ia Rising Number of U.S. Cardiac Arrests Tied to Opioid Abuse By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Rising Number of U.S. Cardiac Arrests Tied to Opioid AbuseCategory: Health NewsCreated: 8/23/2021 12:00:00 AMLast Editorial Review: 8/24/2021 12:00:00 AM Full Article
ia Salmonella Outbreak in 17 States Tied to Italian-Style Meats By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Salmonella Outbreak in 17 States Tied to Italian-Style MeatsCategory: Health NewsCreated: 8/24/2021 12:00:00 AMLast Editorial Review: 8/25/2021 12:00:00 AM Full Article
ia Expert Panel Lowers Routine Screening Age for Diabetes to 35 By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Expert Panel Lowers Routine Screening Age for Diabetes to 35Category: Health NewsCreated: 8/24/2021 12:00:00 AMLast Editorial Review: 8/25/2021 12:00:00 AM Full Article
ia Cooler Weather Could Mean More Diabetes in Dogs By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Cooler Weather Could Mean More Diabetes in DogsCategory: Health NewsCreated: 8/22/2022 12:00:00 AMLast Editorial Review: 8/22/2022 12:00:00 AM Full Article
ia COVID Incubation Shorter With Each New Variant By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: COVID Incubation Shorter With Each New VariantCategory: Health NewsCreated: 8/23/2022 12:00:00 AMLast Editorial Review: 8/23/2022 12:00:00 AM Full Article
ia COVID Boosters Targeted to Latest Variants Could Be Ready After Labor Day By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: COVID Boosters Targeted to Latest Variants Could Be Ready After Labor DayCategory: Health NewsCreated: 8/24/2022 12:00:00 AMLast Editorial Review: 8/24/2022 12:00:00 AM Full Article
ia Michigan Officials Puzzled by Mysterious Deaths of 30 Dogs By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Michigan Officials Puzzled by Mysterious Deaths of 30 DogsCategory: Health NewsCreated: 8/24/2022 12:00:00 AMLast Editorial Review: 8/24/2022 12:00:00 AM Full Article
ia Wife of California Congressman Died After Using Herbal Remedy for Diabetes, Weight Loss By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Wife of California Congressman Died After Using Herbal Remedy for Diabetes, Weight LossCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/25/2022 12:00:00 AM Full Article
ia Gene Therapy Makes Inroads Against a Form of Hemophilia By www.medicinenet.com Published On :: Fri, 22 Jul 2022 00:00:00 PDT Title: Gene Therapy Makes Inroads Against a Form of HemophiliaCategory: Health NewsCreated: 7/22/2022 12:00:00 AMLast Editorial Review: 7/22/2022 12:00:00 AM Full Article
ia Change to Diagnosis of Gestational Diabetes Helped Women By www.medicinenet.com Published On :: Thu, 18 Aug 2022 00:00:00 PDT Title: Change to Diagnosis of Gestational Diabetes Helped WomenCategory: Health NewsCreated: 8/18/2022 12:00:00 AMLast Editorial Review: 8/18/2022 12:00:00 AM Full Article
ia Cheap, Same-Day Test Could Help Spot Miscarriage Risk By www.medicinenet.com Published On :: Fri, 19 Aug 2022 00:00:00 PDT Title: Cheap, Same-Day Test Could Help Spot Miscarriage RiskCategory: Health NewsCreated: 8/18/2022 12:00:00 AMLast Editorial Review: 8/19/2022 12:00:00 AM Full Article
ia Osteopenia By www.medicinenet.com Published On :: Mon, 15 Aug 2022 00:00:00 PDT Title: OsteopeniaCategory: Diseases and ConditionsCreated: 2/7/2011 12:00:00 AMLast Editorial Review: 8/15/2022 12:00:00 AM Full Article
ia 'Stepped' Approach to Treating Diabetic Eye Disease May Be Best By www.medicinenet.com Published On :: Fri, 15 Jul 2022 00:00:00 PDT Title: 'Stepped' Approach to Treating Diabetic Eye Disease May Be BestCategory: Health NewsCreated: 7/15/2022 12:00:00 AMLast Editorial Review: 7/15/2022 12:00:00 AM Full Article
ia Statins vs. Niacin By www.medicinenet.com Published On :: Tue, 14 Jun 2022 00:00:00 PDT Title: Statins vs. NiacinCategory: MedicationsCreated: 10/6/2017 12:00:00 AMLast Editorial Review: 6/14/2022 12:00:00 AM Full Article
