Altered Expression Research Articles

N-[4-(Benzyloxy)-3-methoxybenzyl)]adamantane-1-amine (DZH2), a dual CCR5 and CXCR4 inhibitor as a potential agent against triple negative breast cancer.

DZH2, a dual inhibitor of the chemokine receptors CCR5 and CXCR4, was discovered from virtual screening for CCR5 antagonists. In specific Ca2+ chemokine signaling assays, DZH2 displayed low micromolar IC50 values at both chemokine receptors. Its binding to intracellular allosteric binding sites of CCR5 and CXCR4 was confirmed by MD simulations and binding free-energy calculations. DZH2 is superior to the CCR5 antagonist maraviroc in terms of its inhibitory activity on the growth of two breast cancer cell lines. In MCF7 and MDA-MB-231 cells, DZH2 was a >100-fold more potent inhibitor of cell viability compared to maraviroc. DZH2 (6.7 µM) reduced migration of MDA-MB-231 cells to 4% compared to 50% inhibition of migration caused by maraviroc (780 µM). Also, DZH2 was a significantly more potent inhibitor of colony formation in MDA-MB-231 cells than maraviroc. In MCF10 cells, DZH2 caused no alteration in the gene expression with respect to cellular pathways mediating cell death, indicating its selectivity to breast cancer cells.

Hoxa5 alleviates adipose tissue metabolic distortions in high-fat diet mice associated with a reduction in MERC

BackgroundMitochondria-endoplasmic reticulum membrane contact (MERC) is an important mode of intercellular organelle communication and plays a crucial role in adipose tissue metabolism. Functionality of Hoxa5 is an important transcription factor involved in adipose tissue fate determination and metabolic regulation, but the relationship between Hoxa5 and MERC is not well understood.ResultsIn our study, we established an obesity model mouse by high-fat diet (HFD), induced the alteration of Hoxa5 expression by adenoviral transfection, and explored the effect of Hoxa5 on MERC dysfunction and metabolic distortions of adipose tissue with the help of transmission electron microscopy, calcium ion probe staining, and other detection means. The results showed Hoxa5 was able to reduce MERC production, alleviate endoplasmic reticulum stress (ERS) and calcium over-transport, and affect cGAS-STING-mediated innate immune response affecting adipose tissue energy metabolism, as well as affect the AKT-IP3R pathway to alleviate insulin resistance and ameliorate metabolic distortions in adipose tissue of mice.ConclusionsOur results suggest that Hoxa5 can ameliorate high-fat diet-induced MERC overproduction and related functional abnormalities, in which finding is expected to provide new ideas for the improvement of obesity-related metabolic distortions.

Association of genetically predicted human metabolomic gene expression with incident heart failure

Abstract Background Heart failure (HF) represents a significant challenge both for patients and healthcare systems worldwide. Despite ongoing efforts, therapeutic options are limited. The underlying pathophysiology involves intricate changes in cardiac metabolism that strongly influence the clinical phenotype, thus potentially offering novel options for therapeutic targeting. Systematic prioritisation of metabolic genes regarding their phenotypic impact on HF is outstanding. Purpose We investigate the association of genetically predicted metabolic gene expression with the onset of HF within UK Biobank (UKB). We followed up on identified candidate genes using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) models of cardiomyocyte hypertrophy. Methods Utilising genomic data of 484,372 UKB participants and left ventricle-specific expression quantitative trait loci (eQTL) information from Genotype-Tissue Expression (GTEx) project, we predicted genetically regulated gene expression using established methods (PrediXcan) for all metabolic genes. Subsequently, we employed per-gene Cox proportional hazards (COX-PH) models to assess the association of genetically predicted metabolic gene expression with incident HF. We adjusted models for clinical risk using established risk models (Pooled Cohort Equations to Prevent HF (PCP-HF)). To validate our findings in vitro, we subjected hiPSC-CMs to a sympathomimetic stimulus via treatment with endothelin-1 (ET-1; 10 nM). We evaluate alterations in expression via real-time quantitative polymerase chain reaction (RT-qPCR) and establish methods for assessing hypertrophic remodelling. Results COX-PH models revealed the predicted expression of 104/1515 metabolic genes to be independently associated with the onset of HF. Subsequent refinement with a meta-analysis of commonly dysregulated genes in end-stage HF narrowed our findings to 46 candidate genes, of which several were known for their role in HF pathophysiology. We further traced nine genes for validation in hiPSC-CM models and showed significant dysregulation of several genes following the treatment with ET-1. Flow cytometry measured hiPSC-CM hypertrophy following sympathomimetic stimulation (p=0.036). Extracellular flux analysis revealed canonical changes following treatment with ET-1. Conclusions The study revealed several metabolic genes associated with incident HF, thus confirming previous findings and highlighting novel, putative therapeutic target genes. We confirmed transcriptional changes in an in vitro model. Ongoing work includes further validation via silencing candidate genes in hiPSC-CMs and subjection to the established phenotypic in vitro models.

