Phenotypic Outcomes Research Articles

De novo acquisition of antibiotic resistance in six species of bacteria.

Bacteria can become resistant to antibiotics in two ways: by acquiring resistance genes through horizontal gene transfer and by de novo development of resistance upon exposure to non-lethal concentrations. The importance of the second process, de novo build-up, has not been investigated systematically over a range of species and may be underestimated as a result. To investigate the DNA mutation patterns accompanying the de novo antibiotic resistance acquisition process, six bacterial species encountered in the food chain were exposed to step-wise increasing sublethal concentrations of six antibiotics to develop high levels of resistance. Phenotypic and mutational landscapes were constructed based on whole-genome sequencing at two time points of the evolutionary trajectory. In this study, we found that (1) all of the six strains can develop high levels of resistance against most antibiotics; (2) increased resistance is accompanied by different mutations for each bacterium-antibiotic combination; (3) the number of mutations varies widely, with Y. enterocolitica having by far the most; (4) in the case of fluoroquinolone resistance, a mutational pattern of gyrA combined with parC is conserved in five of six species; and (5) mutations in genes coding for efflux pumps are widely encountered in gram-negative species. The overall conclusion is that very similar phenotypic outcomes are instigated by very different genetic changes. The outcome of this study may assist policymakers when formulating practical strategies to prevent development of antimicrobial resistance in human and veterinary health care.IMPORTANCEMost studies on de novo development of antimicrobial resistance have been performed on Escherichia coli. To examine whether the conclusions of this research can be applied to more bacterial species, six species of veterinary importance were made resistant to six antibiotics, each of a different class. The rapid build-up of resistance observed in all six species upon exposure to non-lethal concentrations of antimicrobials indicates a similar ability to adjust to the presence of antibiotics. The large differences in the number of DNA mutations accompanying de novo resistance suggest that the mechanisms and pathways involved may differ. Hence, very similar phenotypes can be the result of various genotypes. The implications of the outcome are to be considered by policymakers in the area of veterinary and human healthcare.

ZFIN Updates to Support Zebrafish Environmental Exposure Data.

The Zebrafish Information Network (ZFIN, zfin.org) is the database resource for genetic, genomic, and phenotypic data from research using zebrafish, Danio rerio. ZFIN curates information about genetic perturbations, gene expression, phenotype, gene function, and human disease models from zebrafish research publications and makes these data available to researchers worldwide. Over the past 20 years, zebrafish have increasingly been used to investigate the effects of environmental exposures, becoming an ideal model to study toxicity, phenotypic outcomes, and gene-chemical interactions. Despite this, database resources supporting zebrafish toxicology and environmental exposure research are limited. To fill this gap, ZFIN has expanded functionality to incorporate and convey toxicology data better. ZFIN annotations for gene expression, phenotype, and human disease models include information about genotypes and experimental conditions used. One type of experimental condition the database captures is the application of chemicals to zebrafish. ZFIN annotates chemicals using the Chemical Entities of Biological Interest Ontology (ChEBI) along with the Zebrafish Experimental Conditions Ontology (ZECO) to denote route of exposure and other experimental conditions. These features allow researchers to search phenotypes and human disease models linked to chemicals more efficiently. Here we discuss how experimental conditions are displayed on ZFIN web pages, the data displayed on chemical term pages, and how to search and download data associated with chemical exposure experiments.

Chemogenomics for steroid hormone receptors (NR3)

The nine human NR3 nuclear receptors translate steroid hormone signals in transcriptomic responses and operate multiple highly important processes ranging from development over reproductive tissue function to inflammatory and metabolic homeostasis. Although several NR3 ligands such as glucocorticoids are invaluable drugs, this family is only partially explored, for example, in autoimmune diseases and neurodegeneration, but may hold therapeutic potential in new areas. Here we report a chemogenomics (CG) library to reveal elusive effects of NR3 receptor modulation in phenotypic settings. 34 highly annotated and chemically diverse ligands covering all NR3 receptors were selected considering complementary modes of action and activity, selectivity and lack of toxicity. Endoplasmic reticulum stress resolving effects of N3 CG subsets in proof-of-concept application validate suitability of the set to connect phenotypic outcomes with targets and to explore NR3 receptors from a translational perspective.

