Specific Phenotypes Research Articles

No association between the novel international classification of bicuspid aortic valve anatomy and performed surgery of the valve or aorta

Abstract Introduction In 2021, international experts introduced a new classification of the diverse anatomy of bicuspid aortic valves (BAV). This classification identifies three BAV types: Fusion, 2-sinus, and Partial-fusion BAV, which may be further subdivided into specific phenotypes according to orientation of the commissure and the presence of a raphe. However, it remains uncertain whether this new BAV classification can identify subgroups of patients with an unfavorable long-term prognosis. Purpose To assess whether the BAV anatomy according to the new classification is associated with the risk of surgery of the aortic valve or aorta. Methods A multicenter case-control study of all current patients with BAV from the outpatient clinics of three major cardiology departments in Denmark in the years 2018, 2019 and 2022. We excluded patients with more than minor concomitant heart defects, uncertain BAV anatomy, and genetic syndromes. Due to the novelty of the concept at the time of study, we excluded 15 patients with Partial-Fusion BAV. Because echocardiography examinations performed prior to January 1 2006 were unavailable, we excluded patients diagnosed prior to this date to ensure comparability between cases and controls. Cases were all patients with BAV, who had had surgery of the aortic valve and/or surgery of the ascending aorta at the end of their accrual year. All other patients with BAV were controls. We assessed BAV anatomy by review of routinely performed echocardiography examinations and compared patients according to BAV type: Fusion or 2-sinus BAV. Secondarily, we compared patients with specific phenotypes: Right-Left Fusion, Right-Non-Coronary Fusion, Left-Non-Coronary Fusion, Latero-Lateral 2-sinus, and Antero-Posterior 2-sinus BAV. Results We included 931 patients (237 cases, 694 controls). Table 1 displays clinical characteristics in BAV phenotype subgroups. In the primary analysis, we found no significant difference in the odds of surgery between the Fusion versus 2-sinus BAV: unadjusted OR 0.65, 95% CI [0.41-1.03]. This did not change after adjusting for age and sex in a logistic regression model: OR 0.72, 95% CI [0.45-1.15]. Results were similar when comparing phenotypes; no difference in odds of surgery between phenotypes in both unadjusted and age- and sex-adjusted analyses (see Fig. 1). In exploratory analyses, we compared patients according to the orientation of the BAV commissure (latero-lateral versus antero-posterior) and a more complex definition of the fusion phenotype that incorporates the visibility of a raphe. Findings were similar; no significant difference in the odds between subgroups. In all models, increasing age and male sex were associated with higher odds of surgery. Conclusion In this study, we did not find any association between BAV anatomy as defined by the new international consensus classification, and performed surgery of the valve or aorta.

Relationship of inflammatory factors with migraine in patients with patent foramen ovale undergoing percutaneous closure

Abstract Background Observational studies have reported the incidental reduction of the frequency and severity of migraine attacks following transcatheter patent foramn ovale (PFO) for established indications. Possible physiologic mechanisms for a relationship between PFO and migraine, if such a link does exist, have been the subject of much speculation, with some researchers suggesting the possible role of PFO as a conduit for the passage of various migraine-inducing inflammatory, vasoactive triggers in cerebral circulation. Purpose The aim of this study was to compare the levels of inflammatory mediators between migraineurs and non –migraineurs and to investigate the impact of PFO closure on the inflammatory state of individuals with migraine and alleviation of migraine symptoms. Methods Forty-five patients (mean age 48.2 ± 10.8 years, 48% male) undergoing percutaneous PFO closure were enrolled in the study. Among them, 15 patients reported recurrent migraine episodes (mean age 46.4 ± 8.90 years, 86% female) while 30 individuals (mean age 49 ± 12.32 years, 70% male) were non-migraineurs. White blood cell count, C-reactive protein (CRP), ferritin and d-dimers levels, as well as the erythrocyte sedimentation rate (ESR) were compared between migraineurs and non-migraineurs. We additionally analyzed the inflammatory levels before and after the percutaneous PFO closure in migraineurs, correlating these changes with migraine relief assessed using the Migraine Disability Assessment Questionnaire (MIDAS) over a 6-month follow-up period. Results White blood cell count, d-dimers levels and ESR were similar in migraineurs and non-migraineurs (6,583 ± 2,251 Χ1 0.e3/uL vs 6,115 ± 1,958 Χ10.e3/uL; p-value = 0.48; 0.54 ± 0.49 μg/L vs 0.45 ± 0.29 μg/L; p- value= 0.49; 23.08 ± 16.68 mm vs 18.51 ± 14.98 mm; p- value 0.402; respectively). However, CRP and ferritin levels were significantly greater in patients with migraine compared to non- migraineurs (3.82 ± 1.87 mg/L vs 1.34 ± 1.52 mg/L; p- value =0.037 and 111.21 ± 82.70 ng/ml vs 50.12 ± 47.9 ng/ml; p- value = 0.023, respectively). Moreover, there was no significant difference between pre- and post-procedural inflammatory levels in migraineurs undergoing percutaneous PFO closure. Of note, following the procedure a reduction in CRP levels was observed without, however, reaching statistical significance. Finally, all patients observed a cessation in the occurrence of migraine attacks after closure. Conclusions Our study revealed significantly higher baseline levels of CRP and ferritin in migraineurs compared to non-migrainers with PFO. Although no alteration in inflammatory factors was observed following the procedure in migraineurs with PFO, all individuals experienced relief from migraine symptoms. Given the limitation of our study due to the small sample size, future studies may provide more insights into the potential benefits of PFO closure in specific migraine patient phenotypes.

