Significant Enrichment Research Articles

Dynamic development of gut microbiota and metabolism during and after weaning of kittens

BackgroundAs the pet population grows, there is increasing attention on the health and well-being of companion animals. Weaning, a common challenge for young mammals, often leads to issues such as diarrhea, growth retardation, and in severe cases, even mortality. However, the specific changes in gut microbiota and metabolites in kittens following weaning remain unclear. In this study, we conducted a comprehensive investigation of the dynamic changes in the gut microbiota, serum metabolism, antioxidant capacity, and immune function of kittens at various time points: days 0, 4, and 30 post-weaning.ResultsSignificant changes in the immune response and gut microbiota were observed in kittens following weaning. Specifically, IgM levels increased significantly (P < 0.01, n = 20), while IgA and IgG levels showed a sustained elevation. Weaning also disrupted the intestinal microbiota, leading to notable changes in serum metabolism. On day 4 post-weaning, there was a decrease in beneficial bacteria such as Bacteroides vulgatus, Fusobacterium nucleatum, Anaerostipes caccae, and Butyricico-ccaceae. However, by day 30, beneficial bacteria including Candidatus Arthro-mitus, Holdemanella, and Bifidobacterium had increased (P < 0.05, n = 20). Serum metabolites showed clear separation across time points, with day 0 and day 4 exhibiting similar patterns. A total of 45 significantly altered metabolites (P < 0.05, n = 20) were identified, primarily related to vitamins, steroids, peptides, organic acids, lipids, and carbohydrates. Pathway analysis revealed significant enrichment in eight metabolic pathways, with key changes in arginine metabolism and biosynthesis. Additionally, bacteria such as Bacteroides fragilis, Bacteroides stercoris, Leuconostoc citreum, and Bifidobacterium adolescentis were positively correlated with serum metabolic changes, emphasizing the link between gut microbiota and systemic metabolism (P < 0.05, n = 20).ConclusionOur study demonstrated that the composition and function of intestinal microorganisms as well as serum metabolic profiles of weaned kittens presented dynamic changes. These findings not only deepen our understanding of the effects of weaning on kitten health, but also provide valuable insights into post-weaning nutritional regulation strategies for kittens.

Smu_1558c-mediated regulation of growth and biofilm formation in Streptococcus mutans

Streptococcus mutans is a key etiological agent in dental caries, owing to its strong ability to form biofilms through carbohydrate fermentation. Protein acetylation, facilitated by GNAT family acetyltransferases, plays a critical regulatory role in bacterial physiology, but its impact on S. mutans remains largely unexplored. In this study, we investigated the role of the GNAT family acetyltransferase encoded by smu_1558c in regulating the growth and biofilm formation of S. mutans. The deletion of smu_1558c resulted in impaired growth, reduced biofilm formation, and diminished synthesis of water-insoluble extracellular polysaccharides (EPS). Proteomic analysis revealed 166 differentially expressed proteins in the deletion mutant, with significant enrichment in pathways related to carbohydrate transport and metabolism, and translation. Notably, glucosyltransferases GtfB and GtfC, key enzymes in biofilm formation, were significantly downregulated in the deletion mutant, while ClpL, a Clp-like ATP-dependent protease involved in protein homeostasis under stress conditions, was highly upregulated. These findings highlight that acetyltransferase smu_1558c plays a crucial role in the growth, biofilm formation, and EPS synthesis of S. mutans through its regulation of carbohydrate transport and metabolism pathways, as well as stress response mechanisms. This study provides novel insights into the molecular mechanisms governing S. mutans pathogenicity and suggests potential therapeutic targets for caries prevention.

Redistribution of soil water by mature trees towards dry surface soils and uptake by seedlings in a temperate forest.