Unusual hypertrophic cardiomyopathy: case report of an early onset wild-type ATTR amyloidosis accompanied by a chromosomal duplication involving the MYH6 and MYH7 gene

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by an increased left ventricular (LV) wall thickness and LV mass. With an estimated prevalence of 1:200–500, HCM is among the most common genetically determined cardiac diseases. Functionally, enhanced tissue stiffness and reduced elasticity, combined with diastolic dysfunction and myocardial fibrosis, can eventually lead to life-threatening arrhythmias and impaired blood flow through the heart chamber. Typical symptoms associated with HCM include atrial fibrillation (AF), syncope, ventricular fibrillation, and cardiac arrest. At the molecular level, various genetic and/or non-genetic etiologies can lead to HCM.Case summaryIn this case, we report on a 60-year-old male patient with severe, progressive hypertrophic cardiomyopathy (HCM) in an uncommon and ambivalent setting. Right ventricular (RV) biopsy and multi-phase skeletal scintigraphy diagnosed transthyretin amyloidosis with cardiac involvement. Sanger sequencing of the transthyretin gene revealed a wild-type sequence. Phenotypically, the patient initially presented with syncopal episodes, atrioventricular (AV) block, and atrial fibrillation. Subsequently, bilateral carpal tunnel syndrome and polyneuropathy developed. However, the progressive and early onset of left ventricular hypertrophy did not align with the typical presentation of HCM in the context of ATTR. Therefore, next-generation sequencing (NGS) analysis revealed a rare chromosomal duplication in both cardiac myosin genes, MYH6 and MYH7. Consequently, two distinct and rare disease entities co-occurred in this patient, both ultimately leading to HCM.DiscussionTo date, no other case featuring wild-type transthyretin amyloidosis (wtATTR) concurrently with a chromosomal duplication affecting both cardiac myosin heavy chain genes has been reported in the literature. This highlights the extreme rarity of this condition, making it challenging to ascertain the extent to which a presumably mutated hybrid myosin gene construct or the TTR amyloid fibrils contribute to stiffness, tissue fibrosis, and cardiac dysfunction. Ultimately, both effects converged in this case, leading to the same cardiac disease with an exacerbated phenotypical outcome of hypertrophic cardiomyopathy (HCM). While early onset wtATTR is an uncommon clinical finding, another significant clinical condition was identified in this patient, marked by an unusual copy number variation (CNV) in the genes MYH6 and MYH7.

Prognostic impact of hypertension and diabetes in patients with cardiac amyloidosis.

Hypertension and diabetes may increase the risk of adverse events in the general population and patients with cardiomyopathies, however, their role in patients with cardiac amyloidosis (CA) is still unclarified. to evaluate the effect on phenotype and clinical outcomes of hypertension and diabetes in patients with CA. Data from 5 Italian Amyloidosis Referral Centres were used to describe clinical characteristics and outcomes of patients with CA based on the presence of a history of hypertension and diabetes. The study includes 887 patients with CA (311 light chain CA, 87 hereditary transthyretin CA, 489 wild-type transthyretin CA). Median age was 75 years (67-81), and 692 (78 %) were men. Five hundred-seven (57 %) patients had hypertension, 127 (14 %) had diabetes. In multivariable linear regression analysis, hypertension was associated with an increased interventricular septal thickness (coefficient 0.63,95 % CI 0.2-1.06), and augmented E/e' ratio (1.92,95 % CI 0.55-3.29). On Cox regression, diabetes was independently associated with death and heart failure hospitalizations (HR 1.45,95 % CI 1.05-1.99, p = 0.02). Patients with hypertension present a more severe phenotype with increased LV wall thickness and more severe diastolic dysfunction compared to non-hypertensive. The presence of diabetes in this cohort is associated with an increased risk of adverse outcomes.

