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Genetic evidence for amlodipine’s protective role in gastroesophageal reflux disease: A focus on CACNB2
Objective This study aims to elucidate the causal relationship between genetically predicted amlodipine use and the risk of gastroesophageal reflux disease (GERD) using a bidirectional Mendelian Randomization (MR) approach and to explore the underlying genetic and molecular mechanisms through functional enrichment analysis and the construction of a competing endogenous RNA (ceRNA) network. Methods Publicly available GWAS datasets from the Neale Lab consortium were used, including data on amlodipine (13,693 cases, 323,466 controls) and GERD (14,316 cases, 322,843 controls). Genome-wide significant SNPs were selected as instrumental variables and clustered by linkage disequilibrium. MR analysis was conducted using R software with all five methods. Sensitivity analyses assessed pleiotropy and heterogeneity. Drug target genes were analyzed using GO and KEGG pathways. GeneMANIA was used for network visualization, and a ceRNA network was constructed with Cytoscape. Differential gene expression analysis on GERD-related datasets from GEO validated the findings. Results The MR analysis indicated a significant negative association between genetically predicted amlodipine use and GERD risk (IVW OR = 0.872, 95% CI = 0.812–0.937, P = 0.0002). Sensitivity analyses confirmed the robustness of these findings, showing no evidence of pleiotropy or heterogeneity. The enrichment analysis identified key biological processes and pathways involving calcium ion transport and signaling. The ceRNA network highlighted core targets such as CACNB2, which were further validated by differential expression analysis intersecting drug target genes with GERD-related gene expression changes. Conclusion This study provides robust evidence of a protective effect of amlodipine against GERD, supported by genetic and molecular analyses. The findings suggest that calcium channel blockers like amlodipine could be repurposed for GERD treatment. The identification of CACNB2 and other core targets in the ceRNA network offers novel insights into the pathophysiology of GERD and potential therapeutic targets, paving the way for personalized medicine approaches to improve patient outcomes.
In vitro protein expression profile of cultivated muscle cells from Labeo rohita
Dynamic changes in histone lysine lactylation during meiosis prophase I in mouse spermatogenesis
Male germ cells, which are responsible for producing millions of genetically diverse sperm through meiosis in the testis, rely on lactate as their central energy metabolite. Recent study has revealed that lactate induces epigenetic modification in cells through histone lysine lactylation. Here, we report dynamic histone lactylation at histone H4-lysine 5 (K5), -K8, and -K12 during meiosis prophase I in mouse spermatogenesis. By profiling the genome-wide occupancy of histone H4-K8 lactylation (H4K8la), which peaks at zygotene, our data show that H4K8la mark is observed at the promoters of genes exhibiting active expression with Gene Ontology functions enriched for meiosis. Notably, our data also demonstrate that H4K8la is closely associated with recombination hotspots, where machinery involved in the processing DNA double-stranded breaks, such as SPO11, DMC1, RAD51, and RPA2, is engaged. In addition, H4K8la was also detected at the meiosis-specific cohesion sites (marked by RAD21L and REC8) flanking the recombination hotspots. Functionally, our data show that lactate induces upregulation of key meiotic genes through H4K8la modifications. Additionally, H4K8la shows colocalization and interaction with PRDM9 at recombination hotspots. Finally, our data show that HBO1, a lactyltransferase, is highly expressed in meiotic germ cells. In vitro lactylation assays reveal that HBO1 induces H4K8la, and pharmacological inhibition of HBO1 in mice reduces H4K8la levels and disrupts meiosis. Collectively, our findings suggest that histone lactylation serves as an epigenetic mechanism that is involved in meiotic gene expression and recombination in male germ cells during spermatogenesis.
