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Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation: Results from the BiomarCaRE consortium
Background It has been hypothesized but seldom tested that the winter excess in cardiovascular disease (CVD) is related to hypovitaminosis D. The present study examined the association between CVD and (i) seasonality of 25-hydroxyvitamin D (25[OH]D) and (ii) individual 25(OH)D concentrations. Methods and findings Harmonized 25(OH)D data were obtained from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, including 79,570 participants examined between 1984 and 2010. One 25(OH)D measurement was available per participant. Primary endpoints were CVD incidence (coronary heart disease or stroke; n = 6006) and CVD mortality (n = 2985). To study (i), Poisson regression-derived rate ratios were compared according to two-month categories, ordered by baseline 25(OH)D concentrations. To study (ii), Cox regression-derived hazard ratios were compared according to quarters of baseline 25(OH)D concentrations. With respect to (i), despite a median 25(OH)D concentration ratio of 1:1.79, the trough months of 25(OH)D in March and April had a similar CVD incidence as the peak months of 25(OH)D in August and September (rate ratio: 1.07, 95% CI: 0.98–1.17). CVD mortality was slightly higher in the trough months compared to the peak months (rate ratio: 1.27, 95% CI: 1.12–1.44) but not compared to the other months (despite median 25[OH]D concentration ratios up to 1:1.62; p ≥ 0.077). The CVD mortality peak in January preceded the 25(OH)D trough, not adhering to the temporality criterion of Bradford Hill. With respect to (ii), compared to the lowest quarter, the highest quarter of 25(OH)D was associated with lower CVD incidence (hazard ratio: 0.82, 95% CI: 0.76–0.89) and CVD mortality (hazard ratio: 0.64, 95% CI: 0.57–0.72). Conclusion The present study does not support the hypothesis that seasonal increases in CVD are driven by short-term reductions in 25(OH)D. As in most observational studies, higher 25(OH)D concentrations were inversely associated with CVD.
Comprehensive interrogation of synthetic lethality in the DNA damage response
Abstract The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability 1,2 . Unravelling the complementary interplay between these pathways remains a challenge 3,4 . Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.
Identification of potential riboswitch elements in Homo sapiens mRNA 5’UTR sequences using positive-unlabeled machine learning
Riboswitches are a class of noncoding RNA structures that interact with target ligands to cause a conformational change that can then execute some regulatory purpose within the cell. Riboswitches are ubiquitous and well characterized in bacteria and prokaryotes, with additional examples also being found in fungi, plants, and yeast. To date, no purely RNA-small molecule riboswitch has been discovered in Homo Sapiens. Several analogous riboswitch-like mechanisms have been described within the H. Sapiens translatome within the past decade, prompting the question: Is there a H. Sapiens riboswitch dependent on only small molecule ligands? In this work, we set out to train positive unlabeled machine learning classifiers on known riboswitch sequences and apply the classifiers to H. Sapiens mRNA 5’UTR sequences found in the 5’UTR database, UTRdb, in the hope of identifying a set of mRNAs to investigate for riboswitch functionality. 67,683 riboswitch sequences were obtained from RNAcentral and sorted for ligand type and used as positive examples and 48,031 5’UTR sequences were used as unlabeled, unknown examples. Positive examples were sorted by ligand, and 20 positive-unlabeled classifiers were trained on sequence and secondary structure features while withholding one or two ligand classes. Cross validation was then performed on the withheld ligand sets to obtain a validation accuracy range of 75%-99%. The joint sets of 5’UTRs identified as potential riboswitches by the 20 classifiers were then analyzed. 1533 sequences were identified as a riboswitch by one or more classifier(s) and 436 of the H. Sapiens 5’UTRs were labeled as harboring potential riboswitch elements by all 20 classifiers. These 436 sequences were mapped back to the most similar riboswitches within the positive data and examined. An online database of identified and ranked 5’UTRs, their features, and their most similar matches to known riboswitches, is provided to guide future experimental efforts to identify H. Sapiens riboswitches.