Hydraulic redistribution is considered a crucial dryland mechanism that may be important in temperate environments facing increased soil drying-wetting cycles. We investigated redistribution of soil water from deeper, moist to surface, dry soils in a mature mixed European beech forest and whether redistributed water was used by neighbouring native seedlings. In two experiments, we tracked hydraulic redistribution via (1) 2H labeling and (2) 18O natural abundance. In a throughfall exclusion experiment, 2H water was applied to 30-50 cm soil depth around mature beech trees and traced in soils, in coarse and fine roots, and in the rhizosphere. On five additional natural plots, the 18O signal was measured in seedlings of European beech, Douglas fir, silver fir, sycamore maple, and Norway spruce at dawn and noon after a rain-free period. We found a significant enrichment in 2H in surface soil fine roots of mature beech, and an indication for transfer of this water into their rhizosphere, suggesting hydraulic redistribution from deeper, moist to drier surface soils. On four of the five additional plots, δ18O of seedlings' root water was lower at dawn than at noon. This indicated that dawn root water originated from soil layers deeper than the seedlings' rooting depth, suggesting hydraulic redistribution by neighbouring mature trees. Hydraulic redistribution equated to about 10% of daily transpiration in mature beech trees, and contributed to root water in understory seedlings, emphasizing hydraulic redistribution as a notable mechanism in temperate forests. Transport mechanisms and potential of different tree species to redistribute water should be further addressed.

Silica-Activated Redox Signaling Confers Rice with Enhanced Drought Resilience and Grain Yield.

Under a changing climate, enhancing the drought resilience of crops is critical to maintaining agricultural production and reducing food insecurity. Here, we demonstrate that seed priming with amorphous silica (SiO2) nanoparticles (NPs) (20 mg/L) accelerated seed germination speed, increased seedlings vigor, and promoted seedling growth of rice under polyethylene glycol (PEG)-mimicking drought conditions. An orthogonal approach was used to uncover the mechanisms of accelerated seed germination and enhanced drought tolerance, including electron paramagnetic resonance, Fourier transform infrared spectroscopy (FTIR), metabolomics, and transcriptomics. It was revealed that the unique surface chemistry of amorphous silica, characterized by an enrichment of silanol and siloxane groups, can catalyze the production of reactive oxygen species. This, in turn, initiates redox signaling and activates downstream drought-responsive genes. In addition, silica-primed seeds exhibited a significant enrichment of 18 amino acids and 6 sugars compared to those undergoing hydropriming, suggesting the accelerated mobilization of stored energy reserves. The drought-tolerance trait was observed in vegetative tissues of 35 day-old plants, where this tolerance was associated with an accelerated catabolism of amino acids and an enhanced anabolism of antioxidants. A separated field trial showed that SiO2NPs seed priming not only increased rice grain yield by 7.77% (p = 0.051) and 6.48% (p = 0.066), respectively, under normal and drought conditions but also increased the grain amino acid content. These results demonstrate that a simple and cost-effective nanoseed-priming approach can convey life cycle-long drought tolerance while simultaneously increasing rice grain yield and nutrition quality, providing an effective and sustainable strategy to cultivate climate-resilient crops.

Tracing metal sources and groundwater flow paths in the Upper Animas River watershed using rare earth elements and stable isotopes

Groundwater flow paths and processes that govern metal mobility and transport are difficult to characterize in mountainous bedrock watersheds. Despite the difficulty in holistic characterization, conceptual understanding of subsurface hydrologic and geochemical processes is key to developing remediation plans for locations affected by acid mine drainage, such as the Upper Animas River watershed in southwestern Colorado, USA. Stable isotopes of water and rare earth elements were utilized to evaluate groundwater flow and metal sources within this complex catchment. Stable isotope samples collected from draining mine adits and springs display systematic spatial variation wherein sample sites at higher elevations have greater seasonal variability than sites at lower elevations. The Upper Cement Creek watershed, where multiple draining mines are present, displays the lowest seasonal variation in stable isotopic signatures, potentially indicating the presence of a large, well-mixed volume of groundwater storage or interbasin groundwater flow. Rare earth elements display statistically significant variation between different alteration styles in the catchment. Overprinting of regional propylitic alteration is evident based on enrichment of middle rare earth elements in acidic springs and mines that are not spatially associated with surficial exposures of acid generating alteration styles. Europium anomaly and middle rare earth enrichment signatures from two flooded mine tunnels on opposite sides of a watershed divide indicate connections to the same subsurface flooded mine workings.