The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by pathogenic variants in the PKD1 and PKD2 genes. Although the type of ADPKD variant can influence disease severity, rare, hypomorphic PKD1 variants have also been reported to modify disease severity or cause biallelic ADPKD. This study examines whether rare, additional, potentially protein-altering, non-pathogenic PKD1 variants contribute to ADPKD phenotypic outcomes. We investigated the prevalence of rare, additional, potentially protein-altering PKD1 variants in patients with PKD1-associated ADPKD. The association between rare, additional, potentially protein-altering variants and phenotypic outcomes, including progression to kidney failure, age at onset of hypertension and urological events, height-adjusted total kidney volume, and predicting renal outcomes in PKD (PROPKD) score, were examined. Rare, additional, potentially protein-altering variants were detected in 6% of the 932 ADPKD patients in the study. The presence of rare, additional, potentially protein-altering variants was associated with 4years earlier progression to kidney failure (hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.18-2.34; P = 0.003), with in-trans rare, additional, potentially protein-altering variants (n = 13/894) showing a greater risk of kidney failure (HR: 1.83; 95% CI 1.00-3.33; P = 0.049). We did not detect statistically significant differences between rare, additional, potentially protein-altering variants and other phenotypic outcomes compared to those without rare, additional, potentially protein-altering variants. In patients with PKD1-associated ADPKD, our findings suggest that rare, additional, potentially protein-altering variants in PKD1 may influence disease severity. These findings have potential clinical implications in counselling and treating patients with rare, additional, potentially protein-altering variants, but further investigation of such variants in larger, longitudinal cohorts with detailed, standardised phenotype data is required.

Phenotypic outcomes of PKD1 compared with non-PKD1 genetically confirmed autosomal dominant polycystic kidney disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the most common monogenic cause of kidney failure. While identifying genetic variants predicts disease progression, characterization of recently describedADPKD-like variants is limited. We explored disease progression and genetic spectrum of genetically-confirmed ADPKD families with PKD1 and non-PKD1 variants. In this observational study, we evaluated the clinical (ADPKD-related complications, estimated glomerular filtration rate (eGFR) decline, and progression to kidney failure), radiological (height-adjusted total kidney volume (ht-TKV)), and genetic characteristics of ADPKD families referred to the Irish Kidney Gene Project. Logistic regression and Kaplan-Meier analysesexamined relationships between genetic variants and disease progression. Genomic sequencing was performed on 261 ADPKD families, and 75.8% (198/261 families, comprising 391 individuals) were identified to harbor pathogenic/likely pathogenic variants; 74.2% (147/198) PKD1 families and 23.2% (46/198) non-PKD1 families, which include PKD2 (n = 29 families), IFT140 variants (n = 4), ALG5, DNAJB11 and NEK8 (n = 3 each), ALG8 and ALG9 variants (n = 2 each). The remaining 2.6% (5/198) accounted for non-ADPKD variants. Compared to PKD1, non-PKD1 families were characterized by a milder phenotype; milder eGFR decline (-1.4mL/min/1.73m2/year vs. -3.2; p < 0.001), smaller ht-TKV (449.7mL/m vs. 1769; p 0.002) and a delayed progression towards kidney failure (73 vs. 52years; HR: 0.12, p < 0.001 [95% CI: 0.07-0.19]). ADPKD-NEK8 heterozygotes demonstrated earlier progression to kidney failure (average age 8 vs. 49years for PKD1; Bonferroni-corrected p 0.017). Non-PKD1 variants have heterogeneous phenotypic and genotypic attributes resulting in milder disease, although ADPKD-NEK8 is an important exception with early progression.

Distinct phenotypic groups and related clinical outcomes in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder with varying risks of clinical outcomes, including sudden cardiac death (SCD). Purpose We aimed to identify distinct phenotypes among patients with HCM in relation to SCD risk factors, interpret their clinical characteristics, and examine their outcomes. Methods This retrospective study analyzed 1,231 consecutive patients with HCM from two tertiary hospitals. We performed latent class analysis (LCA) to categorize patients into phenotypic groups, which is a probabilistic modeling technique that reveals hidden patterns and subgroups within a dataset. Results Three distinct phenotypic groups were identified using LCA. Group 1 (n=554) consisted of young patients with HCM with minimal SCD risk factors and favorable cardiac remodeling. Group 2 (n=114) comprised young patients with HCM and a high prevalence of SCD risk factors, whereas Group 3 (n=563) included older patients (median age, 68 years). Over a median 6.5-year follow-up, 34 SCD-related events, 131 cardiovascular (CV) events, 133 all-cause mortality, and 70 non-CV mortality were observed. Group 2 exhibited the highest rate of SCD-related events (5-year SCD rate: Group 1 vs. 2 vs. 3: 0.8% vs. 8.2% vs. 4.0%, respectively, p&amp;lt;0.001), and CV events were more frequent in Group 2 and 3 compared to Group 1 (Figure 1). All-cause and non-CV mortality were the most frequent in Group 3. A simplified decision tree was developed for the straightforward assignment of phenotypic group membership, demonstrating fair concordance. The phenotypic categorization and the decision tree is shown in Figure 2. Conclusions This study identified three distinct clinical phenotypes in patients with HCM, each associated with different SCD risks and outcomes. Data-driven phenotyping of patients with HCM offers effective risk stratification and may optimize patient management.

