Tzu Chi Med J. 2024 Mar 26;36(2):127-135. doi: 10.4103/tcmj.tcmj_276_23. eCollection 2024 Apr-Jun.

ABSTRACT

Hematopoietic stem cell transplantation (HSCT) can cure malignant and nonmalignant hematological disorders. From 1983 to 2022, Taiwan performed more than 10,000 HSCT transplants. The Taiwan Blood and Marrow Transplantation Registry collects clinical information to gather everyone's experience and promote the advances of HSCT in Taiwan to gather everyone's experience and promote advances of HSCT in Taiwan. Compared with matched sibling donors, transplants from matched unrelated donors exhibited a trend of superior survival. In Taiwan, transplant donors showed remarkable growth from unrelated (24.8%) and haploidentical (10.5%) donors. The number of older patients (17.4%; aged ≥61 years) who underwent transplantation has increased markedly. This review summarizes several significant developments in HSCT treatment in Taiwan. First, the use of Anti-thymocyte globulin (ATG) and intravenous busulfan regimens were important risk factors for predicting hepatic sinusoidal obstruction syndrome. Second, a new, machine learning-based risk prediction scoring system for posttransplantation lymphoproliferative disorder has identified five risk factors: aplastic anemia, partially mismatched related donors, fludarabine use, ATG use, and acute skin graft-versus-host disease. Third, although the incidence of idiopathic pneumonia syndrome was low (1.1%), its mortality rate was high (58.1%). Fourth, difficult-to-treat mantle cell and T-cell lymphomas treated with autologous HSCT during earlier remission had higher survival rates. Fifth, treatment of incurable multiple myeloma with autologous HSCT showed a median progression-free survival and overall survival of 46.5 and 70.4 months, respectively. Sixth, different haploidentical transplantation strategies were compared. Seventh, caution should be taken in administering allogeneic HSCT treatment in older patients with myeloid leukemia with a Charlson Comorbidity Index ≥3 because of a higher risk of nonrelapse mortality.

PMID:38645784 | PMC:PMC11025591 | DOI:10.4103/tcmj.tcmj_276_23

Bioinform Adv. 2024 Apr 10;4(1):vbae055. doi: 10.1093/bioadv/vbae055. eCollection 2024.

ABSTRACT

SUMMARY: Chromatin accessibility serves as a critical measurement of physical contact between nuclear macromolecules and DNA sequence, providing valuable insights into the comprehensive landscape of regulatory mechanisms, thus we previously developed the OpenAnnotate web server. However, as an increasing number of epigenomic analysis software tools emerged, web-based annotation often faced limitations and inconveniences when integrated into these software pipelines. To address these issues, we here develop two software packages named OpenAnnotatePy and OpenAnnotateR. In addition to web-based functionalities, these packages encompass supplementary features, including the capability for simultaneous annotation across multiple cell types, advanced searching of systems, tissues and cell types, and converting the result to the data structure of mainstream tools. Moreover, we applied the packages to various scenarios, including cell type revealing, regulatory element prediction, and integration into mainstream single-cell ATAC-seq analysis pipelines including EpiScanpy, Signac, and ArchR. We anticipate that OpenAnnotateApi will significantly facilitate the deciphering of gene regulatory mechanisms, and offer crucial assistance in the field of epigenomic studies.

AVAILABILITY AND IMPLEMENTATION: OpenAnnotateApi for R is available at https://github.com/ZjGaothu/OpenAnnotateR and for Python is available at https://github.com/ZjGaothu/OpenAnnotatePy.

PMID:38645715 | PMC:PMC11031356 | DOI:10.1093/bioadv/vbae055

bioRxiv [Preprint]. 2024 Apr 13:2024.04.09.588804. doi: 10.1101/2024.04.09.588804.

ABSTRACT

MOTIVATION: RNA-Seq data analysis is commonly biased towards detecting differentially expressed genes and insufficiently conveys the complexity of gene expression changes between biological conditions. This bias arises because discrete models of RNA-Seq count data cannot fully characterize the mean, variance, and skewness of gene expression distribution using independent model parameters. A unified framework that simultaneously tests for differential expression, variability, and skewness is needed to realize the full potential of RNA-Seq data analysis in a systems biology context.