Defining 2 Biologically and Clinically Distinct Groups in Acute Leukemia with a Mixed Phenotype.

A mixed phenotype is characteristic of de novo Mixed Phenotype Acute Leukemia (MPAL) but can also be seen in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with a mixed phenotype and define Acute Myeloid Leukemia with Mixed Phenotype (AML-MP) and MPAL as two distinct groups by characterizing the clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)-directed induction regimens. AML-MP shows inferior responses (HR, 12.5; 95% CI, 2.72-57.8; p=.001), while MPAL shows better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52, 44%) and TP53 (12/52, 23.1%) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35, 23%, p=.01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures, and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40, 2.5%, vs. 10/28, 35.7%, p=.0003). Lastly, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with a mixed phenotype.

Genomic and cellular responses to aspirin in colonic organoids from African- and European-Americans.

Background: Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer (CRC), though inter-individual responses and cellular mechanisms are not well characterized. Human organoids are ideal to study treatment responses across individuals. Here, colonic organoids from African-Americans (AA) and European-Americans (EA)were used to profile genomic and cellular ASA responses. Methods: Colonic organoids from 67 participants, 33 AA and 34 EA, were treated with 3mM ASA or vehicle control for 24h. Gene expression was assessed by RNA-seq, and differentially responsive genes analyzed by condition, population and for gene set enrichment. Top differentially responsive genes were assessed by time and ASA doses in independent organoids. Expression quantitative trait loci (eQTL) mapping was performed to identify variants associated with condition-specific responses. Proliferation, apoptosis and necrosis assays were performed, and apoptosis gene expression measured in organoids. Results: Overall, 8343 genes were differentially responsive to ASA with differences between AA and EA. Significant enrichment for fatty acid oxidation (FAO) and PPAR signaling was found. Significant treatment eQTLs were identified for relevant genes involved in FAO, apoptosis and prostaglandin metabolism. ASA-induced apoptosis and secondary necrosis were confirmed with identification of significant differential responses of apoptotic genes to ASA. Conclusions: Results demonstrate large transcriptional responses to ASA treatment with differences in responses between individuals. Genomic and cellular results suggest that ASA effects on the mitochondria are key mechanisms of action that could underlie clinical effects. These results could be used to assess clinical treatment responses for chemoprevention in the future.

MicroRNAs signatures as potential molecular markers in mild cognitive impairment: a meta-analysis

Mild cognitive impairment (MCI) is characterized by a decline in cognitive functioning without significant interference in daily activities. Its high heterogeneity and elevated conversion rate to dementia pose challenges for accurate diagnosis and monitoring, highlighting the urgent need to identify methodologies focused on the early detection and intervention of MCI. Due to their biological characteristics, microRNAs (miRNAs) are potential candidates as non-invasive molecular markers for the identification and assessment of MCI progression. Therefore, in this study, we conducted a meta-analysis to identify the miRNAs commonly deregulated in MCI, focusing on expression profiles in plasma, serum, and extracellular vesicle samples. Our analysis identified eight upregulated miRNAs, including hsa-miR-149-3p, and four downregulated miRNAs, such as Let-7f-5p. Notably, hsa-miR-149-3p emerged as a central node in interaction networks, suggesting its crucial role in regulating cellular processes relevant to MCI. Additionally, pathway analysis revealed significant enrichment in biological processes associated with transcriptional regulation and neurodegeneration. Our results underscore the potential of circulating miRNAs as non-invasive molecular markers for MCI and open the possibility for new methodologies that enable more accurate diagnosis and monitoring of disease progression. Validating the expression of miRNAs such as hsa-miR-149-3p and Let-7f-5p, along with identifying their functional role in the specific context of MCI, is essential to establish their biological relevance. This work contributes to the understanding of the miRNA profile in mild cognitive impairment using easily accessible samples, which could be useful for the development of various strategies aimed at preventing or delaying MCI in individuals at risk of developing dementia, including Alzheimer’s disease.