A qualitative exploration of counterfeit, substandard, spurious, and adulterated drugs in Pakistan: A perspective of drug law experts
Objectives The issue of quality of medicine is a worldwide phenomenon and counterfeit, substandard, spurious, and adulterated (CSSA) drugs are a substantial threat to public health. This issue is rampant in the context of low-middle-income countries such as Pakistan. The current study involved a phenomenology-based qualitative approach to explore these drugs’ perception, knowledge, practice, and issues in combating this menace. Methods A semi-structured interview guide was developed. Eleven drug law experts were interviewed through a purposive sampling technique. All interviews were audio recorded, transcribed verbatim, and analysed using a framework analysis approach, yielding seven distinct themes. Results The results showed that CSSA drugs are a serious public health threat and drug law experts confirmed its prevalence in the market. They indicated shortcomings in legislation up to the extent of undue amendments, failure to interpret and implement the law by regulators, ineffective law enforcement machinery, the sub-optimum performance of quality control boards, drug testing laboratories, and courts, and the dubious role of rogue middlemen and wholesalers in drug supply chain and corruption were salient issues highlighted. Conclusion The study revealed that proper drug surveillance, ensuring the presence of a pharmacist, enforcing the law, securing the supply chain, infrastructure for a drug control regime, and training regulators can help tackle this problem.
Maternal complication of instrumental vaginal delivery and its associated factors: Systematic review and meta-analysis
Background While instrumental vaginal delivery is generally a safe procedure, but it is associated with significant risks for both the mother and the newborn in developing countries. However, burden of maternal instrumental delivery complications and its predictors in Ethiopia is highly varied and there isn’t data that indicate nation-level cumulative evidence. Therefore, this study aimed to assess pooled prevalence of maternal complication related to instrumental vaginal delivery and its associated factors among mothers who underwent instrumental vaginal delivery in Ethiopia. Methods In this study, we conducted a search on PubMed, Scopus, Cochrane library, HINARI, and Google Scholar academic databases for studies published until August 2024. Keywords such as instrumental delivery, forceps, vacuum, complication, factors and Ethiopia were used to access literatures from the databases. For quality assessment and data extraction, The Joanna Briggs Critical Appraisal Tools and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were utilized. Random-effect model was used to calculate the pooled prevalence of maternal complication of instrumental vaginal delivery. Subgroup analyses were also conducted to explore potential heterogeneity. The publication bias was assessed using Funnel plot and Egger’s. Results A total of 12 studies with 3745 study participants were participated in the present meta-analysis. The pooled prevalence of maternal complication of instrumental vaginal delivery was 21% (95% CI, 15.0%-28.0%). The prevalence of maternal complication was significantly different among studies conducted between ([2015–2020), and those conducted between [2020 and 2024]. Lowest (14%) in studies conducted before 2020 and highest (26%) among studies conducted 2020 and after (P-value<0.001). Type of instrument (AOR: 1.99, 95% CI: 1.37–2.90), episiotomy status (AOR: 3.49, 95% CI: 2.12–5.76), birthweight (AOR: 3.06, 95% CI: 1.88–4.97) and parity (AOR = 2.96, 95%CI: 1.80–4.85) were the factors associated with maternal complication of instrumental vaginal delivery. Conclusion Our study shows that approximately one in five mothers who underwent instrumental vaginal delivery develop serious maternal complication. Type of the instrument, episiotomy status, birthweight and parity were important predictors of the maternal complication of instrumental vaginal delivery. Effective evaluation of indication, contra indication and precondition for each instrument helps to prevent the maternal complication of instrumental vaginal delivery. Trial registration Registered in PROSPERO with ID: CRD42022366360.
Increased thermal suitability elevates the risk of dengue transmission across the mid hills of Nepal
The burden of climate-sensitive, mosquito-borne diseases, including dengue, has significantly increased in recent years. Understanding the temporal and spatial variations of these diseases is essential for effectively controlling potential outbreaks. In this study, we utilized Moderate Resolution Imaging Spectroradiometer (MODIS) satellite land surface temperature (LST) data (MOD11A2) and a temperature-dependent mechanistic model (R0) to predict the monthly suitability for dengue transmission in Nepal from 2001 to 2020 for both mosquito vectors, Aedes aegypti and Ae. albopictus. We divided the study period into two episodes: 2001–2010, which we characterized as the period of dengue emergence, and 2011–2020, identified as the period of rapid expansion. We compared the thermal suitability across these two time periods. The results indicated that approximately half of Nepal is thermally suitable for dengue transmission for at least one month, with the maximum transmission risk lasting up to nine months each year, a trend that has more or less remained stable over the past 20 years. However, strong temporal dynamics were observed in the hilly regions and around major urban centers such as Kathmandu and Pokhara, where the length of thermal suitability extended up to six months for both vector species. Consequently, the population exposed to thermal suitability increased significantly on a monthly basis. Compared to the emergence period, the proportion of the population exposed to a suitable thermal environment for six months or longer each year increased by 18% for Ae. aegypti and 20% for Ae. albopictus. These findings provide evidence-based insights that could assist health authorities in the control and management of dengue in Nepal.