Three-Dimensional Organotypic Systems for Modelling and Understanding Molecular Regulation of Oral Dentogingival Tissues

Three-dimensional organotypic models benefit from the ability to mimic physiological cell–cell or cell–matrix interactions and therefore offer superior models for studying pathological or physiological conditions compared to 2D cultures. Organotypic models consisting of keratinocytes supported by fibroblasts embedded in collagen matrices have been utilised for the study of oral conditions. However, the provision of a suitable model for investigating the pathogenesis of periodontitis has been more challenging. Part of the complexity relates to the different regional epithelial specificities and connective tissue phenotypes. Recently, it was confirmed, using 3D organotypic models, that distinct fibroblast populations were implicated in the provision of specific inductive and directive influences on the overlying epithelia. This paper presents the organotypic model of the dentogingival junction (DGJ) constructed to demonstrate the differential fibroblast influences on the maintenance of regionally specific epithelial phenotypes. Therefore, the review aims are (1) to provide the biological basis underlying 3D organotypic cultures and (2) to comprehensively detail the experimental protocol for the construction of the organotypic cultures and the unique setup for the DGJ model. The latter is the first organotypic culture model used for the reconstruction of the DGJ and is recommended as a useful tool for future periodontal research.

Clinical phenotypes in relation to outcomes in heart failure patients with cardiac resynchronization therapy and defibrillators (CRT-D): an unsupervised cluster analysis

Abstract Background Patients with heart failure undergoing CRT are an heterogenous and complex population. Selecting patients before implantation is essential to obtain a favorable response to CRT-D. Data-driven cluster analysis may be an approach to identify different patients’ phenotypic categories. Purpose To identify different clusters of patients with CRT-D who share similar clinical phenotypes, and to evaluate the associations between clusters and clinical outcomes, using cluster analysis. Methods Three agglomerative hierarchical cluster analysis were performed in CRT-D patients seen between 2010 and 2019 in French hospitals. Associations between clusters and death at one year and death during whole follow-up (FU) were evaluated using Cox regression analyses. Results The study included 23,029 CRT-D patients with no prior history of VT/VF/cardiac arrest (mean age 67.7 ± 9.9 years; 78.8 % male), who were analyzed in relation to 3 ways, as follows: the first group was a 50% random sample of all patients (n = 11,514), the second group included patients dead at 1 year (n = 1,604) and the third group included those alive at 3 years FU (n = 14,228). A cluster analysis was performed on each group. Four clusters were identified in the first group: Cluster 1 identified young patients with dilated cardiomyopathy and low prevalence of coronary artery disease (CAD), cardiovascular (CV) risk factors and comorbidities (chronic kidney disease, lung and liver disease) (low-risk phenotype); Cluster 2 was composed of male patients with CAD but low burden of CV risk factors and comorbidities (CAD phenotype); Cluster 3 included CRT recipients with several CV risk factors but low prevalence of comorbidities (CV risk factors phenotype); Cluster 4 identified old patients with high prevalence of CAD, atrial fibrillation, CV risk factors and comorbidities (clinical complex phenotype). These phenotypes were maintained in the other two groups (dead at 1 year and alive at 3 years FU), with the highest consistency for low-risk and high-risk phenotypes(Cluster 1 and 4 respectively). Compared with Cluster 1, Clusters 2, 3 and 4 were independently associated with an increased risk of all-cause death at 1-year FU and during the whole FU (Cluster 2: HR 1.21, 95% CI 1.08 - 1.36; Cluster 3: HR 1.15, 95%CI 1.04 - 1.26; and Cluster 4: HR 1.79, 95%CI 1.65 - 1.96). There were high prevalences of CAD, atrial fibrillation, mitral regurgitation, and comorbidities (which are all predictors of CRT-nonresponse) not only in Cluster 4 at baseline, but also among patients who died at 1-year FU in all 4 clusters. Conclusion Cluster analysis identified four statistically driven groups of CRT recipients, with specific clinical phenotypes and associated with different risks for all-cause death. Identifying those patients at higher risk of adverse events might help in the selection of patients with heart failure undergoing CRT-D implantation, especially in relation to CRT-nonresponse.Risk of all-cause death in 4 clusters