Decoding Mechanisms of PTEN Missense Mutations in Cancer and Autism Spectrum Disorder using Interpretable Machine Learning Approaches.

Missense mutations in oncogenic proteins that are concurrently associated with neurodevelopmental disorders have garnered significant attention. Phosphatase and tensin homolog (PTEN) serves as a paradigmatic model for mapping its mutational landscape and identifying genotypic predictors of distinct phenotypic outcomes, including cancer and autism spectrum disorder (ASD). Despite extensive research into the genotype-phenotype correlations of PTEN mutations, the mechanisms underlying the dual association of specific PTEN mutations with both cancer and ASD (PTEN-cancer/ASD mutations) remain elusive. This study introduces an integrative approach that combines machine learning (ML) with structural dynamics to elucidate the molecular effects of PTEN-cancer/ASD mutations. Analysis of biophysical and network biology-based signatures reveals a complex energetic and functional landscape. Subsequently, an ML model and corresponding integrated score were developed to classify and predict PTEN-cancer/ASD mutations, underscoring the significance of protein dynamics in predicting cellular phenotypes. Further molecular dynamics simulations demonstrated that PTEN-cancer/ASD mutations induce dynamic alterations characterized by open conformational changes restricted to the P loop and coupled with inter-domain allosteric regulation. This research aims to enhance the genotypic and phenotypic understanding of PTEN-cancer/ASD mutations through an interpretable ML model integrated with structural dynamics analysis. By identifying shared mechanisms between cancer and ASD, the findings pave the way for the development of novel therapeutic strategies.

Assessing Human Ribosomal DNA Variation and Its Association With Phenotypic Outcomes.

Although genome-scale analyses have provided insights into the connection between genetic variability and complex human phenotypes, much trait variation is still not fully understood. Genetic variation within repetitive elements, such as the multi-copy, multi-locus ribosomal DNA (rDNA), has emerged as a potential contributor to trait variation. Whereas rDNA was long believed to be largely uniform within a species, recent studies have revealed substantial variability in the locus, both within and across individuals. This variation, which takes the form of copy number, structural arrangement, and sequence differences, has been found to be associated with human phenotypes. This review summarizes what is currently known about human rDNA variation, its causes, and its association with phenotypic outcomes, highlighting the technical challenges the field faces and the solutions proposed to address them. Finally, we suggest experimental approaches that can help clarify the elusive mechanisms underlying the phenotypic consequences of rDNA variation.

Generation and Characterization of a Knockout Mouse of an Enhancer of EBF3.

Genomic studies of autism and other neurodevelopmental disorders have identified several relevant protein-coding and noncoding variants. One gene with an excess of protein-coding de novo variants is EBF3 that also is the gene underlying the Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS). In previous work, we have identified noncoding de novo variants in an enhancer of EBF3 called hs737 and further showed that there was an enrichment of deletions of this enhancer in individuals with neurodevelopmental disorders. In this present study, we generated a novel mouse line that deletes the highly conserved, orthologous mouse region of hs737 within the Rr169617 regulatory region, and characterized the molecular and phenotypic aspects of this mouse model. This line contains a 1,160 bp deletion within Rr169617 and through heterozygous crosses we found a deviation from Mendelian expectation (p = 0.02) with a significant depletion of the deletion allele (p = 5.8 × 10 -4 ). Rr169617 +/- mice had a reduction of Ebf3 expression by 10% and Rr169617 -/- mice had a reduction of Ebf3 expression by 20%. Differential expression analyses in E12.5 forebrain, midbrain, and hindbrain in Rr169617 +/+ versus Rr169617 -/- mice identified dysregulated genes including histone genes ( i.e., Hist1h1e , Hist1h2bk , Hist1h3i , Hist1h2ao) and other brain development related genes (e.g., Chd5 , Ntng1 ). A priori phenotyping analysis (open field, hole board and light/dark transition) identified sex-specific differences in behavioral traits when comparing Rr169617 -/- males versus females; whereby, males were observed to be less mobile, move slower, and spend more time in the dark. Furthermore, both sexes when homozygous for the enhancer deletion displayed body composition differences when compared to wild-type mice. Overall, we show that deletion within Rr169617 reduces the expression of Ebf3 and results in phenotypic outcomes consistent with potential sex specific behavioral differences. This enhancer deletion line provides a valuable resource for others interested in noncoding regions in neurodevelopmental disorders and/or those interested in the gene regulatory network downstream of Ebf3 .