Developing a real-time hand-gesture recognition technique for wheelchair control
At present, significant number of people in the world are having motor disabilities. They need to use wheelchair for performing regular movements and activities. However, there are a lot of issues and challenges in using the conventional wheelchairs. Safe navigation, independent mobility and low cost are the key issues for wheelchair users. This paper presents a new mathematical model for an efficient and real-time hand gesture recognition technique for a smart wheelchair control system, in line with contemporary technologies. The model is developed using the positions of the significant hand landmarks, distances among them and some critical thresholds which are determined by good number of samples of hands. The proposed method offers more users’ flexibility through less hand movement in operation of the wheelchair. The model is tested for hands of different sizes, irrespective of any background in indoor or outdoor under sunlight. The experimental study demonstrates that it outperforms the existing methods in terms of success rate with good performance metrics.
Moderate to severe chronic arteriolar lesions is an independent risk factor for adverse renal outcomes in IgA nephropathy
Background The impact of chronic arteriolar lesions on the prognosis of IgA nephropathy remains controversial. This study aims to explore the value of chronic arteriolar lesions of varying degrees in predicting the prognosis of IgA nephropathy patients and analyze the associated risk factors that contribute to the formation. Methods A retrospective analysis was conducted on 853 patients diagnosed with IgA nephropathy through renal biopsy at Guangdong Provincial Hospital of Traditional Chinese Medicine between September 1, 2005, and December 31, 2021. Eventually, a total of 574 cases were included in this study. According to the degree of chronic arteriolar lesions, the patients were divided into four groups: no lesion group (n=115), mild lesion group (n=287), moderate lesion group (n=131), and severe lesion group (n=41). Relevant clinical and pathological features and renal outcomes were recorded. Kaplan-Meier analysis, Cox proportional hazards regression, and receiver operating characteristic (ROC) curve analysis were utilized to examine the relationship between different degrees of chronic arteriolar lesions and the prognosis of IgA nephropathy. Additionally, risk factors associated with the development of moderate to severe chronic arteriolar lesions were identified. Results Worse clinical and pathological features were observed in the moderate to severe lesions group (P<0.05). Moderate to severe chronic arteriolar lesions (aHR=3.357, 95%CI: 1.018–11.071, P=0.047), creatinine, S1, E1, T2, and C2 were identified as independent risk factors for adverse renal outcomes. Cox multivariate regression analysis on moderate to severe chronic arteriolar lesions demonstrated that creatinine, T2, and C2 were independent risk factors for adverse renal outcomes in patients with moderate to severe chronic arteriolar lesions. Conclusion Moderate to severe chronic arteriolar lesions independently increases the risk of adverse renal outcomes.
Inhibitive effect of Urginea epigea methanolic extract and silver/zinc oxide nanoparticles on Aspergillus and aflatoxin production
Food crops contaminated with Aspergillus flavus due to aflatoxins can be hazardous for both humans and animals, hence endeavours are being explored to find natural antifungals to combat the contamination and mycotoxin issue. The current study used the agar dilution method to assess the effect of Urginea epigea methanolic extract and biosynthesized silver-zinc oxide nanoparticles on the toxigenic strain of Aspergillus. In the experiment, an aflatoxin-producing strain was used, and potato dextrose agar was diluted with methanolic extract from U. epigea and silver/zinc oxide nanoparticles at concentrations of 0, 6.5, 12, 25, and 50 mg/mL, respectively. Mycelia growth diameters were measured to test inhibitory activity. A significant decrease in fungal growth was observed at different concentrations (P < 0,05) when compared to the control. At 50 mg/mL, the extract of U. epigea significantly reduced the growth of A. flavus by 100%. PCR data shows that the expression of aflD and aflR was significantly downregulated (P < 0.005) by the treatments, with U. epigea having a 50fold decrease when compared to Ag/ZnO nanoparticles. Compared to the controls, Ag/ZnO nanoparticles down-regulated the expression of aflD and aflR in A. flavus by more than 30-fold. However, there was less expression by nanoparticles, as evidenced by the sequence alignment. A. flavus growth and aflatoxin B1 production were both considerably suppressed by U. epigea methanolic extract, through the presence of phytochemicals thus has the potential to be employed as an alternative antifungal agent to control aflatoxigenic fungus. The study recommends investigating and extracting the active compound present in the U. epigea bulb.