Multi-omics analysis uncovers the transcriptional regulatory mechanism of magnesium Ions in the synthesis of active ingredients in Sophora tonkinensis

Magnesium (Mg) plays a pivotal role as an essential component of plant chlorophyll and functions as a critical coenzyme. However, research exploring the regulatory mechanisms of magnesium ions on the synthesis of secondary metabolites is still in its early stages. Sophora tonkinensis is a widely utilized medicinal plant in China, recognized for its diverse secondary metabolites with active properties. This study investigates variations in these ingredients in tissue-cultured seedlings under varying magnesium concentrations. Simultaneously, an omics data analysis was conducted on tissue-cultured seedlings subjected to treatments with magnesium and low magnesium. These comprehensive omics analyses aimed to elucidate the mechanisms through which magnesium influences active components, growth, and development. Magnesium exerts a pervasive influence on various metabolic pathways, forming an intricate network. Research findings indicate that magnesium impacts diverse metabolic processes, including the absorption of potassium and calcium, as well as photosynthetic activity. Consequently, these influences lead to discernible changes in the levels of pharmacologically active compounds and the growth and developmental status.This study is the first to employ a multi-omics data analysis in S. tonkinensis. This methodology allows us to uncover the overarching impact of metabolic networks on the levels of various active ingredients and specific phenotypes.

Infection-Associated Flares in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is characterised by generalised immune dysfunction, including infection susceptibility. Infection-associated flares (IAFs) are common and might rapidly self-resolve, paralleling infection resolution, but their specific clinical phenotype is poorly understood. Therefore, we screened 2039 consecutive visits and identified 134 flares, defined as a loss of the lupus low disease activity state (LLDAS), from 1089 visits at risk spanning over multiple follow-up years, yielding an average yearly LLDAS deterioration rate of 17%. Thirty-eight IAFs were isolated from the total flares and were mostly related to bacterial and herpesvirus infections. When compared to other flares (OFs; n = 98), IAFs showed no milder patterns of organ involvement and similar rates of long-term damage accrual, as estimated by conventional clinimetrics. Arthritis in IAFs was more severe than that in OFs [median (interquartile range) DAS-28 2.6 (2.3–4.1) vs. 2.0 (1.6–2.7); p = 0.02]. Viral IAFs were characterised by atypically lower levels of anti-DNA antibodies (p < 0.001) and possibly abnormally high complement levels when compared to flares of different origin. These data suggest that IAFs are of comparable or even higher severity than OFs and may subtend distinct pathophysiological mechanisms that are poorly tackled by current treatments. Further research is needed to confirm these data.

A guide to gene-disease relationships in nephrology.

The use of next-generation sequencing technologies such as exome and genome sequencing in research and clinical care has transformed our understanding of the molecular architecture of genetic kidney diseases. Although the capability to identify and rigorously assess genetic variants and their relationship to disease has advanced considerably in the past decade, the curation of clinically relevant relationships between genes and specific phenotypes has received less attention, despite it underpinning accurate interpretation of genomic tests. Here, we discuss the need to accurately define gene-disease relationships in nephrology and provide a framework for appraising genetic and experimental evidence critically. We describe existing international programmes that provide expert curation of gene-disease relationships and discuss sources of discrepancy as well as efforts at harmonization. Further, we highlight the need for alignment of disease and phenotype terminology to ensure robust and reproducible curation of knowledge. These collective efforts to support evidence-based translation of genomic sequencing into practice across clinical, diagnostic and research settings are crucial for delivering the promise of precision medicine in nephrology, providing more patients with timely diagnoses, accurate prognostic information and access to targeted treatments.