Phytochemical analysis and biological activities of solvent extracts and silver nanoparticles obtained from Woodwardia unigemmata (Makino) Nakai.

Multidrug resistant bacteria are causing health problems and economic burden worldwide; alternative treatment options such as natural products and nanoparticles have attained great attention recently. Therefore, we aimed to determine the phytochemicals, antibacterial potential, and anticancer activity of W. unigemmata. Extracts in different organic and inorganic solvents were prepared, silver nanoparticles were prepared using the green synthesis method. Phytochemicals and antioxidant activity was determined spectrophotometry, anticancer potential was determined against gastric cancer and normal gastric epithelial cells using CCK8 and colony formation assays W. unigemmata was found to have a significant enrichment of various phytochemicals including flavonoids, terpenoids, alkaloids, carotenoids, tannins, saponins, quinines, carbohydrates, phenols, coumarins and phlobatanins. Among them phenolics (5289.89 ± 112.67) had high enrichment followed by reducing sugar (851.53 ± 120.15), flavonoids (408.28 ± 20.26) and ascorbic acid (347.64 ± 16.32), respectively. The extracts prepared in organic solvents showed strong antibacterial activity against P. aeruginosa (chloroform, 13.66±0.88, ethyl acetate, 8.66±4.33, methyl alcohol, 13.33±1.66, N-hexane, 12.33±0.88) and S. aureus (chloroform, 15±0.57, ethyl acetate, 16.33±0.33, methyl alcohol, 17.66±0.33 and N-hexane, 16.33±0.33). Aqueously prepared AgNPs showed remarkable activity against P. aeruginosa follwed by E. coli, 17.66 ± 1.85, S. aureus, 16.00 ± 1.73, K. pneumoniae, 14.33 ± 1.20, respectively. The ethanolic extracts (500 μg, 1000 μg, 2000 μg) of the W. unigemmata were found to have cytotoxicity against both gastric cancer (AGS and SGC7901) and normal cell lines (GES-1); a significant cellular proliferation arrest was observed. These results suggest that W. Unigemmata contains numerous bioactive phytochemicals and can be useful as a drug against MDR bacterial strains. These biomolecules covering AgNPs may enhance their biological activities, which can be employed in the treatment of various microbial infections.

GNA15 induces drug resistance in B cell acute lymphoblastic leukemia by promoting fatty acid oxidation via activation of the AMPK pathway.

The prognosis of B cell acute lymphoblastic leukemia (B-ALL) is poor, primarily due to drug resistance and relapse. Ga15, encoded by GNA15, belongs to the G protein family, with G protein-coupled receptors playing a crucial role in multiple biological process. GNA15 has been reported to be involved in various malignancies; however, its potential role in B-ALL remain unknown. In this study, high expression of GNA15 in B-ALL was observed in multiple databases. We further confirmed an increased transcriptional level of GNA15 in newly diagnosed B-ALL patients which was closely correlated with relapse. We showed that GNA15 promoted cell growth, inhibited apoptosis and enhanced drug resistance in leukemia cell lines. Metabolomics analysis revealed a significant enrichment of fatty acid oxidation (FAO) according to the GNA15 expression. We further confirmed that GNA15 could enhance FAO process as evidenced by the upregulation of key molecules involved in FAO including carnitine palmitoyl transferase1 (CPT1), CPT2 and CD36. And inhibition of FAO using etomoxir partially reversed the drug resistance caused by high expression of GNA15. Mechanism study showed that GNA15 promoted FAO by up-regulation of AMPK phosphorylation thus leading to survival advantage in leukemia cells. In conclusion, we observed elevated GNA15 transcript levels in B-ALL, which were associated with relapse. GNA15 could induce drug resistance though activation of the AMPK/FAO axis in leukemia cell lines. Targeting GNA15 and FAO may represent potential therapeutic strategy for improving the prognosis of B-ALL.