Maternal exposure to purified versus grain-based diet during early lactation in mice affects offspring growth and reduces responsivity to Western-style diet challenge in adulthood.

The nutritional environment during fetal and early postnatal life has a long-term impact on growth, development, and metabolic health of the offspring, a process termed "nutritional programming." Rodent models studying programming effects of nutritional interventions use either purified or grain-based rodent diets as background diets. However, the impact of these diets on phenotypic outcomes in these models has not been comprehensively investigated. We used a previously validated (C57BL/6J) mouse model to investigate the effects of infant milk formula (IMF) interventions on nutritional programming. Specifically, we investigated the effects of maternal diet type (i.e., grain-based vs purified) during early lactation and prior to the intervention on offspring growth, metabolic phenotype, and gut microbiota profile. Maternal exposure to purified diet led to an increased post-weaning growth velocity in the offspring and reduced adult diet-induced obesity. Further, maternal exposure to purified diet reduced the offspring gut microbiota diversity and modified its composition post-weaning. These data not only reinforce the notion that maternal nutrition significantly influences the programming of offspring vulnerability to an obesogenic diet in adulthood but emphasizes the importance of careful selection of standard background diet type when designing any preclinical study with (early life) nutritional interventions.

RNF138 contributes to cisplatin resistance in nasopharyngeal carcinoma cells

Resistance to chemotherapy is a significant concern in the treatment of nasopharyngeal carcinoma (NPC), and occurs due to various mechanisms. This study is aimed to evaluate the effects of RING finger protein 138 (RNF138) in the development of cisplatin resistance to NPC. After gene overexpression and silencing, the expression levels of RNF138 were evaluated. The impacts of RNF138 on the proliferation and apoptosis rate of NPC cells were then assessed. γ-H2AX-mediated DNA damage was determined via immunofluorescence assay. Moreover, a tumor xenograft mouse model was developed to investigate the role of RNF138 on NPC progression in vivo. Additionally, transcriptome analysis was performed in 5–8 F cells transfection with OE-RNF1138 or OE-NC.Cisplatin significantly inhibited the proliferation, and promoted apoptosis and DNA damage in NPC cells; however, overexpression of RNF138 reversed the aforementioned regulatory role of cisplatin on NPC cells. Knockdown of RNF138 resulted in contrasting phenotypic outcomes. Additionally, in nude mice, RNF138 overexpression attenuated the suppressive effects of cisplatin on the growth of xenograft tumor, while RNF138 silencing further enhanced the inhibiting role of cisplatin. We further indicated that in 5–8 F cells following RNF138 overexpression, some pathways such as PI3K-Akt signaling pathway, human papillomavirus infection and ErbB signaling pathway that have been reported to be associated with NPC progression and cisplatin resistance were significantly enriched. These findings indicate that the modulation of RNF138 could potentially address the issue of chemotherapy failure by overcoming cisplatin resistance in NPC cells, making it a promising candidate for targeted drug therapy.

A web-based histology atlas for the freshwater sentinel species Daphnia magna.

Daphnia are keystone species of freshwater habitats used as model organisms in ecology and evolutionary biology. Their small size, wide geographic distribution, and sensitivity to chemicals make them useful as environmental sentinels in regulatory toxicology and chemical risk assessment. Biomolecular (-omic) assessments of responses to chemical toxicity, which reveal detailed molecular signatures, become more powerful when correlated with other phenotypic outcomes (such as behavioral, physiological, or histopathological) for comparative validation and regulatory relevance. However, the lack of histopathology or tissue phenotype characterization of this species presently limits our ability to assess cellular mechanisms of toxicity. Here, we address the central concept that interpreting aberrant tissue phenotypes requires a basic understanding of species normal microanatomy. We introduce the female and male DaphniaHistology Reference Atlas (DaHRA) for the baseline knowledge of Daphnia magna microanatomy. We also include developmental stages of female D. magna in the atlas. This interactive web-based resource of adult D. magna features overlaid vectorized demarcation of anatomical structures whose labels comply with an anatomical ontology created for this atlas. We demonstrate the potential utility of DaHRA for toxicological investigations by presenting aberrant phenotypes of acetaminophen-exposed D. magna. We envision DaHRA to facilitate the future integration of molecular and phenotypic data from the scientific community as we seek to understand how genes, chemicals, and environment interactions determine organismal phenotype.