Polygenic Landscape of Cryptogenic New-Onset Refractory Status Epilepticus: A Comprehensive Whole-Genome Sequencing Study.

Cryptogenic new-onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole-genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024.

Causal association of immune cells and endometritis: a Mendelian randomization study

Research exploring the link between immune cell profiles and the development of endometritis remains scant. This gap necessitates further study to decode the complex interrelations influencing this condition. In this analysis, we leveraged two-sample Mendelian randomization to examine the causal ties between the phenotypes of immune cells and the incidence of endometritis. Our evaluation hinged on data from 3757 participants hailing from Sardinia, focusing on a diverse array of 731 immune phenotypes, and cross-referenced with endometritis data sourced from the UK Biobank. To ensure rigor, we performed sensitivity analyses, utilized MR-Egger and MR-Presso to check for pleiotropy, and applied Cochran’s Q test for assessing the heterogeneity of our findings. Our investigation identified numerous immune characteristics associated with endometritis. For certain immune traits, a lower risk of endometritis was observed, including: Absolute Counts of CD39 + CD4 + T cells, CD25 + CD39 + CD4 regulatory T cells, and CD25 + + CD8 + T cells; Absolute Counts of Switched Memory B cells; CD19 expression on IgD + CD38dim and Switched Memory B cells; CD20 expression on IgD + CD38− Unswitched Memory B cells; percentage of Switched Memory B cells among lymphocytes; CD16-CD56 expression on HLA DR + Natural Killer cells; percentage of CD11c + CD62L− monocytes; CD86 expression on monocytes; CCR2 expression on CD14 + CD16 + monocytes; and CD14 expression on Monocytic Myeloid-Derived Suppressor Cells, with Odds Ratios (ORs) between 0.413 and 0.703. On the contrary, increased risks of endometritis were linked with: the percentage of Effector Memory CD4 + T cells within the CD4 + T cell population; percentages of HLA DR + T cells and HLA DR + CD8 + T cells among T cells; CD4 expression on CD28 + CD4 + T cells; CD20 expression on CD20- CD38- B cells; percentage of IgD + CD24 + B cells within the B cell population; CD62L expression on CD62L + myeloid Dendritic Cells; and Absolute Counts of Plasmacytoid Dendritic Cells, with ORs from 1.473 to 2.677, indicating these traits potentially elevate the risk of developing endometritis. Our research delineates distinct causal links between specific immune cell phenotypes and endometritis, offering new perspectives that could contribute to the pinpointing of new therapeutic avenues for this condition.

Intraspecific variability in plant and soil chemical properties in a common garden plantation of the energy crop Populus.

Optimizing crops for synergistic soil carbon (C) sequestration can enhance CO2 removal in food and bioenergy production systems. Yet, in bioenergy systems, we lack an understanding of how intraspecies variation in plant traits correlates with variation in soil biogeochemistry. This knowledge gap is exacerbated by both the heterogeneity and difficulty of measuring belowground traits. Here, we provide initial observations of C and nutrients in soil and root and stem tissues from a common garden field site of diverse, natural variant, Populus trichocarpa genotypes-established for aboveground biomass-to-biofuels research. Our goal was to explore the value of such field sites for evaluating genotype-specific effects on soil C, which ultimately informs the potential for optimizing bioenergy systems for both aboveground productivity and belowground C storage. To do this, we investigated variation in chemical traits at the scale of individual trees and genotypes and we explored correlations among stem, root, and soil samples. We observed substantial variation in soil chemical properties at the scale of individual trees and specific genotypes. While correlations among elements were observed both within and among sample types (soil, stem, root), above-belowground correlations were generally poor. We did not observe genotype-specific patterns in soil C in the top 10 cm, but we did observe genotype associations with soil acid-base chemistry (soil pH and base cations) and bulk density. Finally, a specific phenotype of interest (high vs low lignin) was unrelated to soil biogeochemistry. Our pilot study supports the usefulness of decade-old, genetically-variable, Populus bioenergy field test plots for understanding plant genotype effects on soil properties. Finally, this study contributes to the advancement of sampling methods and baseline data for Populus systems in the Pacific Northwest, USA. Further species- and region-specific efforts will enhance C predictability across scales in bioenergy systems and, ultimately, accelerate the identification of genotypes that optimize yield and carbon storage.

Comparative Analysis on Polyphenolic Composition of Different Olive Mill Wastewater and Related Extra Virgin Olive Oil Extracts and Evaluation of Nutraceutical Properties by Cell-Based Studies.

