted, and properly discarded. We identified demographic, land use, and behavioral data from public sources and direct observations. We modeled total cigarette butt quantities for all census blocks across the eight cities and found similar results for Round 1 (8.63 million) and Round 2 (8.66 million) collections. Single-use plastic cigarette filters were the primary contributor to TEC waste (94%). Total TEC waste counts and cigarette butt counts showed strong linear associations (r = +0.86 and r = +0.91). The area surveyed, land use category, resident demographics, smoking prevalence, and walkability explained 78% of the variance in cigarette butt count. The interval between Round 1 and 2 counts did not affect re-accumulation counts, suggesting that baseline TEC waste levels were re-established within 1–2 months after cleanup. Annually, we estimate up to 200 million cellulose acetate plastic filters may be discarded in public areas of the eight cities. Given the continuous deposition, vast quantity, heterogeneous distribution, and rapid re-accumulation of TEC waste after cleanup, increasing removal efforts alone are financially untenable and impractical downstream solutions for TEC waste. Community-wide policies (e.g., filter bans, outdoor smoking restrictions) and individual behavior changes (e.g., reduced smoking rates, proper disposal of cigarette butts) are necessary to effectively mitigate the environmental impact of TEC waste in urban settings.
The high value utilization characteristics of coal gangue powder with emulsified asphalt mastic through rheological and viscoelastic damage theory
Examining the moderating effects of biopsychosocial factors on the relationship between HIV-related depression and cognitive function among adolescents living with HIV in Tanzania: A protocol for an analytical cross-sectional study
Background Adolescents living with HIV face unique challenges, including mental health issues such as depression and cognitive dysfunction. Despite this significant burden, there is a lack of evidence focusing on this population. This study therefore aims to examine the moderating effects of biopsychosocial factors on the bi-directional relationship between HIV-related depression and cognitive function among adolescents living with HIV in the Mbeya region, Tanzania. Methods The analytical cross-sectional study will be conducted in public healthcare facilities in the Mbeya region, involving 207 adolescents living with HIV who will be selected using a systematic random sampling technique. Depression will be assessed using a standardized PHQ-9 tool, while cognitive functioning will be evaluated using a validated Montreal Cognitive Assessment Tool Version 8.3. A biopsychosocial model will be used to guide this study. Descriptive statistics will be used to describe the frequency distribution of the study variables, a chi-square test will be used to describe the relationship between the variables and a binary logistic regression model will be used to predict the moderating effects of biopsychosocial factors on the relationship between HIV-related depression and cognitive function. The odds ratio and a 95% confidence interval will be reported, and the p-value of 0.05 will be considered statistical significance. This study is expected to be conducted for three months. The high prevalence of mental health issues among HIV-positive adolescents, the detrimental effect of HIV on cognitive development, and the lack of studies focused on this population raised the need to conduct this study. Discussion The findings of this study will inform the development of a comprehensive integrated care model that addresses both the mental and cognitive aspects of living with HIV during adolescence. Moreover, the identification of factors associated with depression and cognitive performance will help healthcare providers in identifying at-risk adolescents and proper management of the conditions. This study’s results will also help reveal areas that need in-depth exploration that will lead to a better understanding of the responsible factors.