Fatty acid synthase inhibition improves hypertension-induced erectile dysfunction by suppressing oxidative stress and NLRP3 inflammasome-dependent pyroptosis through activating the Nrf2/HO-1 pathway

BackgroundErectile dysfunction (ED) is a prevalent male sexual disorder, commonly associated with hypertension, though the underlying mechanisms remain poorly understood.ObjectiveThis study aims to explore the role of Fatty acid synthase (Fasn) in hypertension-induced ED and evaluate the therapeutic potential of the Fasn inhibitor C75.Materials and methodsErectile function was assessed by determining the intracavernous pressure/mean arterial pressure (ICP/MAP) ratio, followed by the collection of cavernous tissue for transcriptomic and non-targeted metabolomic analyses. In vitro, a concentration of 10-6 M angiotensin II (Ang II) was applied to rat aortic endothelial cells (RAOECs) to establish a model of hypertension. In vivo, spontaneously hypertensive rats (SHR) were randomly divided into two groups. The SHR+C75 group received intraperitoneal injections of C75 at a dose of 2 mg/kg once a week. After five weeks of treatment, the erectile function of the rats was assessed, and penile tissues were harvested for further analysis. Molecular and protein expression were assessed using Western blotting, qRT-PCR, immunofluorescence staining, and immunohistochemistry.ResultsThe SHR exhibited ED, indicated by reduced maximum ICP/MAP ratios. Histologically, corpus cavernosum tissue of SHR showed elevated fibrosis and endothelial dysfunction. Additionally, increased expression of the NLRP3 inflammasome, Caspase-1, GSDMD, and the pro-inflammatory cytokines IL-1β and IL-18 was observed. Multi-omics analysis revealed significant enrichment in lipid metabolic pathways, with Fasn identified as a hub gene. In vitro, siFasn and C75 enhanced antioxidant markers Nrf2 and HO-1, reduced ROS accumulation, and suppressed NLRP3 and GSDMD levels. In vivo, C75 treatment restored endothelial function and reversed erectile dysfunction, accompanied by decreased oxidative stress and pyroptosis in the penile corpus cavernosum.ConclusionThese findings suggest that Fasn inhibition may offer a promising therapeutic strategy for hypertension-induced ED by alleviating oxidative stress and suppressing NLRP3 inflammasome-dependent endothelial cell pyroptosis via activation of the Nrf2/HO-1 pathway.

Pretargeted Multimodal Tumor Imaging by Enzymatic Self-Immobilization Labeling and Bioorthogonal Reaction.

Covalent modification of cell membranes has shown promise for tumor imaging and therapy. However, existing membrane labeling techniques face challenges such as slow kinetics and poor selectivity for cancer cells, leading to off-target effects and suboptimal in vivo efficacy. Here, we present an enzyme-triggered self-immobilization labeling strategy, termed E-SIM, which enables rapid and selective labeling of tumor cell membranes with bioorthogonal trans-cycloctene (TCO) handles in vivo. E-SIM utilizes P-TCO, an alkaline phosphatase (ALP) responsive quinone methide (QM) precursor with a TCO group, facilitating the rapid conjugation of high-density TCO handles onto tumor cell membranes via proximity labeling. These TCO groups then react efficiently with tetrazine (Tz)-bearing reporters via a fast bioorthogonal reaction, resulting in significant enrichment of reporters of various sizes and imaging modalities on tumor cell membranes. We demonstrate the efficacy of E-SIM labeling and bioorthogonal reaction for pretargeted multimodality imaging of tumors in vivo. Notably, we achieve selective and efficient installation of Tz-modified Renilla luciferase on tumor cells in vivo, thereby offering highly sensitive bioluminescence signals for detecting and guiding the surgical removal of small human HepG2 liver tumor peritoneal metastases. E-SIM represents a robust tool for precise tumor cell labeling in complex in vivo environments, feasible for pretargeted enrichment of various reporters in tumors for multimodal imaging applications.