Transcriptome analyses reveal differences in the response to temperature in Florida and Northern largemouth bass (Micropterus spp.) during early life stages
Temperature is one of the most relevant factors influencing the development of aquatic species, making it a key parameter to consider for aquaculture. Largemouth bass (LMB; Micropterus spp.) are highly relevant for human consumption and sport fishing, representing one of North America’s most important freshwater fisheries. Yet, questions remain on how LMB raised in recirculating aquaculture systems (RAS) respond to different temperatures. The main objective of this study was to determine the impact of thermal rearing conditions (21°C, 24°C, and 27°C) on gene expression of Florida and Northern LMB larvae at 8- and 28-days post hatch (DPH). Using de novo transcriptomes as a reference, our results suggest that gene expression differences for Florida LMB were mostly associated with temperature, while differences for Northern LMB were controlled by temperature and developmental stage. In general, both lineages showed activation of molecular pathways associated growth, such as development of muscle, nervous system, and vascular system. There were molecular signatures of stress with warming as well, including immune function, apoptosis, regulation of inflammation, and heat shock proteins. Florida LMB showed large differences between temperatures at both stages, while differences were much larger for Northern LMB at 28 DPH, specifically for individuals reared at 27°C. The results from this study are in line with previous phenotypic studies that indicated faster growth at warmer temperatures and better performance of Northern LMB raised in RAS. Overall, this study exemplifies how controlling developmental temperatures during the critical early life stages can be essential to guarantee the success of commercial hatchery production techniques.
Toward a green strategy of sponge mariculture and bioactive compounds recovery
Debiasing job ads by replacing masculine language increases gender diversity of applicant pools
Job advertisements for jobs in male-dominated fields tend to contain more masculine language, and a commonly proposed intervention to increase gender diversity in applicant pools is to remove this language. In our research, we offer predictions about the broader impact of such interventions on individuals who may not “fit” with traditional masculine identity. Across four multimethod studies ( N = 37,920) spanning both field and lab settings, we demonstrate that a gender debiasing intervention that replaces masculine language in job postings with synonymous gender-neutral language increases application rates among women and men whose self-identities are less aligned with masculinity. Our research highlights that conceptualizing identity incongruence along a continuum can help explain when and why gender diversity initiatives foster the inclusion of a broader group of individuals than initially anticipated.
Assessing benthic invertebrate vulnerability to ocean acidification and de-oxygenation in California: The importance of effective oceanographic monitoring networks
Greenhouse gas emissions from land-use change, fossil fuel, agriculture, transportation, and electricity sectors expose marine ecosystems to overlapping environmental stressors. Existing climate vulnerability assessment methods analyze the frequency of extreme conditions but often minimally consider how environmental data gaps hinder assessments. Here, we show an approach that assesses vulnerability and the uncertainty introduced by monitoring data gaps, using a case study of ocean acidification and deoxygenation in coastal California. We employ 5 million publicly available oceanographic observations and existing studies on species responses to low pH, low oxygen conditions to calculate vulnerability for six ecologically and economically valuable benthic invertebrate species: red sea urchin (Mesocentrotus franciscanus), purple sea urchin (Strongylocentrotus purpurpatus), warty sea cucumber (Apostichopus parvimensis), pink shrimp (Pandalus jordani), California spiny lobster (Panulirus interruptus), and Dungeness crab (Metacarncinus magister). Further, we evaluate the efficacy of current monitoring programs by examining how data gaps heighten associated uncertainty. We find that most organisms experience low oxygen (<35% saturation) conditions less frequently than low pH ( < 7.6) conditions. It is only deeper dwelling (>75 m depth) life stages such as Dungeness crab adults and pink shrimp embryos, juveniles, and adults that experience more frequent exposure to low oxygen conditions. Adult Dungeness crabs experience the strongest seasonal variation in exposure. Though these trends are intriguing, exposure remains low for most species despite well-documented pH and oxygen declines and strengthening upwelling in the central portions of the California Current. Seasonal biases of data collection and sparse observations near the benthos and at depths where organisms most frequently experience stressful conditions undermine exposure estimates. Herein we provide concrete examples of how pink shrimp and Dungeness crab fisheries may be impacted by our findings, and provide suggestions for incorporating oceanographic data into management plans. By limiting our scope to California waters and assessing the limitations presented by current monitoring coverage, this study aims to provide a granular, actionable framework that policymakers and managers can build from to prioritize targeted enhancements and sustained funding of oceanographic monitoring recommendations.