ia California Will Produce Its Own Insulin to Bring Down Prices By www.medicinenet.com Published On :: Fri, 8 Jul 2022 00:00:00 PDT Title: California Will Produce Its Own Insulin to Bring Down PricesCategory: Health NewsCreated: 7/8/2022 12:00:00 AMLast Editorial Review: 7/8/2022 12:00:00 AM Full Article
ia Disability Payments Can Help Keep Veterans With Diabetes Out of the Hospital By www.medicinenet.com Published On :: Fri, 8 Jul 2022 00:00:00 PDT Title: Disability Payments Can Help Keep Veterans With Diabetes Out of the HospitalCategory: Health NewsCreated: 7/8/2022 12:00:00 AMLast Editorial Review: 7/8/2022 12:00:00 AM Full Article
ia Is Brown Rice Safe if You Have Diabetes? By www.medicinenet.com Published On :: Wed, 13 Jul 2022 00:00:00 PDT Title: Is Brown Rice Safe if You Have Diabetes?Category: Health and LivingCreated: 7/13/2022 12:00:00 AMLast Editorial Review: 7/13/2022 12:00:00 AM Full Article
ia Fasting Diet Could Help Folks With Type 2 Diabetes By www.medicinenet.com Published On :: Tue, 26 Jul 2022 00:00:00 PDT Title: Fasting Diet Could Help Folks With Type 2 DiabetesCategory: Health NewsCreated: 7/26/2022 12:00:00 AMLast Editorial Review: 7/26/2022 12:00:00 AM Full Article
ia Mental Health Issues Can Plague Families of Kids With Type 1 Diabetes By www.medicinenet.com Published On :: Fri, 5 Aug 2022 00:00:00 PDT Title: Mental Health Issues Can Plague Families of Kids With Type 1 DiabetesCategory: Health NewsCreated: 8/5/2022 12:00:00 AMLast Editorial Review: 8/5/2022 12:00:00 AM Full Article
ia Blood Protein Might Predict Future Diabetes, Cancer Risk By www.medicinenet.com Published On :: Fri, 5 Aug 2022 00:00:00 PDT Title: Blood Protein Might Predict Future Diabetes, Cancer RiskCategory: Health NewsCreated: 8/5/2022 12:00:00 AMLast Editorial Review: 8/5/2022 12:00:00 AM Full Article
ia Common Diabetes Drug May Contain Traces of Carcinogen By www.medicinenet.com Published On :: Fri, 12 Aug 2022 00:00:00 PDT Title: Common Diabetes Drug May Contain Traces of CarcinogenCategory: Health NewsCreated: 8/12/2022 12:00:00 AMLast Editorial Review: 8/12/2022 12:00:00 AM Full Article
ia Certain Painkillers Raise Heart Failure Risk in People With Type 2 Diabetes By www.medicinenet.com Published On :: Wed, 24 Aug 2022 00:00:00 PDT Title: Certain Painkillers Raise Heart Failure Risk in People With Type 2 DiabetesCategory: Health NewsCreated: 8/24/2022 12:00:00 AMLast Editorial Review: 8/24/2022 12:00:00 AM Full Article
ia Even Chores, Socializing Might Lower Your Odds for Dementia By www.medicinenet.com Published On :: Fri, 29 Jul 2022 00:00:00 PDT Title: Even Chores, Socializing Might Lower Your Odds for DementiaCategory: Health NewsCreated: 7/28/2022 12:00:00 AMLast Editorial Review: 7/29/2022 12:00:00 AM Full Article
ia Lifestyle May Be Key to Helping You Avoid Dementia By www.medicinenet.com Published On :: Fri, 5 Aug 2022 00:00:00 PDT Title: Lifestyle May Be Key to Helping You Avoid DementiaCategory: Health NewsCreated: 8/4/2022 12:00:00 AMLast Editorial Review: 8/5/2022 12:00:00 AM Full Article
ia Rural Americans With Early Alzheimer's Find It Tough to See Specialists By www.medicinenet.com Published On :: Tue, 9 Aug 2022 00:00:00 PDT Title: Rural Americans With Early Alzheimer's Find It Tough to See SpecialistsCategory: Health NewsCreated: 8/9/2022 12:00:00 AMLast Editorial Review: 8/9/2022 12:00:00 AM Full Article
ia Abnormal Upper Heart Chamber May Boost Dementia Risk By www.medicinenet.com Published On :: Wed, 10 Aug 2022 00:00:00 PDT Title: Abnormal Upper Heart Chamber May Boost Dementia RiskCategory: Health NewsCreated: 8/10/2022 12:00:00 AMLast Editorial Review: 8/10/2022 12:00:00 AM Full Article
ia Everyday Activities That Can Cut Your Odds for Dementia By www.medicinenet.com Published On :: Mon, 15 Aug 2022 00:00:00 PDT Title: Everyday Activities That Can Cut Your Odds for DementiaCategory: Health NewsCreated: 8/12/2022 12:00:00 AMLast Editorial Review: 8/15/2022 12:00:00 AM Full Article
ia AHA News: People With Dementia May Be Less Likely to Receive an Advanced Treatment For Stroke By www.medicinenet.com Published On :: Wed, 24 Aug 2022 00:00:00 PDT Title: AHA News: People With Dementia May Be Less Likely to Receive an Advanced Treatment For StrokeCategory: Health NewsCreated: 8/24/2022 12:00:00 AMLast Editorial Review: 8/24/2022 12:00:00 AM Full Article