Systematic identification of pathological mechanisms, prognostic biomarkers and therapeutic targets by integrating lncRNA expression variation in salivary gland mucoepidermoid carcinoma

Biologicalprocesses intricately intertwine with tumorigenesis, significantly influencing treatment outcomes and prognosis. However, the mechanisms fostering mucoepidermoid carcinoma (MEC) remain inadequately elucidated. This research utilizes expression profiles of lncRNAs from clinical MEC tissues and matched normal glandular tissues, integrating public data to explore the biological mechanisms and immune microenvironment characteristics of tumorigenesis. Gene set enrichment analysis identified key pathways, and a customized epithelial-mesenchymal transition (EMT) score elucidated the relationship between pathological processes and prognosis, while an immune signature revealed tumor microenvironment characteristics. MECs exhibited significant enrichment in EMT pathway, with key genes such as Secretogranin II, tissue factor pathway inhibitor 2, and periostin identified as contributors to the EMT process. High EMT scores correlated with upregulated EMT and immune response activity, indicating poor prognosis. Single-sample gene set enrichment analysis unveiled the tumors’ immune infiltration signature, suggesting active antigen presentation and a positive immune response for immunotherapy. Additionally, SLC2A1-AS1 and CERS6-AS1 were identified as potential mediators of EMT and the immune environment. This study provides insights into the biological processes of MEC tumorigenesis and identifies potential therapeutic targets for future research.

Formation mechanism of boehmite and diaspore in karstic bauxites: trace element geochemistry in source materials using large sample geochemical dataset and random forest model

Abstract Boehmite and diaspore are the two economic ore minerals of karstic bauxites. Although their genesis has been studied from different perspectives, their formation mechanism is controversial. Random forest (RF) model of machine learning was employed to extract the combining characteristics of trace elements in boehmite-type bauxite (BTB) and diaspore-type bauxite (DTB). The BTB predominantly exhibits higher median concentrations of Co, Ni, V, and Cr, while the DTB exhibits a more significant enrichment in elements of U, Hf, Th, and Zr. Combining the characteristics of La/Yb and Ga/Al ratios, it is found that disparities between BTB and DTB are mirroring to those between basic rocks and intermediate-felsic rocks. Furthermore, the Zr-Cr-Ga diagram and Ni/Zr versus Cr/Zr plot were utilized to examine the correlation between karstic bauxite (BTB or DTB), lateritic bauxite, and their respective weathered parent rocks. It is found that BTB exhibits consistent characteristics with lateritic bauxite weathered from basic rock and its parent rocks. Similarly, DTB displays consistent characteristics with lateritic bauxite weathered from intermediate-felsic rock and its parent rocks. Through studying the relationship between Ni content and Fe3+/Fe2+ ratios, it has been discovered that the presence of trace elements like Ni in source materials can affect or regulate ore-forming process, ultimately driving the transformation of gibbsite into either boehmite or diaspore. Consequently, the formation of BTB and DTB is significantly influenced, or even governed, by the composition of their source materials. Our study initially highlights a novel insight into the significant impact of source material’s geochemical composition on the formation of boehmite and diaspore, which is associated with weathered igneous rocks categories.

Humanin alone and in Combination with GnRHa therapy attenuates ovarian dysfunction induced by prepubertal cyclophosphamide chemotherapy in female mice.