This study reports a comparative analysis of the polyphenolic composition and nutraceutical properties of different olive mill wastewater (OMWW) and corresponding extra virgin olive oil (EVOO) extracts. Specifically, four OMWWs and corresponding EVOOs from cultivars Frantoio (A) and Leccino (B) obtained from different crushing seasons (early-stage (A1 and B1) and later-stage (A2 and B2)) were analyzed. Employing HPLC-DAD and LC-MS methods, the primary polyphenol content was identified and quantified. Overall, OMWW extracts showed a greater polyphenolic content compared to corresponding EVOO extracts, with OMWW B1 displaying the highest levels of polyphenols. The antiradical properties of extracts towards radical species (DPPH, ABTS, O2-, and HOCl-) were demonstrated in vitro, revealing a correlation with polyphenolic content. In fact, OMWW B1 and B2 demonstrated the strongest antiradical activity. Exploring nutraceutical properties of OMWWs, the intestinal permeation of the main polyphenols in a co-culture model (Caco-2 and HT29-MTX cell lines) was assessed, with tyrosol achieving a permeation of almost 60%. Furthermore, the involvement in the inflammation process has been evaluated in cell studies on THP1-derived macrophages by immunocytochemistry, demonstrating that OMWW B1 may exert an anti-inflammatory effect by modulating specific phenotype expression on macrophages. In conclusion, this study provides evidence supporting the reuse of OMWWs as a source of polyphenols with nutraceutical properties.

Integrated temporal transcriptional and epigenetic single-cell analysis reveals the intrarenal immune characteristics in an early-stage model of IgA nephropathy during its acute injury

RationaleKidney inflammation plays a crucial role in the pathogenesis of IgA nephropathy (IgAN), yet the specific phenotypes of immune cells involved in disease progression remain incompletely understood. Utilizing joint profiling through longitudinal single-cell RNA-sequencing (scRNAseq) and single-cell assay for transposase-accessible chromatin sequencing (scATACseq) can provide a comprehensive framework for elucidating the development of cell subset diversity and how chromatin accessibility regulates transcription.ObjectiveWe aimed to characterize the dynamic immune cellular landscape at a high resolution in an early IgAN mouse model with acute kidney injury (AKI).Methods and resultsA murine model was utilized to mimic 3 immunological states –”immune stability (IS), immune activation (IA) and immune remission (IR)” in early human IgAN-associated glomerulopathy during AKI, achieved through lipopolysaccharide (LPS) injection. Urinary albumin to creatinine ratio (UACR) was measured to further validate the exacerbation and resolution of kidney inflammation during this course. Paired scRNAseq and scATACseq analysis was performed on CD45+ immune cells isolated from kidney tissues obtained from CTRL (healthy vehicle), IS, IA and IR (4 or 5 mice each). The analyses revealed 7 major cell types and 24 clusters based on 72304 single-cell transcriptomes, allowing for the identification and characterization of various immune cell types within each cluster. Our data offer an impartial depiction of the immunological characteristics, as the proportions of immune cell types fluctuated throughout different stages of the disease. Specifically, these analyses also revealed novel subpopulations, such as a macrophage subset (Nlrp1b Mac) with distinct epigenetic features and a unique transcription factor motif profile, potentially exerting immunoregulatory effects, as well as an early subset of Tex distinguished by their effector and cytolytic potential (CX3CR1-transTeff). Furthermore, in order to investigate the potential interaction between immune cells and renal resident cells, we conducted single-cell RNA sequencing on kidney cells obtained from a separate cohort of IS and IA mice without isolating immune cells. These findings underscored the diverse roles played by macrophages and CD8+ T cells in maintaining homeostasis of endothelial cells (ECs) under stress.ConclusionsThis study presents a comprehensive analysis of the dynamic changes in immune cell profiles in a model of IgAN, identifying key cell types and their roles and interactions. These findings significantly contribute to the understanding of the pathogenesis of IgAN and may provide potential targets for therapeutic intervention.