The effects of an unfamiliar experimenter on proactive and reactive control in children
Abstract Cognitive control development across childhood is critical for later academic achievement. Despite recent advances in the comprehension of how the context influences cognitive control development, no study has ever addressed whether one of the most frequent contextual features of children’s lives (i.e., the presence of another person) impacts control engagement. Here, 123 Chinese children aged 5 and 9 years-old performed, either in the presence of an experimenter or alone, an AX-CPT, a task assessing reactive and proactive control. We found that children were overall negatively affected by the experimenter presence in terms of latencies but not of accuracy. Further, when analysing the trial types separately, we observed that this effect mainly concerned trials requiring children to engage more proactive control and was greater for younger than older children. These results indicate that direct social factors such as the presence of an unfamiliar experimenter seem to modulate cognitive control performance. Future research should continue to examine these effects in the light of the numerous existing social presence theories in order to unravel what are the cognitive mechanisms affected by social presence in childhood.
Ancient origin and high diversity of zymocin-like killer toxins in the budding yeast subphylum
Zymocin is a well-characterized killer toxin secreted by some strains of the yeast Kluyveromyces lactis . It acts by cleaving a specific tRNA in sensitive recipient cells. Zymocin is encoded by a killer plasmid or virus-like element (VLE), which is a linear DNA molecule located in the cytosol. We hypothesized that a tRNA-cleaving toxin similar to zymocin may have caused the three parallel changes to the nuclear genetic code that occurred during yeast evolution, in which the codon CUG became translated as Ser or Ala instead of Leu. However, zymocin-like toxins are rare — both among species, and among strains within a species —and only four toxins of this type have previously been discovered. Here, we identified 45 zymocin-like toxin genes in Saccharomycotina, the budding yeast subphylum, using a bioinformatics strategy, and verified that many of them are toxic to Saccharomyces cerevisiae when expressed. Some of the toxin genes are located on cytosolic VLEs, whereas others are on VLE-derived DNA integrated into the nuclear genome. The toxins are extraordinarily diverse in sequence and show evidence of positive selection. Toxin genes were found in five taxonomic orders of budding yeasts, including two of the three orders that reassigned CUG codons, indicating that VLEs have been parasites of yeast species for at least 300 My and that their existence predates the genetic code changes.
Transcriptomic analysis of human primary T cells after short-term leucine-deprivation and evaluation of kinase GCN2’s role in regulating differential gene expression
Chimeric Antigen Receptor T (CAR-T) cells offer a promising strategy for cancer treatment. These CAR-T cells are either autologous or allogeneic T cells that are genetically modified to express a chimeric antigen receptor targeting a specific tumor antigen. Ongoing research aims to optimize the CAR-T cell efficacy, including strategies to modulate their metabolism. One such approach involves inducing transgene expression by activating the GCN2 kinase signaling pathway through dietary deprivation of an essential amino acid. In this study, we investigated the general impact of a 6-hour leucine deprivation on primary activated human T cells using RNA-seq technology. Our analysis identified 3,431 differentially expressed genes between T cells cultured in regular medium and those cultured in leucine-deprived medium. Gene Set Enrichment Analysis revealed that “TNFα signaling via NFκB”, “interferon-γ response”, and “unfolded protein response” gene sets were positively enriched, while “mTORC1 signaling”, “Myc targets”, and “oxidative phosphorylation” gene sets were negatively enriched. To further evaluate the involvement of GCN2 kinase in regulating the differential gene expression during the 6-hour leucine deprivation, T cells were cultured with or without a GCN2 inhibitor. We found that 59% of the differentially expressed genes in our dataset were dependent on the kinase GCN2 (n = 2028), with 1,140 up-regulated and 888 down-regulated genes. These findings suggest a promising strategy to enhance CAR-T cell efficacy by combining short amino acid starvation with transient overexpression of a target gene.