Prepubertal chemotherapy induced ovarian damage poses a significant threat to female fertility, particularly following cyclophosphamide (CP) treatment. Humanin (HNG), a small molecule polypeptide encoded by mitochondrial DNA, has a variety of effects, this study aimed to investigate the protective effects of HNG and its combination with conventional Gonadotropin Releasing Hormone Agonist (GnRHa) on ovarian function in a CP-induced damage model. The 21-day-old C57BL/6J female mice were randomly assigned to six groups: Control, CP model, HNG, HNG+CP, GnRHa+CP, and HNG+GnRHa+CP. Ovarian function was assessed through histopathological examination, follicle counts, serum sex hormone levels, estrous cycle monitoring, and oxidative stress evaluation. Results indicated that CP treatment led to significant reproductive dysfunction especially ovarian dysfunction, evidenced by reduced follicles, hormonal imbalances, prolonged estrous cycles, reduced body weight, and diminished ovarian and uterine weights, alongside pathological alterations. Notably, HNG treatment, both alone and in conjunction with GnRHa, significantly mitigated these adverse effects, however the combination did not provide additional benefits over HNG alone regarding follicles preservation and antioxidant capacity. Transcriptomic analysis revealed significant enrichment in inflammation and immune response pathways following HNG treatment. In conclusion, HNG demonstrates potential as a therapeutic agent to protect against CP-induced ovarian damage, offering insights for future strategies aimed at preserving female fertility during chemotherapy.

Connecting genomic results for psychiatric disorders to human brain cell types and regions reveals convergence with functional connectivity

Identifying cell types and brain regions critical for psychiatric disorders and brain traits is essential for targeted neurobiological research. By integrating genomic insights from genome-wide association studies with a comprehensive single-cell transcriptomic atlas of the adult human brain, we prioritized specific neuronal clusters significantly enriched for the SNP-heritabilities for schizophrenia, bipolar disorder, and major depressive disorder along with intelligence, education, and neuroticism. Extrapolation of cell-type results to brain regions reveals the whole-brain impact of schizophrenia genetic risk, with subregions in the hippocampus and amygdala exhibiting the most significant enrichment of SNP-heritability. Using functional MRI connectivity, we further confirmed the significance of the central and lateral amygdala, hippocampal body, and prefrontal cortex in distinguishing schizophrenia cases from controls. Our findings underscore the value of single-cell transcriptomics in understanding the polygenicity of psychiatric disorders and suggest a promising alignment of genomic, transcriptomic, and brain imaging modalities for identifying common biological targets.

Data Mining Approach to Melatonin Treatment in Alzheimer's Disease: New Gene Targets MMP2 and NR3C1.

Melatonin is a hormone released by the pineal gland that regulates the sleep-wake cycle. It has been widely studied for its therapeutic effects on Alzheimer's disease (AD), particularly through the amyloidosis, oxidative stress, and neuroinflammation pathways. Nevertheless, the mechanisms through which it exerts its neuroprotective effects in AD are still largely unknown. Data mining was used to identify potential gene targets that link melatonin's effects to AD pathways, yielding a comprehensive view of the underlying molecular mechanisms. We identified 3397 genes related to AD from DisGeNet and 329 melatonin gene targets from ChEMBL, which revealed 223 overlapping genes and the potential shared pathways. These genes were used to construct a protein-protein interaction (PPI) network comprising 143 nodes and 823 edges, which demonstrated significant PPI enrichment. A cluster analysis highlighted two key clusters centered on MMP2 and NR3C1, with both genes playing crucial roles in steroid hormone signaling, apoptosis, and monoamine neurotransmission. Gene Ontology (GO) enrichment and KEGG pathway analyses further elucidated their involvement in critical pathways, for instance, steroid hormone signaling and apoptosis regulation, significantly influencing AD pathology through mechanisms such as extracellular matrix remodeling, epigenetic modifications, and neuroinflammation. Our findings emphasize MMP2 and NR3C1 as important gene targets for future research on melatonin treatment in AD, paving the way for further investigations into their roles in AD pathophysiology.