Cell-cycle phase progression analysis identifies three unique phenotypes in soft tissue sarcoma

PurposeLoddo et al. (Br J Cancer 100:959–70, 2009) established the prognostic significance of cell cycle markers and "Cell-Cycle Phenotypes" in breast carcinoma. This study aims to 1) identify prognostic cell-cycle markers in sarcoma, and 2) assess the prognostic potential of specific cell-cycle phenotypes in sarcoma.MethodsTissue samples from 128 soft tissue sarcomas were stained for four cell cycle-specific markers: Mcm2, Geminin, Plk1, and H3S10ph. Only primary soft tissue tumors (liposarcoma, leiomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma) were included in the analysis. Any tumor coming from a recurrent or metastatic lesion were excluded from the analysis. Three cell-cycle phenotypes (I, II, III) were derived from marker expression patterns. Prognostic significance was evaluated in a subset of primary soft tissue sarcomas using Cox regression for survival analysis.ResultsCompared to phenotype I, the phenotype III tumors had a decreased 5-year overall survival (HR 6.81 [2.36–19.61]; p = < 0.001), 5-year disease-free survival (HR 1.07 (1.02–1.18); p = 0.004), and 5-year metastasis-free survival (HR 4.34 [1.58–11.93]; p = 0.004).High expression of Plk1 was associated with decreased 5-year overall survival (HR: 4.04 CI [1.21–6.67; p = 0.02) and 5-year metastasis-free survival (HR: 2.91 CI [1.15–7.37]; p = 0.03). Geminin was also found to have a decreased 5-year overall survival (HR:2.84 CI [1.21–6.67]; p = 0.02). No statistical difference in prognostication were noted between phenotypes and the AJCC system.ConclusionsWe identified three unique sarcoma cell cycle phenotypes that have prognostic significance. This performs similarly to the AJCC staging system.

The clinical and genetic spectrum of paediatric speech and language disorders.

Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far. Here, we performed an in-depth characterization of speech and language disorders in 52 143 individuals, reconstructing clinical histories using a large-scale data-mining approach of the electronic medical records from an entire large paediatric healthcare network. The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of 26 broad speech and language diagnoses. We used natural language processing to assess the degree to which clinical diagnoses in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be retrieved easily through ICD-10 diagnosis codes, whereas stuttering as a speech phenotype was coded in only 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and, to a lesser degree, with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our analysis of electronic medical records were STXBP1 (n = 21), PTEN (n = 20) and CACNA1A (n = 18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations of STXBP1 and aphasia (P = 8.57 × 10-7, 95% confidence interval = 18.62-130.39) and MYO7A with speech and language development delay attributable to hearing loss (P = 1.24 × 10-5, 95% confidence interval = 17.46-infinity). Finally, in a sub-cohort of 726 individuals with whole-exome sequencing data, we identified an enrichment of rare variants in neuronal receptor pathways, in addition to associations of UQCRC1 and KIF17 with expressive aphasia, MROH8 and BCHE with poor speech, and USP37, SLC22A9 and UMODL1 with aphasia. In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.

Microglia Signatures: A Cause or Consequence of Microglia-Related Brain Disorders?

Microglia signatures refer to distinct gene expression profiles or patterns of gene activity that are characteristic of microglia. Advances in gene expression profiling techniques, such as single-cell RNA sequencing, have allowed us to study microglia at a more detailed level and identify unique gene expression patterns that are associated, but not always, with different functional states of these cells. Microglial signatures depend on the developmental stage, brain region, and specific pathological conditions. By studying these signatures, it has been possible to gain insights into the underlying mechanisms of microglial activation and begin to develop targeted therapies to modulate microglia-mediated immune responses in the CNS. Historically, the first two signatures coincide with M1 pro-inflammatory and M2 anti-inflammatory phenotypes. The first one includes upregulation of genes such as CD86, TNF-α, IL-1β, and iNOS, while the second one may involve genes like CD206, Arg1, Chil3, and TGF-β. However, it has long been known that many and more specific phenotypes exist between M1 and M2, likely with corresponding signatures. Here, we discuss specific microglial signatures and their association, if any, with neurodegenerative pathologies and other brain disorders.

Persistent Activation of the P2X7 Receptor Underlies Chronic Inflammation and Carcinogenic Changes in the Intestine.

Aberrant signaling through damage-associated molecular patterns (DAMPs) has been linked to several health disorders, attracting considerable research interest over the last decade. Adenosine triphosphate (ATP), a key extracellular DAMP, activates the purinergic receptor P2X7, which acts as a danger sensor in immune cells and is implicated in distinct biological functions, including cell death, production of pro-inflammatory cytokines, and defense against microorganisms. In addition to driving inflammation mediated by immune and non-immune cells, the persistent release of endogenous DAMPs, including ATP, has been shown to result in epigenetic modifications. In intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), consequent amplification of the inflammatory response and the resulting epigenetic reprogramming may impact the development of pathological changes associated with specific disease phenotypes. P2X7 is overexpressed in the gut mucosa of patients with IBD, whereas the P2X7 blockade prevents the development of chemically induced experimental colitis. Recent data suggest a role for P2X7 in determining gut microbiota composition. Regulatory mechanisms downstream of the P2X7 receptor, combined with signals from dysbiotic microbiota, trigger intracellular signaling pathways and inflammasomes, intensify inflammation, and foster colitis-associated CRC development. Preliminary studies targeting the ATP-P2X7 pathway have shown favorable therapeutic effects in human IBD and experimental colitis.