The essential role of the miRNA-208a/TARBP2/Sox6 axis in myosin expression in the end stage human heart failure

Abstract Despite diverse aetiologies, failing human hearts (HF) of various origins (coronary artery disease (CAD), dilated cardiomyopathy (DCM), restrictive cardiomyopathy, and hypertrophic cardiomyopathy (HCM)) exhibit impaired contractility and share alterations in MYH6, MYH7, and MYH7B gene expression. Here, we explore the miRNA-208a/TARBP2/Sox6 axis in regulating myosin expression within left ventricles of explanted human hearts. Methods Samples of left ventricles were obtained from explanted hearts of patients with terminal HF (NYHA III-IV) and reduced left ventricle ejection fraction (LVEF <25%) due to CAD (n=10), DCM (n=10), HCM (n=6), and controls (n=5). We analysed the expression of cardiac myosin heavy chains (MYH6, MYH7, MYH7B), cardiac damage markers (ANP, BNP), and heart-related MyoMiRs using quantitative real-time PCR. Results Pre-transplant data for the 31 subjects (25 male, 3 female) included: age 54.4±8.2y, BP 112±18/67±11 mmHg, HR 79±16 min-1, LVEF 27±14%, LVEDD 8.8±15.8mm, RVEDD 32.8±5.1mm, QRS 0.140±0.05s, QT 0.42±0.04s, NT-proBNP 5551±4259 ng/l. In all diseased groups, MYH6 mRNA was downregulated, while MYH7 and MHRT ncRNA were upregulated. We observed strong positive correlations between MYH7, MYH7B, and MHRT transcription, suggesting coordinated expression. The miRNA-208a/miRNA-208b ratio shifted heavily towards miRNA-208b in controls, with a similar effect for miRNA-499 and MYH7B. A strong negative correlation existed between miRNA-499 and MYH7B expression across HF samples. TARBP2 expression decreased slightly in all pathological groups, while Sox6 mRNA increased. Conclusion Elevated Sox6 expression may contribute to MYH6 downregulation and MYH7/MYH7B upregulation. Altered TARBP2 expression could promote cardiomyopathy via Sox6-mediated repression of cardiac slow-twitch myofiber proteins. Changes in miRNA-208a processing leading to Sox6 upregulation may inhibit Sox6-dependent myosin transcript expression.

Deciphering STAT3’s negative regulation of LHPP in ESCC progression through single-cell transcriptomics analysis

BackgroundEsophageal Squamous Cell Carcinoma (ESCC) remains a predominant health concern in the world, characterized by high prevalence and mortality rates. Advances in single-cell transcriptomics have revolutionized cancer research by enabling a precise dissection of cellular and molecular diversity within tumors.ObjectiveThis study aims to elucidate the cellular dynamics and molecular mechanisms in ESCC, focusing on the transcriptional influence of STAT3 (Signal Transducer and Activator of Transcription 3) and its interaction with LHPP, thereby uncovering potential therapeutic targets.MethodsSingle-cell RNA sequencing was employed to analyze 44,206 cells from tumor and adjacent normal tissues of ESCC patients, identifying distinct cell types and their transcriptional shifts. We conducted differential gene expression analysis to assess changes within the tumor microenvironment (TME). Validation of key regulatory interactions was performed using qPCR in a cohort of 21 ESCC patients and further substantiated through experimental assays in ESCC cell lines.ResultsThe study revealed critical alterations in cell composition and gene expression across identified cell populations, with a notable shift towards pro-tumorigenic states. A significant regulatory influence of STAT3 on LHPP was discovered, establishing a novel aspect of ESCC pathogenesis. Elevated levels of STAT3 and suppressed LHPP expression were validated in clinical samples. Functional assays confirmed that STAT3 directly represses LHPP at the promoter level, and disruption of this interaction by promoter mutations diminished STAT3's repressive effect.ConclusionThis investigation underscores the central role of STAT3 as a regulator in ESCC, directly impacting LHPP expression and suggesting a regulatory loop crucial for tumor behavior. The insights gained from our comprehensive cellular and molecular analysis offer a deeper understanding of the dynamics within the ESCC microenvironment. These findings pave the way for targeted therapeutic interventions focusing on the STAT3-LHPP axis, providing a strategic approach to improve ESCC management and prognosis.