ia Too Few Psychiatric Beds: Psychiatrists' Group Takes Aim at Ongoing Crisis By www.medicinenet.com Published On :: Thu, 18 Aug 2022 00:00:00 PDT Title: Too Few Psychiatric Beds: Psychiatrists' Group Takes Aim at Ongoing CrisisCategory: Health NewsCreated: 8/17/2022 12:00:00 AMLast Editorial Review: 8/18/2022 12:00:00 AM Full Article
ia Torn ACL (Anterior Cruciate Ligament Tear) By www.medicinenet.com Published On :: Mon, 15 Aug 2022 00:00:00 PDT Title: Torn ACL (Anterior Cruciate Ligament Tear)Category: Diseases and ConditionsCreated: 11/4/2010 12:00:00 AMLast Editorial Review: 8/15/2022 12:00:00 AM Full Article
ia Nerve Block Plus Lidocaine Clears Psoriasis in Small Study By www.medicinenet.com Published On :: Tue, 16 Aug 2022 00:00:00 PDT Title: Nerve Block Plus Lidocaine Clears Psoriasis in Small StudyCategory: Health NewsCreated: 8/15/2022 12:00:00 AMLast Editorial Review: 8/16/2022 12:00:00 AM Full Article
ia How Do I Know if I Have an Ovarian Cyst or Tumor? By www.medicinenet.com Published On :: Thu, 7 Jul 2022 00:00:00 PDT Title: How Do I Know if I Have an Ovarian Cyst or Tumor?Category: Diseases and ConditionsCreated: 7/7/2022 12:00:00 AMLast Editorial Review: 7/7/2022 12:00:00 AM Full Article
ia Vegetarian Women at Higher Odds for Hip Fracture By www.medicinenet.com Published On :: Fri, 12 Aug 2022 00:00:00 PDT Title: Vegetarian Women at Higher Odds for Hip FractureCategory: Health NewsCreated: 8/11/2022 12:00:00 AMLast Editorial Review: 8/12/2022 12:00:00 AM Full Article
ia New Multiple Sclerosis Treatment Shows Promise in Trial By www.medicinenet.com Published On :: Fri, 26 Aug 2022 00:00:00 PDT Title: New Multiple Sclerosis Treatment Shows Promise in TrialCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/26/2022 12:00:00 AM Full Article
ia Is Chlamydia Contagious? By www.medicinenet.com Published On :: Mon, 1 Aug 2022 00:00:00 PDT Title: Is Chlamydia Contagious?Category: Diseases and ConditionsCreated: 5/28/2015 12:00:00 AMLast Editorial Review: 8/1/2022 12:00:00 AM Full Article
ia silver sulfadiazine By www.medicinenet.com Published On :: Tue, 2 Aug 2022 00:00:00 PDT Title: silver sulfadiazineCategory: MedicationsCreated: 8/2/2022 12:00:00 AMLast Editorial Review: 8/2/2022 12:00:00 AM Full Article
ia Being Social May Be Key to 'Sense of Purpose' as You Age By www.medicinenet.com Published On :: Tue, 12 Jul 2022 00:00:00 PDT Title: Being Social May Be Key to 'Sense of Purpose' as You AgeCategory: Health NewsCreated: 7/12/2022 12:00:00 AMLast Editorial Review: 7/12/2022 12:00:00 AM Full Article
ia Looking for Reliable Hay Fever Advice? It's Probably Not on YouTube By www.medicinenet.com Published On :: Tue, 16 Aug 2022 00:00:00 PDT Title: Looking for Reliable Hay Fever Advice? It's Probably Not on YouTubeCategory: Health NewsCreated: 8/16/2022 12:00:00 AMLast Editorial Review: 8/16/2022 12:00:00 AM Full Article
ia SIBO (Small Intestinal Bacterial Overgrowth) By www.medicinenet.com Published On :: Mon, 8 Aug 2022 00:00:00 PDT Title: SIBO (Small Intestinal Bacterial Overgrowth)Category: Diseases and ConditionsCreated: 10/28/2005 12:00:00 AMLast Editorial Review: 8/8/2022 12:00:00 AM Full Article
ia Australia's Current Flu Season Is Tough: Will America's Be the Same? By www.medicinenet.com Published On :: Fri, 5 Aug 2022 00:00:00 PDT Title: Australia's Current Flu Season Is Tough: Will America's Be the Same?Category: Health NewsCreated: 8/4/2022 12:00:00 AMLast Editorial Review: 8/5/2022 12:00:00 AM Full Article
ia damiana By www.medicinenet.com Published On :: Mon, 15 Aug 2022 00:00:00 PDT Title: damianaCategory: MedicationsCreated: 8/15/2022 12:00:00 AMLast Editorial Review: 8/15/2022 12:00:00 AM Full Article