Stability assessment of hygroscopic medications in one dose packaging using community pharmacist surveys and experimental storage methods
Abstract Some medications are unsuitable for one-dose packaging due to issues such as moisture absorption. A survey of community pharmacists was conducted to understand the status of one-dose packaging and identify hygroscopic medications for stability testing. Stability was assessed using a moisture-suppression bag and clinical applications were investigated. Survey results were used to extract the medications that should be included in the one-dose package. Medications were stored with and without moisture-suppression bags, and quality was assessed using weight change and breaking force. Suvorexant, Telmisartan, Aspirin Dialuminate, Kampo extract formulations (Yokukansan and Daikenchu-tou), and Yokuinin extract tablets were selected for the stability test. Storage without moisture-suppression bags resulted in substantial changes in weight and breaking force for all tested medications; the use of moisture-suppression bags maintained the quality of some medications. Although there was a substantial difference in weight change from day 3, there was almost no change in appearance. Currently, the decision to include hygroscopic pharmaceuticals in a single package based on changes in appearance is insufficient. However, further research is necessary to justify the decision not to include hygroscopic pharmaceuticals in such packaging. Therefore, pharmaceutical companies should cultivate appropriate awareness and information literacy of pharmacists should be improved.
Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer’s disease
Cell surface receptors, including erythropoietin-producing hepatocellular A4 (EphA4), are important in regulating hippocampal synapse loss, which is the key driver of memory decline in Alzheimer’s disease (AD). However, the cell-specific roles and mechanisms of EphA4 are unclear. Here, we show that EphA4 expression is elevated in hippocampal CA1 astrocytes in AD conditions. Specific knockout of astrocytic EphA4 ameliorates excitatory synapse loss in the hippocampus in AD transgenic mouse models. Single-nucleus RNA sequencing analysis revealed that EphA4 inhibition specifically decreases a reactive astrocyte subpopulation with enriched complement signaling, which is associated with synapse elimination by astrocytes in AD. Importantly, astrocytic EphA4 knockout in an AD transgenic mouse model decreases complement tagging on excitatory synapses and excitatory synapses within astrocytes. These findings suggest an important role of EphA4 in the astrocyte-mediated elimination of excitatory synapses in AD and highlight the crucial role of astrocytes in hippocampal synapse maintenance in AD.
Mean platelet volume as a biomarker for liver fibrosis in patients with Non-alcoholic fatty liver disease
Introduction Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. Accurate assessment of liver fibrosis is essential for the prognosis and management of NAFLD. Mean platelet volume (MPV), an index of platelet activation, has been associated with liver fibrosis in various chronic liver diseases; however, its role in NAFLD remains uncertain. Methods This study analyzed data from 70,830 patients with NAFLD who underwent a comprehensive health examination between 2015 and 2019. Patients were stratified into three groups based on the fibrosis-4 (FIB-4) index: low (<1.30), indeterminate (1.30–2.67), and high (>2.67). We evaluated the differences in MPV among these groups and analyzed the association between MPV and the FIB-4 index. Results MPV varied significantly across the three groups categorized by the FIB-4 index (p < 0.001). Additionally, a weak but statistically significant positive correlation was observed between MPV and the FIB-4 index (rho = 0.170, p < 0.001). Multivariable linear regression adjusted for multiple covariates showed that MPV remained significantly associated with the FIB-4 index (β = 0.01, p < 0.001). Conclusions MPV may serve as a supplementary non-invasive marker for assessing liver fibrosis in patients with NAFLD. Further studies are required to validate these findings and explore the utility of MPV in conjunction with other non-invasive markers.