Elevator fault precursor prediction based on improved LSTM-AE algorithm and TSO-VMD denoising technique
This study proposes an advanced elevator fault precursor prediction method integrating Variational Mode Decomposition (VMD), Bidirectional Long Short-Term Memory (BILSTM), and an Autoencoder with an Attention Mechanism (AEAM), collectively referred to as the VMD-BILSTM-AEAM algorithm. This model addresses the challenges of feature redundancy and noise interference in elevator operation data, improving the stability and accuracy of fault predictions. Using a dataset of elevator operation parameters, including current, voltage, and running speed, the model utilizes the Attribute Correlation Density Ranking (ACDR) method for feature selection and the TSO-optimized VMD for denoising, enhancing data quality. Cross-validation and statistical analyses, including confidence interval calculations, were employed to validate the robustness of the model. The results demonstrate that the VMD-BILSTM-AEAM algorithm achieves a mean True Positive Rate (TPR) of 0.919 with a 95% confidence interval of 0.915 to 0.924, a mean False Positive Rate (FPR) of 0.090 with a 95% confidence interval of 0.087 to 0.092, and a mean Area Under the Curve (AUC) of 0.919 with a 95% confidence interval of 0.915 to 0.923. These performance metrics indicate a significant improvement over traditional and other deep learning models, confirming the model’s superiority in predictive maintenance of elevators. The robust capability of the VMD-BILSTM-AEAM algorithm to accurately process and analyze time-series data, even in the presence of noise, highlights its potential for broader applications in predictive maintenance and fault detection across various domains.
Allostatic load and its determinants in a German sample—Results from the Carla cohort
Background Allostatic load (AL) is a surrogate of the physiological response to stress and reflects the ‘wear and tear’ on the body. Previous studies indicated that socioeconomic and behavioral determinants influence AL, which in turn is associated with health outcomes. Therefore, AL is increasingly used to operationalize the relationship between social inequality, stress, and health outcomes. This study aimed to investigate associated factors and patterns of AL in the population over a 20-year period using data from the CARLA cohort. Methods The analysis included 473 participants from the CARLA study (Cardiovascular Disease, Living and Ageing in Halle), aged 45–80 years at baseline. From recruitment in 2002 in Halle (Saale), three follow-up examinations took place until 2022. We calculated AL scores as the sum of standardized z-scores for metabolic, immune, cardiovascular, and anthropometric components. Descriptive statistics of AL scores were stratified by sex and age categories. Multiple regression analyses were conducted for the first and third follow-up to assess if there were changes in associations between sociodemographic factors and AL. Results Average AL scores of men decreased, while women’s AL scores returned to baseline levels after an initial decrease observed at the first follow−up. Stratified analyses of AL scores revealed that women in the younger age cohorts had lower mean AL scores at baseline than men (women: −3.47, 95% CI [−4.24; −2.71] vs. men: −1.13, 95% CI [−1.84; −0.42] at age <55). At the same time, women showed higher mean AL scores than men in older age cohorts (women: −0.32, 95% CI [−1.58; 0.95] vs. men: −0.93, 95% CI [−1.99; 0.14] at age 65−<70). Results of multiple regression models indicated lower AL scores for women (β: −1.21, 95% CI [−1.93, −0.49]). Professional status was associated with lower AL scores for men but not for women (β: −1.06, 95% CI [−2.02, −0.11] for men). Further, physical activity was negatively associated with AL scores for the total study sample and for women (β: −0.54, 95% CI [−0.82, −0.26]) for total sample and β: −0.74, 95% CI [−1.17, −0.32] for women). Conclusion Our results highlight the importance of health awareness and physical activity for overall health, assessed by AL. Distinct AL score changes and sex-specific socioeconomic influences offer insights into sex-related patterns of aging. Further research is needed to understand the underlying mechanisms of socioeconomic influences on stress-related aging processes between sexes.
Capacity configuration optimization of electricity heat hydrogen regional integrated energy system considering supply-demand uncertainties
Rationally configuring the capacity of the electricity heat hydrogen regional integrated energy system is conducive to improving its economy and energy utilization efficiency. In view of the dual effects of the uncertainties of energy supply and demand in system configuration on power supply reliability and wind power consumption, a min-max-min two-stage robust optimization configuration model aiming at the minimum sum of system investment and operating cost is established for achieving an optimal capacity configuration of multi-vector technologies involved in it. On the basis of typical scenarios, a box-type uncertainty set independent of a probability distribution is used to describe the uncertainty of wind power and demand and the robustness constraint is formed. An innovative parameter, named the uncertainty adjustment parameter, is introduced into the box-type uncertainty set to avoid sacrificing economic benefits caused by too conservative configuration scheme. In this paper, the column and constraint generation algorithm and strong duality theory are used to decompose the original problem into the linearized master problem and subproblem, which can improve the solving speed. Finally, an integrated energy system in the north of China is taken as a case study. The results demonstrate that the proposed model effectively addresses the uncertainty problems of wind power and demand, leading to improved reliability and wind power integration performance. By changing the uncertainty adjustment parameter, the conservativeness of the configuration scheme can be flexibly adjusted. The effectiveness and applicability of the proposed model and solution algorithm are verified.