RESULTS: We present SIEVE, a statistical methodology that provides the desired unified framework. SIEVE embraces a compositional data analysis framework that transforms discrete RNA-Seq counts to a continuous form with a distribution that is well-fitted by a skew-normal distribution. Simulation results show that SIEVE controls the false discovery rate and probability of Type II error better than existing methods for differential expression analysis. Analysis of the Mayo RNA-Seq dataset for Alzheimer's disease using SIEVE reveals that a gene set with significant expression difference in mean, standard deviation and skewness between the control and the Alzheimer's disease group strongly predicts a subject's disease state. Furthermore, functional enrichment analysis shows that relying solely on differentially expressed genes detects only a segment of a much broader spectrum of biological aspects associated with Alzheimer's disease. The latter aspects can only be revealed using genes that show differential variability and skewness. Thus, SIEVE enables fresh perspectives for understanding the intricate changes in gene expression that occur in complex diseases.

AVAILABILITY: The SIEVE R package and source codes are available at https://github.com/Divo-Lee/SIEVE .

PMID:38645120 | PMC:PMC11030344 | DOI:10.1101/2024.04.09.588804

Plant Cell Environ. 2024 Apr 21. doi: 10.1111/pce.14921. Online ahead of print.

ABSTRACT

The stems of some herbaceous species can undergo basal secondary growth, leading to a continuum in the degree of woodiness along the stem. Whether the formation of secondary growth in the stem base results in differences in embolism resistance between the base and the upper portions of stems is unknown. We assessed the embolism resistance of leaves and the basal and upper portions of stems simultaneously within the same individuals of two divergent herbaceous species that undergo secondary growth in the mature stem bases. The species were Solanum lycopersicum (tomato) and Senecio minimus (fireweed). Basal stem in mature plants of both species displayed advanced secondary growth and greater resistance to embolism than the upper stem. This also resulted in significant vulnerability segmentation between the basal stem and the leaves in both species. Greater embolism resistance in the woodier stem base was found alongside decreases in the pith-to-xylem ratio, increases in the proportion of secondary xylem, and increases in lignin content. We show that there can be considerable variation in embolism resistance across the stem in herbs and that this variation is linked to the degree of secondary growth present. A gradient in embolism resistance across the stem in herbaceous plants could be an adaptation to ensure reproduction or basal resprouting during episodes of drought late in the lifecycle.

PMID:38644584 | DOI:10.1111/pce.14921

Int J Med Inform. 2024 Apr 17;187:105461. doi: 10.1016/j.ijmedinf.2024.105461. Online ahead of print.

ABSTRACT

OBJECTIVE: Female reproductive disorders (FRDs) are common health conditions that may present with significant symptoms. Diet and environment are potential areas for FRD interventions. We utilized a knowledge graph (KG) method to predict factors associated with common FRDs (for example, endometriosis, ovarian cyst, and uterine fibroids).

MATERIALS AND METHODS: We harmonized survey data from the Personalized Environment and Genes Study (PEGS) on internal and external environmental exposures and health conditions with biomedical ontology content. We merged the harmonized data and ontologies with supplemental nutrient and agricultural chemical data to create a KG. We analyzed the KG by embedding edges and applying a random forest for edge prediction to identify variables potentially associated with FRDs. We also conducted logistic regression analysis for comparison.

RESULTS: Across 9765 PEGS respondents, the KG analysis resulted in 8535 significant or suggestive predicted links between FRDs and chemicals, phenotypes, and diseases. Amongst these links, 32 were exact matches when compared with the logistic regression results, including comorbidities, medications, foods, and occupational exposures.

DISCUSSION: Mechanistic underpinnings of predicted links documented in the literature may support some of our findings. Our KG methods are useful for predicting possible associations in large, survey-based datasets with added information on directionality and magnitude of effect from logistic regression. These results should not be construed as causal but can support hypothesis generation.

CONCLUSION: This investigation enabled the generation of hypotheses on a variety of potential links between FRDs and exposures. Future investigations should prospectively evaluate the variables hypothesized to impact FRDs.

PMID:38643701 | DOI:10.1016/j.ijmedinf.2024.105461

Leukemia. 2024 Apr 20. doi: 10.1038/s41375-024-02222-w. Online ahead of print.

ABSTRACT

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

PMID:38643304 | DOI:10.1038/s41375-024-02222-w

Commun Biol. 2024 Apr 20;7(1):483. doi: 10.1038/s42003-024-06181-x.

ABSTRACT

Leukemias and their bone marrow microenvironments undergo dynamic changes over the course of disease. However, little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of CLC dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1-2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: (i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and (ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells.

PMID:38643279 | PMC:PMC11032325 | DOI:10.1038/s42003-024-06181-x

Sci Rep. 2024 Apr 20;14(1):9064. doi: 10.1038/s41598-024-59110-7.