Different microRNA expression in the right ventricular outflow tract myocardium of tetralogy of Fallot

Abstract Background When repairing tetralogy of Fallot (TOF), there are two surgical options according to the size of the pulmonary valve: transannular patch repair and valve-preserving repair. Since the development of the pulmonary valve depends on the degree of obstruction of the right ventricular outflow tract (RVOT), molecular profiles of the RVOT muscles may be associated with the surgical decision. As a recent study shows altered microRNA expression of the right ventricular myocardium even in TOF patients, microRNA expression of the RVOT infundibular muscle may be different between the two procedures. Purpose To evaluate differences in microRNA expression levels of RVOT infundibular muscles between the transannular patch repair and valve-preserving repair groups. Methods Surgically resected infundibular muscles from TOF patients are frozen in liquid nitrogen and stored in our hospital biobank. Nine samples collected between August 2020 and July 2022 were used in this study. Five patients underwent a valve-preserving repair and the others underwent a transannular patch repair. Six patients were female and mean age at operation was 453 ± 240 days. These samples were homogenized and total RNA including microRNAs were extracted. MicroRNA expression levels were measured using a microRNA array capable of detecting over 2000 microRNAs simultaneously. Results 1171 microRNAs were detected in all nine samples. The expression levels of 22 microRNAs were significantly different between the transannular patch repair group and the valve-preserving repair group (P<0.05). The expression levels of 19 microRNAs were significantly higher in the transannular patch repair group and the others were significantly higher in the valve-preserving repair group. More than 2-fold changes were observed in 2 microRNAs between the transannular patch repair and valve-preserving repair groups. Conclusion MicroRNA expression of RVOT infundibular muscle differs between the transannular patch repair and valve-preserving repair groups. Therefore, microRNA analysis will be useful to evaluate the pathophysiology of TOF. In addition, microRNAs may become a useful biomarker for surgical decision making in TOF.

Toll-like receptor 2-mediated ERK activation significantly upregulates interleukin-6 expression in M2-polarized macrophages

Abstract Objectives M2-polarized macrophages and interleukin (IL)-6 significantly alter the tumor microenvironment and promote the malignant behaviors of tumor cells. This study aimed to establish M2-type macrophages from THP-1 cells, which are human leukemia monocytes, and investigate the significance of toll-like receptor 2 (TLR2) signaling in IL-6 production. Methods THP-1 cells were treated with phorbol 12-myristate 13-acetate, IL-4, and IL-13 to stimulate their differentiation into M2 macrophages. Cell differentiation was confirmed by cytokine production, marker expression, and morphological alterations. Treatment with TLR agonists induced TLR stimulation in M2 macrophages. Subsequently, secretion and expression levels of IL-6 in M2 macrophages were measured using enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, and western blotting. Results Myeloid differentiation factor 88, tumor necrosis factor-associated factor 6, and IL-1 receptor-associated kinase-1/4 signaling pathways contributed to IL-6 production upon TLR2 activation in M2 macrophages. While both TLR2 and TLR4 activated NF-κB in M2 macrophages, IL-6 production was mainly dependent on TLR2, not TLR4, suggesting the involvement of major mechanisms other than NF-κB in IL-6 production. Notably, TLR2-stimulated extracellular signal-regulated kinase (ERK) was necessary for abundant IL-6 production, indicating that TLR2-mediated ERK signaling plays an essential role in M2 macrophages. Conclusions These results highlight the significance of TLR2 signaling in IL-6 production by M2 macrophages and provide insights into the underlying regulatory mechanisms.

Novel Perspectives in the Management of Colorectal Cancer: Mechanistic Investigations Into the Reversal of Drug Resistance via Active Constituents Derived From Herbal Medicine.