Dynamic analysis of a novel 3D chaotic map with two internal frequencies
A community based, bottom-up, multi-pronged, technology integrated approach to enhance tuberculosis related awareness and treatment adherence in Uganda: The ACTS model
Background Tuberculosis (TB) is still a major public health challenge globally and Uganda is one among the top 30 high TB burden countries. One of the key factors determining TB treatment success rates and thereby Cure Rates is the adherence to TB treatment, which is still a major challenge globally. WHO DOTS (Directly Observed Treatment Short course) strategy has several limitations and WHO End TB Strategy 2017 suggests a suite of new interventions to improve adherence. Objectives of the study a. To present the development and design of ZMQ’s Active Care and Treatment Strategy (ACTS) Model. b. To present the results of a pilot study done using the ACTS Model. c. To compare Treatment Adherence Rates between DOTS and Video Observed Treatment (VOT) in the four districts of Uganda. Materials and methods Includes presenting the ACTS Model, a pilot study to assess the AGB and ACF by way of a pre-post (Quasi-experimental) study (n = 1000) to assess the impact of AGB exercises, Focus Group Discussions (FGD) to get insights into factors contributing to treatment non-adherence and a comparison between VOT (n = 800) vs. DOTS for treatment adherence. Results There was a significant improvement (p<0.01) in knowledge and awareness levels of community members post the AGB exercises which included creating awareness using digital storytelling, house visits and more. TB treatment adherence rates among TB patients using VOT was significantly better (p<0.01) than those using DOTS. Conclusion AGB and ACF play a significant role in creating more awareness amongst the community members and identifying more number of cases. It helps in better treatment seeking behaviour, improved treatment rates and treatment adherence rates and in turn better cure rates. VOT is far more superior to DOTS, as a strategy for TB treatment adherence and VOT decreases the resources required in terms of human resource, time and money and is also a more sustainable mode of treatment adherence.
Object detection algorithm based on improved YOLOv8 for drill pipe on coal mines
Abstract Gas extraction is an important measure for coal mine gas disaster control. Its effect is closely correlated to the drilling depth. The existing methods usually determine the drilling depth by manually counting the number of drill pipes, and the number of drill pipes can be automatically counted by object detection and real-time tracking algorithms. An improved object detection model was proposed for the problem of the poor performance of the object detection algorithm due to such interference factors as bright light, low illuminance and heavy dust and mist in coal mines. In terms of data augmentation, the ACE dehazing algorithm is introduced to improve image quality. In order to solve the problem of leak detection caused by the irregular shape that appears due to the interference of bright light, the deformable convolution DCNv2 module was integrated in the C2f module to make the sampling points of the convolution kernel diffuse irregularly, so as to fully extract the shape features of the drill pipe and then improve the detection rate of the model. For the problem of too low confidence of the model in detecting drill pipes due to uneven illumination, the attention paid by the model to the features of the drill pipe could be improved by embedding the SimAM non-parametric attention mechanism module in the backbone network, which can further improve the confidence of the drill pipe. For the problem of low average category detection accuracy caused by the changeable environment of the underground drilling site, the dynamic head was used to improve the ability of the model to extract the features of the drill pipe in scale, space, and channel, and improve the average category detection accuracy of the drill pipe. To address the issue of diverse angle differences between predicted and real boxes, CIoU loss function is replaced with the SIoU loss function. Finally, the improved detection algorithm was verified with the homemade drill pipe dataset. The experimental results showed that: the improved model effectively alleviated the problem of partial leak detection of the original network for scenes such as heavy dust and mist and uneven illumination; the recall rate increased by 4.9%; the mean average precision was improved by 5.3%. At the same time, it maintains a high real-time performance (the FPS is 117), providing the basis of the drill pipe detection model for the application of real-time tracking of the number of drill pipes.