ABSTRACT

Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.

PMID:38643236 | PMC:PMC11032351 | DOI:10.1038/s41598-024-59110-7

BMC Oral Health. 2024 Apr 20;24(1):477. doi: 10.1186/s12903-024-04251-4.

ABSTRACT

BACKGROUND: This study examines the oral health benefits of heat-killed Lacticaseibacillus paracasei GMNL-143, particularly its potential in oral microbiota alterations and gingivitis improvement.

METHODS: We assessed GMNL-143's in vitro interactions with oral pathogens and its ability to prevent pathogen adherence to gingival cells. A randomized, double-blind, crossover clinical trial was performed on gingivitis patients using GMNL-143 toothpaste or placebo for four weeks, followed by a crossover after a washout.

RESULTS: GMNL-143 showed coaggregation with oral pathogens in vitro, linked to its surface layer protein. In patients, GMNL-143 toothpaste lowered the gingival index and reduced Streptococcus mutans in crevicular fluid. A positive relationship was found between Aggregatibacter actinomycetemcomitans and gingival index changes, and a negative one between Campylobacter and gingival index changes in plaque.

CONCLUSION: GMNL-143 toothpaste may shift oral bacterial composition towards a healthier state, suggesting its potential in managing mild to moderate gingivitis.

TRIAL REGISTRATION: ID NCT04190485 ( https://clinicaltrials.gov/ ); 09/12/2019, retrospective registration.

PMID:38643116 | PMC:PMC11031891 | DOI:10.1186/s12903-024-04251-4

J Exp Bot. 2024 Apr 20:erae165. doi: 10.1093/jxb/erae165. Online ahead of print.

ABSTRACT

Developmental and environmental constraints influence genome expression through complex panels of regulatory mechanisms. Epigenetic modifications and remodelling of chromatin are some of the major actors regulating the dynamic of gene expression. Unravelling the factors relaying environmental signals to gene expression reprogramming under stress conditions is an important and fundamental question. Indeed, many enzymes involved in epigenetic and chromatin modifications, are regulated by redox pathways, through post-translational modifications of proteins or by modifications of the flux of metabolic intermediates. Such modifications are potential hubs to relay developmental and environmental changes for gene expression reprogramming. In this review, we aim to update the current knowledge on the interaction between major redox mediators such as ROS, RNS and antioxidant, and epigenetic changes in plants. We will detail how redox status alters the post-translational modifications of proteins, intracellular epigenetic and epitranscriptional modifications, and how redox regulation interplays with DNA methylation, histone acetylation and methylation, miRNA biogenesis, and chromatin structure and remodelling, to reprogram genome expression under environmental constraints.

PMID:38642408 | DOI:10.1093/jxb/erae165

J Exp Bot. 2024 Apr 20:erae177. doi: 10.1093/jxb/erae177. Online ahead of print.

ABSTRACT

Redox signalling is crucial for regulating plant development and adaptation to environmental changes. Proteins with redox-sensitive cysteines can sense oxidative stress and modulate their functions. Recent proteomics efforts have comprehensively mapped the proteins targeted by oxidative modifications. The nucleus, the epicentre of transcriptional reprogramming, contains a large number of proteins that control gene expression. Specific redox-sensitive transcription factors have long been recognised as key players in decoding redox signals in the nucleus and thus in regulating transcriptional responses. Consequently, the redox regulation of the nuclear transcription machinery and its cofactors has received less attention. In this review, we screened proteomic datasets for redox-sensitive cysteines on proteins of the core transcription complexes and chromatin modifiers in Arabidopsis thaliana. Our analysis indicates that redox regulation affects every step of gene transcription, from initiation to elongation and termination. We report previously undescribed redox-sensitive subunits in transcription complexes and discuss the emerging challenges in unravelling the landscape of redox-regulated processes involved in nuclear gene transcription.

PMID:38642390 | DOI:10.1093/jxb/erae177

Asian Pac J Allergy Immunol. 2024 Apr 20. doi: 10.12932/AP-290823-1677. Online ahead of print.

ABSTRACT

BACKGROUND: Although allergy might be another factor that exacerbates lupus as demonstrated by several epidemiologic studies, the direct correlation between lupus activities and allergy is still in question.

OBJECTIVE: To explore the correlation between allergic reaction and lupus activities.