Exploring the antimicrobial and antibiofilm potency of four essential oils against selected human pathogens using in vitro and in silico approaches
Multi-drug-resistant (MDR) pathogens pose a significant global health challenge, underscoring the urgent need for novel antimicrobial agents with minimal toxicity to humans. This study investigated the in vitro and in silico antimicrobial and antibiofilm potentials of four essential oils (EOs): clove bud oil (CBO; Syzygium aromaticum L.), black seed oil (BSO; Nigella sativa L.), cinnamon bark oil (CNBO; Cinnamomum zeylanicum), and citronella oil (CTLO; Cymbopogon nardus L.), against 19 selected human pathogens, including MDR strains. Among the tested EOs, CBO, BSO, and CNBO exhibited the highest antibacterial activity against Staphylococcus epidermidis, with the mean zone of inhibition diameters (ZIDs) of 20.0 ± 0.2 mm, 46.0 ± 0.3 mm, and 32.0 ± 0.1 mm, respectively, at a concentration of 10 µL/disc, while CTLO displayed no antibacterial activity. CNBO demonstrated superior antifungal activity, with the mean ZIDs of 49.0 ± 0.3 mm and 36.0 ± 0.3 mm for Candida albicans and Aspergillus niger, respectively. Molecular docking analyses revealed robust interactions of key bioactive compounds—eugenol (EU) from CBO, thymoquinone (TQ) from BSO, cinnamaldehyde (CN) from CNBO, citronellal (CIT) and linalool (LIN) from CTLO—with microbial target proteins, substantiating their antimicrobial and antibiofilm potential. Notably, CTLO, despite limited in vitro activity, exhibited unique binding interactions in silico, suggesting potential niche applications. These findings underscore the translational potential of EOs as alternative antimicrobial therapies against MDR infections, particularly biofilm-associated infections, and highlight the need for further in vivo studies to validate their efficacy and safety.
Recurrent humid phases in Arabia over the past 8 million years
Abstract The Saharo-Arabian Desert is one of the largest biogeographical barriers on Earth, impeding dispersals between Africa and Eurasia, including movements of past hominins. Recent research suggests that this barrier has been in place since at least 11 million years ago1. In contrast, fossil evidence from the late Miocene epoch and the Pleistocene epoch suggests the episodic presence within the Saharo-Arabian Desert interior of water-dependent fauna (for example, crocodiles, equids, hippopotamids and proboscideans)2–6, sustained by rivers and lakes7,8 that are largely absent from today’s arid landscape. Although numerous humid phases occurred in southern Arabia during the past 1.1 million years9, little is known about Arabia’s palaeoclimate before this time. Here, based on a climatic record from desert speleothems, we show recurrent humid intervals in the central Arabian interior over the past 8 million years. Precipitation during humid intervals decreased and became more variable over time, as the monsoon’s influence weakened, coinciding with enhanced Northern Hemisphere polar ice cover during the Pleistocene. Wetter conditions likely facilitated mammalian dispersals between Africa and Eurasia, with Arabia acting as a key crossroads for continental-scale biogeographic exchanges.
Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia
Abstract Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer1,2. However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81 years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1, were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3–14 years (confidence interval 2–16 years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.
Evidence of star cluster migration and merger in dwarf galaxies
Abstract Nuclear star clusters (NSCs) are the densest stellar systems in the Universe. These clusters can be found at the centre of all galaxy types but tend to favour galaxies of intermediate stellar mass around 109 M ⊙ (refs. 1,2). At present, two main processes are under debate to explain their formation: in situ star formation from gas infall3 and migration and merging of globular clusters (GCs) caused by dynamical friction4. Studies5–9 of NSC stellar populations suggest that the former predominates in massive galaxies, whereas the latter prevails in dwarf galaxies, and both contribute equally at intermediate mass. However, until now, no ongoing merger of GCs has been observed to confirm this scenario. Here we report the serendipitous discovery of five dwarf galaxies with complex nuclear regions, characterized by multiple nuclei and tidal tails, using high-resolution images from the Hubble Space Telescope. These structures have been reproduced in complementary N-body simulations, supporting the interpretation that they result from migrating and merging of star clusters. The small detection rate and short simulated timescales (below 100 Myr) of this process may explain why this has not been observed previously. This study highlights the need for large surveys with high resolution to fully map the migration scenario steps.