ia Impaired lung function and associated risk factors in children born prematurely: a systematic review and meta-analysis By err.ersjournals.com Published On :: 2024-10-09T00:15:15-07:00 Background Immature lung development and respiratory morbidity place preterm-born children at high risk of long-term pulmonary sequelae. This systematic review and meta-analysis aims to quantify lung function in preterm-born children and identify risk factors for a compromised lung function. Methods We searched MEDLINE, Embase, Cochrane Library, Web of Science and Scopus for relevant studies published on preterm cohorts born since 1990. Studies comparing forced expiratory volume in 1 s (FEV1) in preterm-born children aged ≥5 years to term-born controls or normative data were included. Study quality was assessed using the Newcastle–Ottawa Scale for cohort studies. Standardised mean differences in FEV1 and secondary spirometry outcomes per study were pooled using meta-analysis. The impact of different demographic and neonatal variables on studies’ FEV1 effect sizes was investigated by meta-regression analyses. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Results We identified 42 studies with unique cohorts including 4743 preterm children and 9843 controls. Median gestational age in the studies was 28.0 weeks and age at assessment ranged from 6.7 to 16.7 years. Preterm children had lower FEV1 than controls (–0.58 sd, 95% CI –0.69– –0.47 sd, p<0.001) resulting in a relative risk of 2.9 (95% CI 2.4–3.4) for abnormal outcome, with high certainty of evidence. FEV1 was significantly associated with gestational age, birthweight, bronchopulmonary dysplasia and invasive mechanical ventilation in univariate meta-regression analyses (R2=36–96%). Conclusion This systematic review shows robust evidence of impaired lung function in preterm-born children with a high certainty of evidence. Full Article
ia Antibody-mediated protection against respiratory syncytial virus in children By err.ersjournals.com Published On :: 2024-10-09T00:15:15-07:00 Respiratory syncytial virus (RSV) is a major global pathogen, causing lower respiratory tract disease in at-risk populations including young children. Antibodies form a crucial layer of protection from RSV disease, particularly in immunologically naïve infants. Such antibodies are derived from the mother via transplacental transfer and breast milk, but may be particularly low in high-risk infants such as those born preterm. Maternally derived antibodies can now be supplemented by the administration of anti-RSV monoclonal antibodies, while a rising wave of maternal and paediatric vaccine strategies are approaching. The implementation of these prophylactics may profoundly decrease the healthcare burden of RSV. In this article, we review the role of antibody-mediated immunity in protecting children from RSV. We focus on maternally derived antibodies as the main source of protection against RSV and study factors that influence the scale of this transfer. The role of passive and active prophylactic approaches in protecting infants against RSV are discussed and knowledge gaps in our understanding of antibody-mediated protection against RSV are identified. Full Article
ia Noninvasive diagnostic modalities and prediction models for detecting pulmonary hypertension associated with interstitial lung disease: a narrative review By err.ersjournals.com Published On :: 2024-10-09T00:15:15-07:00 Pulmonary hypertension (PH) is highly prevalent in patients with interstitial lung disease (ILD) and is associated with increased morbidity and mortality. Widely available noninvasive screening tools are warranted to identify patients at risk for PH, especially severe PH, that could be managed at expert centres. This review summarises current evidence on noninvasive diagnostic modalities and prediction models for the timely detection of PH in patients with ILD. It critically evaluates these approaches and discusses future perspectives in the field. A comprehensive literature search was carried out in PubMed and Scopus, identifying 39 articles that fulfilled inclusion criteria. There is currently no single noninvasive test capable of accurately detecting and diagnosing PH in ILD patients. Estimated right ventricular