Most of the studied MADS box members are linked to flowering and fruit traits. However, higher volumes of studies on type II of the two types so far suggest that the florigenic effect of the gene members could just be the tip of the iceberg. In the current study, we used a systematic approach to obtain a general overview of the MADS box members\' cross-trait and multifactor associations, and their pleiotropic potentials, based on a manually curated local reference database. While doing so, we screened for the co-occurrence of terms of interest within the title or abstract of each reference, with a threshold of three hits. The analysis results showed that our approach can retrieve multi-faceted information on the subject of study (MADS box gene members in the current case), which could otherwise have been skewed depending on the authors\' expertise and/or volume of the literature reference base. Overall, our study discusses the roles of MADS box members in association with plant organs and trait-linked factors among plant species. Our assessment showed that plants with most of the MADS box member studies included tomato, apple, and rice after Arabidopsis. Furthermore, based on the degree of their multi-trait associations, FLC, SVP, and SOC1 are suggested to have relatively higher pleiotropic potential among others in plant growth, development, and flowering processes. The approach devised in this study is expected to be applicable for a basic understanding of any study subject of interest, regardless of the depth of prior knowledge.

Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n = 84) from clinically well-characterized postmenopausal women (50 to 86 years) without clinical CVD using microchips and RNA sequencing. One thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and associated biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and were differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying any overlap in single nucleotide polymorphisms (SNPs) within several genes encoding aBMD- and CVD-associated transcripts. The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.

Introduction The vast pleiotropic effect of statins has intrigued many researchers to select them as potential candidates against bacterial infections. The role of statins against bacterial pathogens remains debatable. This study was undertaken to evaluate and compare the antibacterial effect of commonly available statins against the most frequently isolated bacterial pathogens causing respiratory tract infections in our tertiary care hospital using sputum as a sample. Materials and methods The study was conducted in the Microbiology Laboratory of our hospital. Drugs including atorvastatin, rosuvastatin, and simvastatin were purchased in pure form from Sigma Aldrich. Dimethylsulfoxide (DMSO) was used as a solvent for all three drugs. The positive controls used were gentamycin and amoxicillin for Gram-negative and Gram-positive bacteria, respectively. Data regarding all the culture and sensitivity results of sputum samples of patients admitted to the Respiratory Intensive Care Unit over the past 12 months were analyzed. The most common bacterial pathogens Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus pneumoniae isolated from sputum specimens were taken for our study. The antibacterial effect of statins was studied using two methods: the agar cup diffusion method and the broth dilution method. The zone of inhibition and minimum inhibitory concentration of the drugs were calculated and analyzed. Statistical analysis was performed using GraphPad Prism software version 10.2.0. A one-way ANOVA test was used to determine if there was any statistical difference between the different statins and antibiotic groups. An unpaired t-test was used to determine the statistical difference between the statins. Results and discussion For the agar cup diffusion method, our results displayed a lack of antibacterial activity of all three statins atorvastatin, rosuvastatin, and simvastatin against all three bacterial strains Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus pneumoniae after overnight incubation by agar cup method at concentrations of 3.125 μg/ml, 6.25 μg/ml, 12.5 μg/ml, 25 μg/ml and 50 μg/ml, respectively. The zone of inhibition observed was less than 4 mm (resistant) for all the serial dilutions of atorvastatin, rosuvastatin, and simvastatin. For the broth dilution method, the ANOVA test showed amoxicillin and gentamicin to have high statistically significant microbial growth inhibitory activity (p-value < 0.005) compared to atorvastatin and rosuvastatin. Statistically, though atorvastatin showed significant antimicrobial activity compared to normal saline and rosuvastatin, this was not considered clinically significant as the antimicrobial activity shown by atorvastatin was very negligible compared to the controls used and did not correspond to the serial dilutions of the drug.  Conclusion Atorvastatin, rosuvastatin, and simvastatin lacked antibacterial activity against all three bacterial strains isolated from sputum specimens: Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus pneumoniae. Hence, the use of statins as an antimicrobial drug for respiratory tract infections has limited applications.