Couples and parenting dynamics during Covid-19 pandemic: A systematic review of the literature
The COVID-19 pandemic constituted a public health crisis bound to impact couples, parents, and families globally. However, the literature on the impacts of COVID-19 in families is not yet integrated. This systematic review aims to (1) provide an overview of how the COVID-19 pandemic potentially changed family systems, especially the couples and parenting dynamics, as well as (2) integrate inconsistent findings, and, finally, (3) define new avenues for research and clinical practice. Inclusion and exclusion criteria were defined for this review. The data was collected in bibliographic databases using a combination of keywords. The study includes empirical research published in English, Spanish, Italian, or Portuguese, appearing in peer-reviewed journals, focusing on the impact of the COVID-19 pandemic on the functioning of different-gender or same-gender couples, married or cohabitating, or cohabitating parents with children aged 2 to 18, between April 2020 and December 2023. Within 381 articles, 58 studies met the inclusion criteria, which 50 were quantitative, four qualitative, and four mixed methods studies. A qualitative thematic analysis of the reviewed articles identified 12 categories that were organized by stress sources, mediators, and outcomes. There is consistent evidence across the literature showing some sources of stress during COVID-19, such as Gender Inequalities (e.g., Unequal Division of Household Duties and Lack of Support for Mothers), and External Stress. Also, we identified some themes on the mediators such as Coping Strategies (e.g., Dyadic Support, Communication as a Mediator and Adaptation to New Daily Routines) and finally as outcomes, Lower Psychological Well-Being, and Relational Growth. However, some inconsistencies were found in Relationship (In) Satisfaction, Sexual Functioning and Communication as an Outcome. Explorations of moderators showed that these inconsistencies should be understood in reference to (1) quality assessment (2) coping and (3) income. After conducting a comprehensive analysis of inconsistencies, our study revealed no notable differences in either relationship satisfaction or sexual frequency before and after the COVID-19 pandemic. Notably, a decline in sexual satisfaction was observed during the COVID-19 period. No conclusive associations were identified between income, relationship satisfaction, sexual satisfaction, sexual frequency, and stress related to COVID-19. Nonetheless, our observations indicated that individuals with moderate or high income, in conjunction with the implementation of effective coping strategies, exhibited a diminished impact of COVID-19-related stress on both relationship satisfaction and sexual functioning. Future studies should focus on a dyadic perspective at various stages of the family cycle, including longitudinal perspectives, as well as studies focused on the role of dyadic coping during times of crises. Findings must be considered with caution because not all studies had equal methodological rigor.
Performance and emission prediction using ANN (artificial neural network) on H2-assisted Garcinia gummi-gutta biofuel doped with nano additives
The influence of survival conditions on farmer willingness to participate in non-grain conversions of cultivated land based on the SOR model
Non-grain conversions (NGC) of cultivated land pose a great threat to national food security, and farmers are the direct actors in the NGC of cultivated land. Exploring the influence of farmer’ survival situation on their willingness to convert cultivated land to non-grain land can provide theoretical support for formulating control policies for NGC of cultivated land. Based on the data obtained from 650 questionnaires in Henan Province and using the SOR model as the theoretical basis, this study explored the impact mechanism of the survival situations of two types of farmers, namely, those with agricultural livelihoods (AL) and those with nonagricultural livelihoods (NL), on their willingness to convert farmland into non-grain land through the use of structural equation models. The results are as follows. The perceived benefits (PB) of NGC can improve their willingness to convert farmland to non-grain land, while the perceived risks (PR) of NGC reduce their willingness to convert farmland to non-grain land. The influence of PB and PR on farmer willingness to engage in NGC of cultivated land in the near term is greater than that in the long term. The influence mechanism of perceived income and perceived risk on the willingness of non-grain conversions of cultivated land varies with the livelihood types of the farmers. The influences of internal family situation (IS) and external family situations (ES) on the willingness to engage in NGC of cultivated land differ according to the types of farmer livelihood. There are differences in the influence mechanism of survival situations on different types of farmers’ willingness to non-grain conversion of cultivated land.