pressure (RVSP) on Doppler echocardiography remains the single most predictive factor of PH, with other indirect echocardiographic markers increasing its diagnostic accuracy. However, RVSP can be difficult to estimate in patients due to suboptimal views from extensive lung disease. The majority of existing composite scores, including variables obtained from chest computed tomography, pulmonary function tests and cardiopulmonary exercise tests, were derived from retrospective studies, whilst lacking validation in external cohorts. Only two available scores, one based on a stepwise echocardiographic approach and the other on functional parameters, predicted the presence of PH with sufficient accuracy and used a validation cohort. Although several methodological limitations prohibit their generalisability, their use may help physicians to detect PH earlier. Further research on the potential of artificial intelligence may guide a more tailored approach, for timely PH diagnosis. Full Article
ia Opioids for the palliation of symptoms in people with serious respiratory illness: a systematic review and meta-analysis By err.ersjournals.com Published On :: 2024-10-09T00:15:15-07:00 Background People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear. Methods We examined the efficacy and safety of opioids for symptom management in people with serious respiratory illness. Embase, MEDLINE and the Cochrane Central Register of Controlled Trials were searched up to 11 July 2022. Reports of randomised controlled trials administering opioids to treat symptoms in people with serious respiratory illness were included. Key exclusion criteria included <80% of participants having a nonmalignant lung disease. Data were extracted regarding study characteristics, outcomes of breathlessness, cough, health-related quality of life (HRQoL) and adverse events. Treatment effects were pooled using a generic inverse variance model with random effects. Risk of bias was assessed using the Cochrane Risk of Bias tool version 1. Results Out of 17 included trials, six were laboratory-based exercise trials (n=70), 10 were home studies measuring breathlessness in daily life (n=788) and one (n=18) was conducted in both settings. Overall certainty of evidence was "very low" to "low". Opioids reduced breathlessness intensity during laboratory exercise testing (standardised mean difference (SMD) –0.37, 95% CI –0.67– –0.07), but not breathlessness measured in daily life (SMD –0.10, 95% CI –0.64–0.44). No effects on HRQoL (SMD –0.42, 95% CI –0.98–0.13) or cough (SMD –1.42, 95% CI –3.99–1.16) were detected. In at-home studies, opioids led to increased frequency of nausea/vomiting (OR 3.32, 95% CI 1.70–6.51), constipation (OR 3.08, 95% CI 1.69–5.61) and drowsiness (OR 1.37, 95% CI 1.01–1.86), with serious adverse events including hospitalisation and death identified. Conclusions Opioids improved exertional breathlessness in laboratory exercise studies, but did not improve breathlessness, cough or HRQoL measured in daily life at home. There were significant adverse events, which may outweigh any benefits. Full Article
ia PWAS Hub for exploring gene-based associations of common complex diseases [RESOURCES] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 PWAS (proteome-wide association study) is an innovative genetic association approach that complements widely used methods like GWAS (genome-wide association study). The PWAS approach involves consecutive phases. Initially, machine learning modeling and probabilistic considerations quantify the impact of genetic variants on protein-coding genes’ biochemical functions. Secondly, for each individual, aggregating the variants per gene determines a gene-damaging score. Finally, standard statistical tests are activated in the case-control setting to yield statistically significant genes per phenotype. The PWAS Hub offers a user-friendly interface for an in-depth exploration of gene–disease associations from the UK Biobank (UKB). Results from PWAS cover 99 common diseases and conditions, each