Novel Insights Into Gyrate Atrophy of the Choroid and Retina (GACR): A Cohort Study.

Gyrate atrophy of the choroid and retina (GACR, OMIM #258870) is a rare inherited metabolic disorder characterized by progressive chorioretinal degeneration and hyperornithinemia. Current therapeutic modalities potentially slow disease progression but are not successful in preventing blindness. To allow for trial development, increased knowledge of the clinical phenotype and current therapeutic outcomes is required. In this study, we analyzed 27 patients with GACR. The median age at inclusion was 24 years (range 8-58), with a median age at diagnosis of 14 years (range 0-42). Symptoms began at a mean age of 9 years (range 0-21). Mixed-models analysis showed a significant association between dietary natural protein intake and plasma ornithine levels. Ornithine increased significantly with age, independent of dietary natural protein intake. We found no statistically significant association between ornithine levels and best-corrected visual acuity over time. Patients who started a natural protein-restricted diet below 10 years of age had better VF outcomes compared to patients that started at a later age. MR spectroscopy was used to asses cerebral creatine deficiency, which was present in 15/20 patients, of whom 10 were supplemented with creatine at the time. Finally, using the Michigan Retinal Degeneration Questionnaire, we provided a first insight into the vision-related disability reported by patients with GACR and showed that higher foveal sensitivity was associated with less perceived disability. To conclude, this study provides insights into the phenotype, genotype, biochemistry, and treatment effects of GACR, which can be used for care pathways and clinical trial design.

Observational methods for human studies of transgenerational effects

ABSTRACT There are substantial challenges in studying human transgenerational epigenetic outcomes resulting from environmental conditions. The task requires specialized methods and tools that incorporate specific knowledge of multigenerational relationship combinations of probands and their ancestors, phenotype data for individuals, environmental information of ancestors and their descendants, which can span historical to present datasets, and informative environmental data that chronologically aligns with ancestors and descendants over space and time. As a result, there are few epidemiologic studies of potential transgenerational effects in human populations, thus limiting the knowledge of ancestral environmental conditions and the potential impacts we face with modern human health outcomes. In an effort to overcome some of the challenges in studying human transgenerational effects, we present two transgenerational study designs: transgenerational space-time cluster detection and transgenerational case-control study design. Like other epidemiological methods, these methods determine whether there are statistical associations between phenotypic outcomes (e.g., adverse health outcomes) among probands and the shared environments and environmental factors facing their ancestors. When the ancestor is a paternal grandparent, a statistically significant association provides some evidence that a transgenerational inheritable factor may be involved. Such results may generate useful hypotheses that can be explored using epigenomic data to establish conclusive evidence of transgenerational heritable effects. Both methods are proband-centric: They are designed around the phenotype of interest in the proband generation for case selection and family pedigree creation. In the examples provided, we incorporate at least three generations of paternal lineage in both methods to observe a potential transgenerational effect.

Bayesian thresholded modeling for integrating brain node and network predictors.

Progress in neuroscience has provided unprecedented opportunities to advance our understanding of brain alterations and their correspondence to phenotypic profiles. With data collected from various imaging techniques, studies have integrated different types of information ranging from brain structure, function, or metabolism. More recently, an emerging way to categorize imaging traits is through a metric hierarchy, including localized node-level measurements and interactive network-level metrics. However, limited research has been conducted to integrate these different hierarchies and achieve a better understanding of the neurobiological mechanisms and communications. In this work, we address this literature gap by proposing a Bayesian regression model under both vector-variate and matrix-variate predictors. To characterize the interplay between different predicting components, we propose a set of biologically plausible prior models centered on an innovative joint thresholded prior. This captures the coupling and grouping effect of signal patterns, as well as their spatial contiguity across brain anatomy. By developing a posterior inference, we can identify and quantify the uncertainty of signaling node- and network-level neuromarkers, as well as their predictive mechanism for phenotypic outcomes. Through extensive simulations, we demonstrate that our proposed method outperforms the alternative approaches substantially in both out-of-sample prediction and feature selection. By implementing the model to study children's general mental abilities, we establish a powerful predictive mechanism based on the identified task contrast traits and resting-state sub-networks.