Substance use and psychiatric phenotypes of youth experiencing homelessness: A cluster analysis.

Due to the complex interactions of psychopathology, psychosocial stressors, and risk behaviors, characterizing high-risk phenotypic groups of transitional-age youth experiencing homelessness (TAY-EH) for targeted interventions remains difficult. We aimed to uncover specific phenotypes of TAY-EH based upon psychiatric and substance use disorder (SUD) diagnoses, and to assess relationships between these phenotypes and negative outcomes including suicidality and high-risk behaviors. Participants (N = 140; 57% male, 54% Black) were individuals aged 16-25 years accessing support at a psychosocial agency in the U.S. Northeast. Data were gathered via structured assessment. Cluster analysis identified sub-groups of TAY-EH with differing diagnostic patterns. Bivariate analyses examined associations between cluster membership and target outcomes. A four-cluster solution was identified. Cluster 1 (Co-occurring; N = 33) was characterized by high levels of comorbidity (i.e., major depressive disorder (MDD), SUD, and notable levels of other diagnoses). Clusters 2 (MDD alone; N = 47) and 3 (SUD alone; N = 18) were characterized by single diagnoses. Cluster 4 (None; N = 42) was characterized by low levels of psychopathology. Clusters differed significantly on several variables including suicidality, adverse childhood experiences, and social connectedness. Comorbid MDD and SUD were most strongly associated with high-risk behaviors and suicidality. These results highlight the importance of diagnosis and targeted interventions for co-occurring MDD and SUD to address the crisis of early mortality and other negative outcomes among TAY-EH. This study is the first to identify specific high-risk psychiatric and psychosocial phenotypes among the highly complex group of TAY-EH based upon structured diagnostic assessments.

Genome-wide DNA methylation and their transgenerational pattern differ in Arabidopsis thaliana populations originated along the elevation of West Himalaya

Methylation at 5' cytosine of DNA molecule is an important epigenetic mark. It is known to play critical role in adaptation of organisms under different biotic and abiotic stressors via modulating gene expression and/or chromatin architecture. Plant populations evolved under variable climatic conditions may have evolved different epigenetic marks including DNA methylation. Here we, describe the genome-wide DNA methylation pattern under native field, F1 and F6 generation followed by their association with phenotypes, climate and global gene expression in the three Arabidopsis thaliana populations originated at different elevation ranges of Indian West Himalaya. We show that the global methyl cytosine (mC) content is more or less similar in the three populations but differ in their distribution across genome. There was an increase in differential methylation between the populations as elevation increased. The methylation divergence was the highest between the low and the high elevation populations. The high elevation populations were hypo-methylated than the low elevation population. The methylation in the genes was associated with population specific phenotypes and climate of the region. The genes which were differentially methylated as well as differentially expressed between the low and high elevation populations were mostly related to abiotic stresses. When grown under controlled condition, there was gain of differential methylation over native condition and the maximum percent changes was observed in CHH-sequence context. Further ~ 99.8% methylated cytosines were stably passed on from F1 to F6 generation. Overall, our data suggest that high elevation population is epigenetically more plastic under changing environmental condition.BackgroundArabidopsis thaliana is the model plant species and has been extensively studied to understand plants life processes. There are numerous reports on its origin, demography, evolution, epigenomes and adaptation etc. however, Indian populations of Arabidopsis thaliana evolved along wide elevation ranging from ~ 700 m amsl to ~ 3400 m amsl not explored yet. Here we, describe the genome-wide DNA methylation pattern under native field, F1 and F6 generation followed by their association with phenotypes, climate and global gene expression in the three Arabidopsis thaliana populations originated at different elevation ranges of Indian West Himalaya.Results In our study we found that total mCs percent was more or less similar in the three populations but differ in their distribution across genome. The proportion of CG-mCs was the highest, followed by CHH-mCs and CHG-mCs in all the three populations. Under native field condition the methylation divergence was more prominent between low and high elevation populations and the high elevation populations were hypo-methylated than the low elevation population. The methylation in the genes was linked to population-specific phenotypes and the regional climate. The genes that showed differential methylation and expression between low and high elevation populations were primarily associated with abiotic stress responses. When grown under controlled condition, there was gain of differential methylation compared to the native condition and the maximum percent changes was observed in CHH-sequence context. Further 99.8% methylated cytosines were stably passed on from F1 to F6 generation.Conclusions The populations of A. thaliana adapted at different climatic conditions were significantly differentially methylated both under native and controlled condition. However, the magnitude and extent of gain or loss of methylation were most significant between the low and the high elevation populations. Overall, our data suggest that high elevation population is epigenetically more plastic under changing environmental condition.