The high incidence and mortality rate of colorectal cancer have become a significant global health burden. Chemotherapy has been the traditional treatment for colorectal cancer and has demonstrated promising antitumor effects, leading to significant improvements in patient survival. However, the development of chemoresistance poses a major challenge during chemotherapy in colorectal cancer, significantly impeding treatment efficacy and affecting patient prognosis. Despite the development of a variety of novel anticolorectal cancer chemotherapy agents, their effectiveness and side effects vary, possibly due to the complex mechanisms of resistance in colorectal cancer. Abnormal drug metabolism or protein targets are the most direct causes of resistance. Further studies have revealed that these resistance mechanisms involve biochemical processes such as altered protein expression, autophagy, and epithelial-mesenchymal transitions. Herbal active ingredients offer an alternative treatment option and have shown promise in reversing colorectal cancer drug resistance. This paper aims to summarize the role of various biochemical processes and key protein targets in the occurrence and maintenance of resistance mechanisms in colorectal cancer. Additionally, it elaborates on the mechanisms of action of herbal active ingredients in reversing colorectal cancer drug resistance. The article also discusses the limitations and opportunities in developing novel anticolorectal cancer drugs based on herbal medicine.

Alterations in expression of TLR2 and TLR4 during successful and pathological aging

The generally accepted theory of aging is the theory of inflammaging. The leading role in its development is played by the mechanisms of innate immunity. Key receptors of innate immunity are TLRs. The patterns of age-related changes in the functioning of the TLR system remain the subject of study. The purpose of the work is to study the expression of TLR2 and TLR4 receptors in peripheral blood cells of centenarians and elderly people at the level of genes and surface molecules. The study analyzed the expression of genes and molecules TLR2 and TLR4 in young donors (n = 50), elderly people (n = 50) and centenarians (n = 100). Analysis of TLR2 and TLR4 gene expression was carried out using RT-PCR. Determination of surface expression of TLR2 and TLR4 was carried out using flow cytofluorimetry. This study is the first to analyze the age-related dynamics of expression of genes and molecules TLR2 and TLR4. It was revealed that in groups of elderly patients and long-livers, TLR2 expression is increased both at the gene and on the cell surface, compared to young donors. In contrast, TLR4 expression decreased with age. Studied groups of patients were divided depending on the aging phenotype into two subgroups: successful and pathological aging. In elderly individuals, TLR2 is increased in both phenotypes, while TLR4 is decreased in the pathological aging. In the group of centenarians with a pathological aging, a decrease in both TLR2 and TLR4 is observed, compared with young. In long-livers with successful aging, an increase in TLR2 expression was observed at the gene and protein level and TLR4 expression was comparable to the group of young individuals. Identified changes in the expression of TLR2 and TLR4, observed in different age groups, can be considered as markers of various aging phenotypes.

Natural compounds targeting miRNAs: a novel approach in oral cancer therapy.

Oral cancer (OC) is a significant global health issue, with high rates of both mortality and morbidity. Conventional treatments, including surgery, radiation, and chemotherapy, are commonly used, but they often come with serious side effects and may not fully eliminate cancer cells, resulting in recurrence and resistance to treatment. In recent years, natural products derived from plants and other biological sources have gained attention for their potential anticancer properties. These compounds offer advantages such as lower toxicity compared to traditional chemotherapy. Notable natural compounds like quercetin, berberine, curcumin, andrographolide, nimbolide, ovatodiolide, and cucurbitacin B have demonstrated effectiveness in inhibiting OC cell growth by targeting various signaling pathways involved in cancer progression. Recent breakthroughs in molecular biology have highlighted the crucial role of microRNAs (miRNAs) in the development of OC. Targeting dysregulated miRNAs with natural products offers a promising strategy for treating the disease. Natural compounds exert anticancer effects by influencing both altered cellular signaling pathways and miRNA expression profiles. This study aims to explore the role of miRNAs as potential molecular targets in OC and to investigate how natural products may regulate these miRNAs. Additionally, this review will shed light on the therapeutic potential of phytochemicals in modulating miRNA expression and their significance in OC treatment.

Human amniotic membrane scaffold enhances adipose mesenchymal stromal cell mitochondrial bioenergetics promoting their regenerative capacities.