Transcriptional regulation of daily sleep amount by TCF4–HDAC4–CREB complex in mice

Abstract Histone deacetylase HDAC4/5 cooperates with cAMP response element-binding protein (CREB) in the transcriptional regulation of daily sleep amount downstream of LKB1-SIK3 kinase cascade in mice. Here, we report a significant enrichment of the E-box motifs for the basic loop–helix–loop (bHLH) proteins near the CREB- and HDAC4-binding sites in the mouse genome. Adeno-associated virus-mediated expression of class I bHLH transcription factors, such as TCF4, TCF3, or TCF12, across the mouse brain neurons reduces the duration of rapid eye movement sleep (REMS) and non-REMS (NREMS). TCF4 requires its bHLH domain to regulate REMS or NREMS amount, of which the latter is mostly independent of the E-box-binding activity. Consistent with that TCF4 interacts with CREB and HDAC4 via the bHLH domain, TCF4 relies on CREB and partly on HDAC4 to regulate NREMS/REMS amount. Conversely, the ability of CREB to regulate sleep duration also requires its binding to TCF4 and HDAC4. Together, these results indicate that TCF4, HDAC4, and CREB could function cooperatively in the transcriptional regulation of daily sleep amount in mice.

Deciphering the cellular and molecular landscape of pulmonary fibrosis through single-cell sequencing and machine learning

Pulmonary fibrosis is characterized by progressive lung scarring, leading to a decline in lung function and an increase in morbidity and mortality. This study leverages single-cell sequencing and machine learning to unravel the complex cellular and molecular mechanisms underlying pulmonary fibrosis, aiming to improve diagnostic accuracy and uncover potential therapeutic targets. By analyzing lung tissue samples from pulmonary fibrosis patients, we identified distinct cellular phenotypes and gene expression patterns that contribute to the fibrotic process. Notably, our findings revealed a significant enrichment of activated B cells, CD4 T cells, macrophages, and specific fibroblast subpopulations in fibrotic versus normal lung tissue. Machine learning analysis further refined these observations, resulting in the development of a diagnostic model with enhanced precision, based on key gene signatures including TMEM52B, PHACTR1, and BLVRB. Comparative analysis with existing diagnostic models demonstrates the superior accuracy and specificity of our approach. Through In vitro experiments involving the knockdown of PHACTR1, TMEM52B, and BLVRB genes demonstrated that these genes play crucial roles in inhibiting the expression of α-SMA and collagen in lung fibroblasts induced by TGF-β. Additionally, knockout of the PHACTR1 gene reduced inflammation and collagen deposition in a bleomycin-induced mouse model of pulmonary fibrosis in vivo. Additionally, our study highlights novel gene signatures and immune cell profiles associated with pulmonary fibrosis, offering insights into potential therapeutic targets. This research underscores the importance of integrating advanced technologies like single-cell sequencing and machine learning to deepen our understanding of pulmonary fibrosis and pave the way for personalized therapeutic strategies.

Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study.

An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African American (AA) adults consume greater quantities of fructose and are more likely to develop right-side colon cancer than European American (EA) adults. We examined the hypothesis that fructose consumption leads to epigenomic and transcriptomic differences associated with CRC tumor biology. Deoxyribonucleic acid (DNA) methylation data from this cross-sectional study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of food frequency questionnaire data on fructose consumption in normal colon biopsies (n=79) of AA adults undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Right colon organoids derived from AA (n=5) and EA (n=5) adults were exposed to 4.4mM of fructose for 72 hours. Differentially expressed genes (DEGs) were identified using DESeq2. We identified 4,263 right colon fructose-associated DMRs (FDR<0.05). In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in at least one of three datasets. A highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in right colon organoids of AA individuals (P=3.28E-30). Overlapping and significant enrichments for fatty acid metabolism, glycolysis and cell proliferation pathways were also found. Cross-referencing genes within these pathways to DEGs in CRC tumors reveals potential roles for ankyrin repeat domain-containing protein 23 (ANKRD23) and phosphofructokinase, platelet (PFKP) in fructose-mediated CRC risk for AA individuals. Our data support that dietary fructose exerts a greater CRC risk-related effect in right than left colon among AA adults, alluding to its potential role in contributing to racial disparities in CRC.