Clustering Analysis Identified Distinct Clinical Phenotypes among Hemodialysis Patients in Their Immunological Response to the BNT162b2 mRNA Vaccine against SARS-CoV-2.

Background: The 2019 coronavirus disease (COVID-19) pandemic induced a major health crisis worldwide, notably among end-stage kidney disease (ESKD) patients. Vaccination against SARS-CoV-2, especially with messenger RNA (mRNA) vaccines, is highly effective and reduces hospitalization and mortality in both the general and ESKD populations. Age and previous COVID-19 infection have been identified as major determinants of the vaccine response in both the general population and ESKD patients. Methods: To determine the specific phenotype of ESKD patients in relation to their vaccine response, a clustering approach was used in a cohort of 117 fully vaccinated patients. Results: Clustering revealed three distinct clinical phenotypes among hemodialysis patients in terms of immunological response. Two clusters, consisting of either women with a long dialysis history or male subjects with diabetes with a moderate history of dialysis, exhibited low levels of IgG anti-spike antibodies. The third cluster consisted of non-diabetic middle-aged men with a moderate dialysis vintage and a very good serological response to vaccination. Conclusions: These vaccinal phenotypes of dialysis patients are easily identifiable in current practice, allowing for differential serological follow-up and tailored booster SARS-CoV-2 vaccination.

Association of the gut microbiome and different phenotypes of COPD and asthma: a bidirectional Mendelian randomization study.

Mounting evidence has revealed the association between gut microbiota and both chronic obstructive pulmonary disease (COPD) and asthma; however, the causal association between gut microbiota and specific disease phenotypes remains to be determined. This study employed bidirectional two-sample Mendelian randomization (MR) analyses to investigate the potential causal relationship between gut microbiota and these conditions. The research utilized genome-wide association study (GWAS) data from the MiBioGen consortium for gut microbiota and the integrative epidemiology unit (IEU) Open GWAS for these conditions. Four MR analysis methods were employed: the inverse variance weighted (IVW) test, MR-Egger, weighted median, and weighted mode methods. The IVW method results are considered the primary findings. Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy analysis, and leave-one-out analysis, were used to enhance robustness. Our MR study identified eight gut microbiota taxa potentially associated with the risk of different types of COPD and asthma. These include two taxa for early-onset COPD: Streptococcaceae [odds ratio (OR) = 1.315, 95% confidence interval (CI) = 1.071-1.616, P = 0.009] and Holdemanella (OR = 1.199, 95% CI = 1.063-1.352, P = 0.003); three for later-onset COPD: Acidaminococcaceae (OR = 1.312, 95% CI = 1.098-1.567, P = 0.003), Holdemania (OR = 1.165, 95% CI = 1.039-1.305, P = 0.009), and Marvinbryantia (OR = 0.814, 95% CI = 0.697-0.951, P = 0.009); one for allergic asthma: Butyricimonas (OR = 0.794, 95% CI = 0.693-0.908, P = 0.001); and two for non-allergic asthma: Clostridia (OR = 1.255, 95% CI = 1.043-1.511, P = 0.016) and Clostridiales (OR = 1.256, 95% CI = 1.048-1.506, P = 0.014).IMPORTANCEIndividuals with diverse phenotypes of chronic obstructive pulmonary disease (COPD) and asthma exhibit different responses to the conventional "one treatment fits all" approach. Recent research has revealed the significant role of the gut-lung axis in both COPD and asthma. However, the specific impact of gut microbiota on different subtypes of these conditions remains poorly understood. Our study has identified eight gut microbiota that may be associated with the risk of different types of COPD and asthma. These findings provide evidence suggesting a potential causal relationship between gut microbiota and various phenotypes of COPD and asthma. This offers a new perspective on the origins of different disease phenotypes and points toward future exploration of phenotype-specific and personalized therapies.