The human amniotic membrane (hAM) has been applied as a scaffold in tissue engineering to sustain stem cells and enhance their regenerative capacities. We investigated the molecular and biochemical regulations of mesenchymal stromal cells (MSCs) cultured on hAM scaffold in a three-dimensional (3D) setting. Culture of adipose-MSCs (AMSCs) on decellularized hAM showed significant improvement in their viability, proliferative capacity, resistance to apoptosis, and enhanced MSC markers expression. These cultured MSCs displayed altered expression of markers associated with pro-angiogenesis and inflammation and demonstrated increased potential for differentiation into adipogenic and osteogenic lineages. The hAM scaffold modulated cellular respiration by upregulating glycolysis in MSCs as evidenced by increased glucose consumption, cellular pyruvate and lactate production, and upregulation of glycolysis markers. These metabolic changes modulated mitochondrial oxidative phosphorylation (OXPHOS) and altered the production of reactive oxygen species (ROS), expression of OXPHOS markers, and total antioxidant capacity. They also significantly boosted the urea cycle and altered the mitochondrial ultrastructure. Similar findings were observed in bone marrow-derived MSCs (BMSCs). Live cell imaging of BMSCs cultured in the same 3D environment revealed dynamic changes in cellular activity and interactions with its niche. These findings provide evidence for the favorable properties of hAM as a biomimetic scaffold for enhancing the in vitro functionality of MSCs and supporting their potential usefulness in clinical applications.

HNCDrugResDb: a platform for deciphering drug resistance in head and neck cancers

Drug resistance poses a significant obstacle to the success of anti-cancer therapy in head and neck cancers (HNCs). We aim to develop a platform for visualizing and analyzing molecular expression alterations associated with HNC drug resistance. Through data mining, we convened differentially expressed molecules and context-specific signaling events involved in drug resistance. The driver genes, interaction networks and transcriptional regulations were explored using bioinformatics approaches. A total of 2364 differentially expressed molecules were identified in 78 distinct drug-resistant cells against 14 anti-cancer drugs, comprising 1131 mRNAs, 746 proteins, 62 lncRNAs, 257 miRNAs, 1 circRNA, and 166 post-translational modifications. Among these, 255 molecules were considerably, the signature driver genes of HNC drug resistance. Further, we also developed a landscape of signaling pathways and their cross-talk with diverse signaling modules involved in drug resistance. Additionally, a publicly-accessible database named “HNCDrugResDb” was designed with browse, query, and pathway explorer options to fetch and enrich molecular alterations and signaling pathways altered in drug resistance. HNCDrugResDb is also enabled with a Drug Resistance Analysis tool as an initial platform to infer the likelihood of resistance based on the expression pattern of driver genes. HNCDrugResDb is anticipated to have substantial implications for future advancements in drug discovery and optimization of personalized medicine approaches.

Coronavirus S protein alters dsRNA accumulation and stress granule formation through regulation of ADAR1-p150 expression.

The precise role of the highly variable coronavirus S protein in modulating innate immune responses remains unclear. In this study, we demonstrated that the mutant strain of swine coronavirus porcine enteric diarrhea virus induced significantly lower levels of double-stranded RNA (dsRNA) accumulation, inhibited protein kinase R (PKR) activation and suppressed stress granule (SG) formation compared with the classical strain. The 29th amino acid at N-terminus of S was identified as the key functional site for regulation of SG formation, and found that mutant S inhibited PKR phosphorylation and SG formation by upregulating adenosine deaminase acting on RNA 1 (ADAR1)-p150. Notably, the Zα domain of ADAR1-p150 was essential for inhibiting SG formation. Upregulation of ADAR1-p150 also reduced accumulation of dsRNA depending on its RNA editing function. Virus rescue confirmed that the mutant carrying a substitution at amino acid 29 failed to induce ADAR1-p150, leading to dsRNA accumulation, PKR activation and SG formation. Interestingly, the latest severe acute respiratory syndrome coronavirus-2 strains exhibit a novel 25PPA27 deletion at N-terminus of S that was also shown to lead to altered ADAR1-p150 expression and SG inhibition. The transcription factor TCF7L2 was identified as a player in S-mediated transcriptional enhancement of ADAR1-p150. This study is the first to clarify the crucial role of N-terminus of S in immune regulation of coronaviruses.