METHODS: The allergic asthma model using ovalbumin (OVA) administration in wildtype (WT) and Fc gamma receptor IIb deficient (FcgRIIb-/-) mice (a lupus-prone model) together with in vitro experiments on bone marrow-derived dendritic cells (DCs) were performed.

RESULTS: At 2-weeks-post OVA, both WT and FcgRIIb-/- mice demonstrated similar allergic reaction as indicated by an elevation of IgE and IL-4 in serum with asthma-liked lung histology (lung weight, inflammatory score, and bronchial thickness) with increased spleen weight. Apoptosis in the lungs and spleens (activated caspase 3 immunohistochemistry) was detected only in OVA-administered FcgRIIb-/- mice. Surprisingly, OVA-administered FcgRIIb-/- mice, demonstrated active lupus nephritis, as indicated by anti-dsDNA, proteinuria, and renal immune complex deposition (immunohistochemistry analysis) implying an impact of allergy on lupus activities. Meanwhile, serum creatinine and gut permeability defect (FitC-dextran assay and endotoxemia) were not different between the FcgRIIb-/- mice with OVA versus with control. In parallel, FcgRIIb-/- DCs were more susceptible to activations by OVA and lipopolysaccharide (LPS) than WT DCs as demonstrated by CD80 with major histocompatibility complex II (MHC II) using flow cytometry analysis.

CONCLUSION: OVA-induced allergy in FcgRIIb-/- mice exacerbated lupus activity, possibly due to hyper-responsiveness of FcgRIIb-/- DCs over WT from the loss of inhibitory FcgRIIb. The proper control of allergy might be beneficial for lupus.

PMID:38642328 | DOI:10.12932/AP-290823-1677

Biochim Biophys Acta Mol Cell Res. 2024 Apr 17:119735. doi: 10.1016/j.bbamcr.2024.119735. Online ahead of print.

ABSTRACT

The Hypoxia-Inducible Factor 1 (HIF-1) is essential for cellular adaptation to reduced oxygen levels. It also facilitates the maintenance and re-establishment of skin homeostasis. Among others, it is involved in regulating keratinocyte differentiation. The stability of the oxygen-liable HIF-1α subunit is regulated by various non-canonical oxygen-independent mechanisms, which among others involve Heat Shock Proteins of the A family (HSPA/HSP70). This group of highly homologous chaperones and proteostasis-controlling factors includes HSPA2, a unique member crucial for spermatogenesis and implicated in the regulation of keratinocyte differentiation. HIF-1 can control the HSPA2 gene expression. In this study, we revealed that HIF-1α is the first confirmed client of HSPA2 in human somatic cells. It colocalises and interacts directly with HSPA2 in the epidermis in situ and immortalised keratinocytes in vitro. Using an in vitro model based on HSPA2-overexpressing and HSPA2-deficient variants of immortalised keratinocytes we showed that changes in HSPA2 levels do not affect the levels and intracellular localisation of HIF-1α or influence the ability of HIF-1 to modulate target gene expression. However, HIF-1α stability in keratinocytes appears critically reliant on HSPAs as a group of functionally overlapping chaperones. In addition to HSPA2, HIF-1α colocalises and forms complexes with HSPA8 and HSPA1, representing housekeeping and stress-inducible HSPA family paralogs, respectively. Chemical inhibition of HSPA activity, but not paralog-specific knockdown of HSPA8 or HSPA1 expression reduced HIF-1α levels and HIF-1-dependent gene expression. These observations suggest that pharmacological targeting of HSPAs could prevent excessive HIF-1 signalling in pathological skin conditions.

PMID:38641179 | DOI:10.1016/j.bbamcr.2024.119735

Sci Total Environ. 2024 Apr 17:172451. doi: 10.1016/j.scitotenv.2024.172451. Online ahead of print.

ABSTRACT

Here we addressed the capacity of distinct amendments to reduce arsenic (As), copper (Cu), selenium (Se) and zinc (Zn) associated risks and improve the biogeochemical functions of post-mining soil. To this, we examined nanoparticles (NPs) and/or biochar effects, combined with phytostabilization using Lolium perenne L. Soil samples were taken in a former metal mine surroundings. Ryegrass seeds were sown in pots containing different combinations of NPs (zero-valent iron (nZVI) or hydroxyapatite (nH)) (0 and 2 %), and biochar (0, 3 and 5 %). Plants were grown for 45 days and the plant yield and element accumulation were evaluated, also soil properties (element distribution within the soil fractions, fertility, and enzymatic activities associated with microbiota functionality and nutrient cycling) were determined. Results showed biochar-treated soil had a higher pH, and much higher organic carbon (C) content than control soil and NP-treated soils, and it revealed increased labile C, total N, and available P concentrations. Soil treatment with NP-biochar combinations increased exchangeable non-acid cation concentrations and reduced exchangeable Na%, improved soil fertility, reduced sodicity risk, and increased ryegrass biomass. Enzymatic activities, particularly dehydrogenase and glucosidase, increased upon the addition of biochar, and this effect was fostered by NPs. Most treatments led to a significant reduction of metal(loid)s contents in biomass, mitigating contamination risks. The two different NPs had similar effects in many parameters, nH outperformed nZVI in terms of increased nutrients, C content, and enzymatic activities. On the basis of our results, combined biochar-NP amendments use, specially nH, emerges as a potential post-mining soil restoration strategy.