Variant Spectrum of Renal Ciliopathies in Turkish Cohort and Genotype-Phenotype Association Specifically in Autosomal Dominant Polycystic Kidney Disease.

Renal ciliopathies are a genetically and phenotypically heterogeneous group of diseases characterized by cystic and dysplastic kidneys. The aim of this study was to investigate the correlation between genetic changes that cause renal ciliopathies and phenotypic outcomes. The study group consisted of 137 patients diagnosed with renal ciliopathy disease. One hundred nineteen patients had ADPKD phenotype, 7 patients had ARPKD phenotype, 4 patients had nephronophthisis, 1 patient had Senior-Loken syndrome, 4 patients had Bardet-Biedl syndrome, 1 patient had Joubert syndrome and 1 patient had Meckel Gruber syndrome phenotype. Among patients with autosomal dominant polycystic kidney disease, patients with the PKD1 gene mutation had higher creatinine levels (p value: 0.020) and no arachnoid cysts were revealed in the PKD2 group (p value: 0.014). When the domains were compared, the finding of arachnoid cyst in patients with mutations in the transmembrane domain was statistically significant (p value: 0.021). Homozygous likely pathogenic variant in the TCTN1 gene was reported in a fetus who had findings of Meckel-Gruber syndrome; microphthalmia and cardiac hypoplasia were reported as novel findings. As a conclusion, we identified variant spectrum of renal ciliopathies in Turkish cohort and revealed the association between the transmembrane domain and arachnoid cyst.

Short-Term High Light Stress Analysis Through Differential Methylation Identifies Root Architecture and Cell Size Responses.

DNA methylation repatterning is an epigenomic component of plant stress response, but the extent that methylome data can elucidate changes in plant growth following stress onset is not known. We applied high-resolution DNA methylation analysis to decode plant responses to short- and long-term high light stress and, integrating with gene expression data, attempted to predict components of plant growth response. We identified 105 differentially methylated genes (DMGs) following 1 h of high light treatment and 193 DMGs following 1 week of intermittent high light treatment. Two distinct methylome-predicted plant growth responses to high light treatment could be confirmed by linking methylome changes in auxin response pathways to observed changes in root architecture and methylome changes in cell cycle pathway components to endoreduplication and palisade cell enlargement. We observed methylome changes in a cyclic GMP-dependent protein kinase in association with high light stress signalling. The ability to associate intragenic methylation repatterning with predictable plant phenotypic outcomes after a limited period of high light treatment allows for data-based early prediction of plant growth responses. The approach also permits the dissection of gene networks underpinning plant growth adjustments during environmental change to uncover dynamic phenotype determinants.

A deep dive into monogenic lupus: insights on DNASE1L3 mutation.

In this study, we aim to describe the largest cohort of monogenic lupus caused by DNASE1L3 yet reported, describing its phenotypic characteristics and outcomes. We performed a multicentre retrospective chart review for enrolled patients with childhood-onset systemic lupus erythematosus (cSLE) followed in pediatric rheumatology tertiary centers in the Sultanate of Oman. We included cSLE patients with genetically confirmed DNASE1L3 mutation. The demographic, clinical and laboratory data of the monogenic lupus cohort was compared with sporadic cSLE cohort. We recruited 33 patients from 15 families with confirmed homozygous DNASE1L3 mutation. The median age of disease onset was 4 years, with 18 (55%) of cohort presenting before the age of 5 years. There were higher proportion of boys 20(61%) affected. Significant proportion of cohort had hypocomplementemic urticarial vasculitis (HUV) symptoms including arthritis (82%), urticarial vasculitis (79%), fever (49%), abdominal pain (36%) and conjunctivitis (25%). Compared with sporadic cohort, there was higher frequency of nephritis (60%) and pulmonary hemorrhage (15%). SLE disease activity index score on presentation was 13.3 ± 3.64 (SD), while disease damage was identified in n = 14 (42%) of patients with mean damage index score of 2.14 ± 1.12 (SD). Despite treatment, significant proportion continued to display HUV symptoms that were refractory to standard treatment. Given the early onset, aggressive nature and refractory natures of cSLE caused by DNASE1L3 mutation, further research aimed at targeted therapies that could restore the function of DNASE1L3 or compensate for its deficiency is warranted.