Evaluation of fenugreek (Trigonella foenum-graecum L.) powder supplementation on metabolic syndrome, oxidative stress and inflammation in high fat diet fed rats

As an anti-diabetic medicinal plant, fenugreek seed (FG) (Trigonella foenum-graecum L.) has long been utilized and has many therapeutic uses. The current investigation sought to ascertain the effects of FG powder supplementation on insulin resistance, dyslipidemia, and oxidative stress in rats given a high-fat (HF) diet. Measurements of biochemical and antioxidant indicators were made in animal blood and tissue samples, including malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (AOPP), reduced glutathione (GSH), superoxide dismutase (SOD), triglycerides (TG), and catalase (CAT). Furthermore, the tissues of the kidney, heart, and liver were stained histologically. HF diet feeding in rats declined in antioxidant enzyme activities, along with a rise in MDA and other indicators of oxidative stress, which were mitigated by the supplementation of FG. Additionally, FG supplementation enhanced the expression of genes corresponding to antioxidants in the liver of rats given HF diet. FG supplements in HF diet-fed rats displayed altered gene expression in the livers that metabolized fat. Histological staining of the liver demonstrated that FG supplementation reduced necrosis and the accumulation of fat droplets in the liver of rats given HF diets. In conclusion, this finding showed that FG supplementation in HF diet fed rats reduced the plasma lipids, decreased oxidative stress and raised antioxidant enzyme activities. FG may therefore aid in reducing the chronic complications linked to the HF diet in experimental rats.

Heat stress causes chromatin accessibility and related gene expression changes in crown tissues of barley (Hordeum vulgare).

Plant responses to stress caused by high temperatures involve changes occurring at the molecular, metabolic, and physiological levels. Understanding the mechanisms by which plants recognize signals to activate this response is a prerequisite for identifying key genes and signaling pathways and for obtaining heat-tolerant plants. We demonstrated the first implementation of an assay for transposase-accessible chromatin to identify open chromatin regions (OCRs) in crown tissues of barley using three genotypes carrying different allelic forms of the sdw1 gene encoding gibberellin 20-oxidase subjected to elevated temperatures. In parallel, we performed gene expression analysis, which allowed us to relate changes in chromatin state to changes in transcriptional activity. The obtained data revealed that the hypersensitive chromatin regions within the genes were more repeatable than those outside the gene intervals. We observed that prolonged exposure to high temperatures increased chromatin accessibility. Genes with OCRs in their regulatory regions were involved in stress signaling and tolerance, including calcium-dependent protein kinase, mitogen-activated protein kinase (MAPK3), receptor-like cytoplasmic kinase (RLK), TIFY domain-containing transcriptional regulator, bZIP transcription factor, and regulatory protein NPR1. The effect of genotype on gene expression was not as pronounced as that of temperature. By combining results from the differential analysis of chromatin accessibility and expression profiles, we identified genes with high temperature-induced changes in chromatin accessibility associated with expression alterations. Importantly, our data revealed a relationship between the loss of chromatin accessibility in response to heat and the downregulation of genes related to gibberellin signaling.

Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants.

Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the 'closed' regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.

Gene Expression Profiling and Immune Pathway Dysregulation in Ribonucleoprotein Autoantibody-Positive Systemic Lupus Erythematosus Patients

Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune dysregulation and chronic inflammation across various organ systems. While anti-dsDNA and anti-Sm antibodies are commonly associated with SLE, the presence of anti-RNP antibodies is often linked to unique gene expression profiles and immune responses. This study aims to investigate the gene expression profiles in ribonucleoprotein (RNP) autoantibody-positive SLE patients by analyzing publicly available transcriptomic data. Methods: This study analyzed transcriptomic data from the GEO dataset GSE61635, which includes gene expression profiles from 79 anti-RNP-positive SLE patients and 30 healthy controls. Differentially expressed genes (DEGs) were identified using the GEO2R tool with a p-value < 0.05 and |log2fold change| > 1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Tissue-specific and cell-type enrichment analyses highlighted the involvement of immune tissues. Results: A total of 1891 DEGs were identified between anti-RNP-positive SLE patients and healthy controls. Among the identified DEGs, SLC4A1 and EPB42 were notably downregulated, while PIP4K2A was highly upregulated. Enrichment analyses revealed significant dysregulation in antiviral response and immune regulation pathways. PPI network analysis highlighted key hub genes, suggesting a heightened antiviral state in these patients. Tissue-specific enrichment and cell-type enrichment identified the bone marrow and immune tissues as being highly affected by the altered gene expression. Additionally, gene frequency analysis highlighted RASD2 as being recurrently significant across multiple studies. Conclusions: The findings suggest that anti-RNP-positive SLE patients exhibit distinct gene expression and immune dysregulation profiles, particularly in antiviral and immune regulation pathways. These results provide insights into the molecular mechanisms driving SLE in this patient subset and may guide future therapeutic interventions.