PMID:38641107 | DOI:10.1016/j.scitotenv.2024.172451

Immunity. 2024 Apr 12:S1074-7613(24)00142-0. doi: 10.1016/j.immuni.2024.03.021. Online ahead of print.

ABSTRACT

Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.

PMID:38640930 | DOI:10.1016/j.immuni.2024.03.021

Cell Cycle. 2024 Apr 19:1-30. doi: 10.1080/15384101.2024.2340859. Online ahead of print.

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global coronavirus disease-2019 (COVID-19) pandemic. This study aimed to elucidate potential therapeutic avenues by scrutinizing approved drugs through the identification of the genetic signature associated with SARS-CoV-2 infection in individuals with asthma. This exploration was conducted through an integrated analysis, encompassing interaction networks between the ACE2 receptor and common host (co-host) factors implicated in COVID-19/asthma comorbidity. The comprehensive analysis involved the identification of common differentially expressed genes (cDEGs) and hub-cDEGs, functional annotations, interaction networks, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and module construction. Interaction networks were used to identify overlapping disease modules and potential drug targets. Computational biology and molecular docking analyzes were utilized to discern functional drug modules. Subsequently, the impact of the identified drugs on the expression of hub-cDEGs was experimentally validated using a mouse model. A total of 153 cDEGs or co-host factors associated with ACE2 were identified in the COVID-19 and asthma comorbidity. Among these, seven significant cDEGs and proteins - namely, HRAS, IFNG, JUN, CDH1, TLR4, ICAM1, and SCD-were recognized as pivotal host factors linked to ACE2. Regulatory network analysis of hub-cDEGs revealed eight top-ranked transcription factors (TFs) proteins and nine microRNAs as key regulatory factors operating at the transcriptional and post-transcriptional levels, respectively. Molecular docking simulations led to the proposal of 10 top-ranked repurposable drug molecules (Rapamycin, Ivermectin, Everolimus, Quercetin, Estradiol, Entrectinib, Nilotinib, Conivaptan, Radotinib, and Venetoclax) as potential treatment options for COVID-19 in individuals with comorbid asthma. Validation analysis demonstrated that Rapamycin effectively inhibited ICAM1 expression in the HDM-stimulated mice group (p < 0.01). This study unveils the common pathogenesis and genetic signature underlying asthma and SARS-CoV-2 infection, delineated by the interaction networks of ACE2-related host factors. These findings provide valuable insights for the design and discovery of drugs aimed at more effective therapeutics within the context of lung disease comorbidities.

PMID:38640424 | DOI:10.1080/15384101.2024.2340859

Elife. 2024 Apr 19;12:RP92574. doi: 10.7554/eLife.92574.

ABSTRACT

We propose a new framework for human genetic association studies: at each locus, a deep learning model (in this study, Sei) is used to calculate the functional genomic activity score for two haplotypes per individual. This score, defined as the Haplotype Function Score (HFS), replaces the original genotype in association studies. Applying the HFS framework to 14 complex traits in the UK Biobank, we identified 3619 independent HFS-trait associations with a significance of p < 5 × 10-8. Fine-mapping revealed 2699 causal associations, corresponding to a median increase of 63 causal findings per trait compared with single-nucleotide polymorphism (SNP)-based analysis. HFS-based enrichment analysis uncovered 727 pathway-trait associations and 153 tissue-trait associations with strong biological interpretability, including 'circadian pathway-chronotype' and 'arachidonic acid-intelligence'. Lastly, we applied least absolute shrinkage and selection operator (LASSO) regression to integrate HFS prediction score with SNP-based polygenic risk scores, which showed an improvement of 16.1-39.8% in cross-ancestry polygenic prediction. We concluded that HFS is a promising strategy for understanding the genetic basis of human complex traits.