The common clinical symptoms and immunopathological mechanisms have been observed among multiple autoimmune diseases (ADs), but the shared genetic etiology remains unclear.
GWAS summary statistics of seven ADs were downloaded from Open Targets Genetics and Dryad. Linkage disequilibrium score regression (LDSC) was applied to estimate overall genetic correlations, bivariate causal mixture model (MiXeR) was used to qualify the polygenic overlap, and stratified-LDSC partitioned heritability to reveal tissue and cell type specific enrichments. Ultimately, we conducted a novel adaptive association test called MTaSPUsSet for identifying pleiotropic genes.
The high heritability of seven ADs ranged from 0.1228 to 0.5972, and strong genetic correlations among certain phenotypes varied between 0.185 and 0.721. There was substantial polygenic overlap, with the number of shared SNPs approximately 0.03K to 0.21K. The specificity of SNP heritability was enriched in the immune/hematopoietic related tissue and cells. Furthermore, we identified 32 pleiotropic genes associated with seven ADs, 23 genes were considered as novel genes. These genes were involved in several cell regulation pathways and immunologic signatures.
We comprehensively explored the shared genetic architecture across seven ADs. The findings progress the exploration of common molecular mechanisms and biological processes involved, and facilitate understanding of disease etiology.

The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer\'s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug-drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design.

Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called \"FVIII-inhibitors (FEIs)\" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and F8-mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects-206 with black-African-ancestry and 244 with white-European-ancestry-was the dependent variable. The F8-mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to NOS2A (rs117382854; p=3.2E-6) and B3GNT2 (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with CTLA4 assigned SNPs (p=2.2E-5). The F8-mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of F8-mutation-effects and non-F8-genetics.

Coordinated plant adaptation involves the interplay of multiple traits driven by habitat-specific selection pressures. Pleiotropic effects, wherein genetic variants of a single gene control multiple traits, can expedite such adaptations. Until present, only a limited number of genes have been reported to exhibit pleiotropy. Here, we create a recombinant inbred line (RIL) population derived from two Arabidopsis thaliana (A. thaliana) ecotypes originating from divergent habitats. Using this RIL population, we identify an allelic variation in a MADS-box transcription factor, SHORT VEGETATIVE PHASE (SVP), which exerts a pleiotropic effect on leaf size and drought-versus-humidity tolerance. Further investigation reveals that a natural null variant of the SVP protein disrupts its normal regulatory interactions with target genes, including GRF3, CYP707A1/3, and AtBG1, leading to increased leaf size, enhanced tolerance to humid conditions, and changes in flowering time of humid conditions in A. thaliana. Remarkably, polymorphic variations in this gene have been traced back to early A. thaliana populations, providing a genetic foundation and plasticity for subsequent colonization of diverse habitats by influencing multiple traits. These findings advance our understanding of how plants rapidly adapt to changing environments by virtue of the pleiotropic effects of individual genes on multiple trait alterations.

Red clover is a raw material of interest primarily due to its isoflavone content. However, other groups of compounds may affect the pleiotropic biological effects of this raw material. It is used to alleviate menopausal symptoms, but the fact that there are many varieties of this plant that can be grown makes it necessary to compare the biological activity and phytochemical composition of this plant. Also of interest are the differences between the leaves and flowers of the plant. The aim of this study was to evaluate the properties of the leaves and flowers of six clover varieties-\'Tenia\', \'Atlantis\', \'Milena\', \'Magellan\', \'Lemmon\' and \'Lucrum\'-with respect to their ability to inhibit α-glucosidase, lipase, collagenase and antioxidant activity. Therefore, the contents of polyphenols and the four main isoflavones-genistein, daidzein, biochanin and formononetin-were assessed. The study was complemented by testing for permeability through a model membrane system (PAMPA). Principal component analysis (PCA) identified a relationship between activity and the content of active compounds. It was concluded that antioxidant activity, inhibition of glucosidase, collagenase and lipase are not correlated with isoflavone content. A higher content of total polyphenols (TPC) was determined in the flowers of red clover while a higher content of isoflavones was determined in the leaves of almost every variety. The exception is the \'Lemmon\' variety, characterized by high isoflavone content and high activity in the tests conducted.

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cAMP responsive element-binding protein (CREB) is one of the most intensively studied phosphorylation-dependent transcription factors that provide evolutionarily conserved mechanisms of differential gene expression in vertebrates and invertebrates. Many cellular protein kinases that function downstream of distinct cell surface receptors are responsible for the activation of CREB. Upon functional dimerization of the activated CREB to cis-acting cAMP responsive elements within the promoters of target genes, it facilitates signal-dependent gene expression. From the discovery of CREB, which is ubiquitously expressed, it has been proven to be involved in a variety of cellular processes that include cell proliferation, adaptation, survival, differentiation, and physiology, through the control of target gene expression. In this review, we highlight the essential roles of CREB proteins in the nervous system, the immune system, cancer development, hepatic physiology, and cardiovascular function and further discuss a wide range of CREB-associated diseases and molecular mechanisms underlying the pathogenesis of these diseases.