Altered Expression of Neuroplasticity-Related Genes in Alcohol Addiction and Treatment

Alcohol use disorder’s complexity arises from genetic and environmental factors, with alcohol metabolism genes and neurotransmitter pathways being critical. This study aims to analyze synaptic plasticity gene expression changes in individuals with AUD in order to study their contribution to AUD development and to identify potential biomarkers of treatment response. RNA was extracted from whole peripheral blood (20 patients, 10 healthy controls), before and after treatment (Qiagen AllPrep RNA/DNA Mini Kit), and the gene expression of 84 genes related to neuroplasticity was studied using the RT2 Profiler for Human Synaptic Plasticity RT-PCR Array (PAHS-126ZA, Qiagen), comparing AUD patients to control and responders to non-responders. The potential prognostic/predictive biomarkers were searched using machine learning models. A total of 35 dysregulated genes were found in AUD patients. EPHB2, EGR, and AKT1 were increased, while TIMP1, NCAM1, and GRM2 were decreased. Responders showed distinct gene expression profiles at baseline. After treatment, the expression of 57 genes was normalized, while NCAM1, GRM2, and BDNF showed the most significant recovery. EGR4, INHBA, and NCAM1 emerged as potential biomarkers to predict treatment success. These results indicate that gene profiles in peripheral blood can serve as prognostic markers for the prognosis and treatment of AUD, although further validation is required.

Biocontrol Ability of Strain Bacillus amyloliquefaciens SQ-2 against Table Grape Rot Caused by Aspergillus tubingensis.

Bacillus amyloliquefaciens strain SQ-2, isolated from a cured product, has been demonstrated to exhibit a highly efficacious performance against phytopathogens, including Stemphylium solani, Fusarium moniliforme, Fusarium graminearum, and Aspergillus tubingensis. In particular, with regard to A. tubingensis, which causes summer bunch rot, SQ-2 has been observed to suppress the mycelial growth of all tested grape cultivars by over 40%. Especially on Kyoho grapes, it has the highest inhibition rate of 53%. Scanning electron microscopy (SEM) confirms that SQ-2 is an effective agent for suppressing the mycelia proliferation, differentiation, and spore formation of A. tubingensis. Furthermore, an LC/MS analysis revealed that SQ-2 produces two principal lipopeptides, namely, bacillibactin and surfactin, in addition to a polyketide, bacillaene. Further analysis through gas chromatography-mass spectrometry (GC/MS) identified 41 distinct volatile organic compounds secreted by SQ-2. Transcriptomic analysis indicated that exposure to the metabolite of SQ-2 induced substantial gene expression alterations in A. tubingensis. These data suggest that B. amyloliquefaciens strain SQ-2 exhibits promising crop protection potential of inhibiting plant pathogens through the secretion of bacillibactin, surfactin, bacillaene, and VOCs.

Transcriptomic Analysis Reveals Dynamics of Gene Expression in Liver Tissue of Spotted Sea Bass Under Acute Thermal Stress.

The spotted sea bass (Lateolabrax maculatus), a eurythermal species, exhibits strong adaptability to temperature variations and presents an ideal model for studying heat stress-responsive mechanisms in fish. This study examined the liver transcriptome of spotted sea bass over a 24-h period following exposure to elevated temperatures, rising from 25 to 32°C. The results revealed significant alterations in gene expression in response to this thermal stress. Specifically, we identified 1702, 1199, 3128, and 2636 differentially expressed genes at 3, 6, 12, and 24h post-stress, respectively. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify specific gene modules responsive to heat stress, containing hub genes such as aco2, eci2, h6pd, suclg1, fgg, fga, fgb, f2, and apoba, which play central roles in the heat stress response. Enrichment analyses via KEGG and GSEA indicated that upregulated differentially expressed genes (DEGs) are predominantly involved in protein processing in the endoplasmic reticulum, while downregulated genes are primarily associated with the AGE-RAGE signaling pathways. Additionally, 272 genes exhibited differential alternative splicing, primarily through exon skipping, underscoring the complexity of transcriptomic adaptations. These findings provide deeper insights into the molecular responses to thermal stress and are crucial for advancing the breeding of heat-resistant strains of spotted sea bass.