PMID:38639992 | DOI:10.7554/eLife.92574

JACC Clin Electrophysiol. 2024 Apr 1:S2405-500X(24)00184-1. doi: 10.1016/j.jacep.2024.03.003. Online ahead of print.

ABSTRACT

BACKGROUND: Serum bone morphogenetic protein 10 (BMP10) blood levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in patients with AF, including stroke, AF recurrences after catheter ablations, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphologic properties of atrial tissues are unknown.

OBJECTIVES: This study sought to study the correlation between BMP10 levels and preoperative clinical traits, occurrence of early and late postoperative atrial fibrillation (POAF), and atrial fibrosis in patients undergoing cardiac surgery.

METHODS: Patients with and without preoperative AF history undergoing first cardiac surgery were included (RACE V, n = 147). Preoperative blood biomarkers were analyzed, left (n = 114) and right (n = 125) atrial appendage biopsy specimens were histologically investigated after WGA staining, and postoperative rhythm was monitored continuously with implantable loop recorders (n = 133, 2.5 years).

RESULTS: Adjusted multinomial logistic regression indicated that BMP10 accurately reflected a history of persistent AF (OR: 1.24, 95% CI: 1.10-1.40, P = 0.001), similar to NT-pro-BNP. BMP10 levels were associated with increased late POAF90 occurrence after adjustment for age, sex, AF history, and early POAF occurrence (HR: 1.07 [per 0.1 ng/mL increase], 95% CI: 1.00-1.14, P = 0.041). Left atrial endomysial fibrosis (standardized β = 0.22, P = 0.041) but not overall fibrosis (standardized Β = 0.12, P = 0.261) correlated with circulating BMP10 after adjustment for age, sex, AF history, reduced LVF, and valvular surgery indication.

CONCLUSIONS: Increased BMP10 levels were associated with persistent AF history, increased late POAF incidence, and LAA endomysial fibrosis in a diverse sample of patients undergoing cardiac surgery.

PMID:38639699 | DOI:10.1016/j.jacep.2024.03.003

J Interferon Cytokine Res. 2024 Apr 19. doi: 10.1089/jir.2024.0026. Online ahead of print.

ABSTRACT

Interleukin-26 (IL-26) is a cytokine that belongs to the IL-20 subfamily and is primarily expressed in T helper 1 cells and Th17 memory CD4+ cells. Its receptor complex, consisting of IL-20R1 and IL-10R2, activates a signaling pathway involving several proteins such as Janus kinase 1 and tyrosine-protein kinase, signal transducer and activator of transcription (STAT) 1, and STAT3. This leads to the initiation of downstream signaling cascades that play a crucial role in various biological processes, including inflammation, immune response regulation, atopic dermatitis, macrophage differentiation, osteoclastogenesis, antibacterial host defense, anti-apoptosis, and tumor growth. In this study, we curated literature data pertaining to IL-26 signaling. The curated map includes a total of seven activation/inhibition events, 16 catalysis events, 33 gene regulation events, 25 protein expression types, two transport events, and three molecular associations.

PMID:38639111 | DOI:10.1089/jir.2024.0026

Front Microbiol. 2024 Apr 4;15:1351678. doi: 10.3389/fmicb.2024.1351678. eCollection 2024.

ABSTRACT

Advances in high-throughput technologies have enhanced our ability to describe microbial communities as they relate to human health and disease. Alongside the growth in sequencing data has come an influx of resources that synthesize knowledge surrounding microbial traits, functions, and metabolic potential with knowledge of how they may impact host pathways to influence disease phenotypes. These knowledge bases can enable the development of mechanistic explanations that may underlie correlations detected between microbial communities and disease. In this review, we survey existing resources and methodologies for the computational integration of broad classes of microbial and host knowledge. We evaluate these knowledge bases in their access methods, content, and source characteristics. We discuss challenges of the creation and utilization of knowledge bases including inconsistency of nomenclature assignment of taxa and metabolites across sources, whether the biological entities represented are rooted in ontologies or taxonomies, and how the structure and accessibility limit the diversity of applications and user types. We make this information available in a code and data repository at: https://github.com/lozuponelab/knowledge-source-mappings. Addressing these challenges will allow for the development of more effective tools for drawing from abundant knowledge to find new insights into microbial mechanisms in disease by fostering a systematic and unbiased exploration of existing information.

PMID:38638909 | PMC:PMC11024261 | DOI:10.3389/fmicb.2024.1351678