with over 10,000 diagnosed individuals per phenotype. Users can explore genes associated with these diseases, with separate analyses conducted for males and females. For each phenotype, the analyses account for sex-based genetic effects, inheritance modes (dominant and recessive), and the pleiotropic nature of associated genes. The PWAS Hub showcases its usefulness for asthma by navigating through proteomic-genetic analyses. Inspecting PWAS asthma-listed genes (a total of 27) provide insights into the underlying cellular and molecular mechanisms. Comparison of PWAS-statistically significant genes for common diseases to the Open Targets benchmark shows partial but significant overlap in gene associations for most phenotypes. Graphical tools facilitate comparing genetic effects between PWAS and coding GWAS results, aiding in understanding the sex-specific genetic impact on common diseases. This adaptable platform is attractive to clinicians, researchers, and individuals interested in delving into gene–disease associations and sex-specific genetic effects. Full Article
ia Theoretical framework for the difference of two negative binomial distributions and its application in comparative analysis of sequencing data [METHODS] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 High-throughput sequencing (HTS) technologies have been instrumental in investigating biological questions at the bulk and single-cell levels. Comparative analysis of two HTS data sets often relies on testing the statistical significance for the difference of two negative binomial distributions (DOTNB). Although negative binomial distributions are well studied, the theoretical results for DOTNB remain largely unexplored. Here, we derive basic analytical results for DOTNB and examine its asymptotic properties. As a state-of-the-art application of DOTNB, we introduce DEGage, a computational method for detecting differentially expressed genes (DEGs) in scRNA-seq data. DEGage calculates the mean of the sample-wise differences of gene expression levels as the test statistic and determines significant differential expression by computing the P-value with DOTNB. Extensive validation using simulated and real scRNA-seq data sets demonstrates that DEGage outperforms five popular DEG analysis tools: DEGseq2, DEsingle, edgeR, Monocle3, and scDD. DEGage is robust against high dropout levels and exhibits superior sensitivity when applied to balanced and imbalanced data sets, even with small sample sizes. We utilize DEGage to analyze prostate cancer scRNA-seq data sets and identify marker genes for 17 cell types. Furthermore, we apply DEGage to scRNA-seq data sets of mouse neurons with and without fear memory and reveal eight potential memory-related genes overlooked in previous analyses. The theoretical results and supporting software for DOTNB can be widely applied to comparative analyses of dispersed count data in HTS and broad research questions. Full Article
ia Systematic identification of interchromosomal interaction networks supports the existence of specialized RNA factories [METHODS] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 Most studies of genome organization have focused on intrachromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Interchromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework that uses Hi-C data to identify sets of loci that jointly interact in trans. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans-contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands," and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes coregulated by the same trans-acting element (i.e., a transcription or splicing factor) colocalize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same DNA-binding proteins interact with one another in trans, especially those bound by factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA-binding proteins correlates with trans interaction of the encoding loci. We observe that these trans-interacting loci are close to nuclear speckles. These findings support the existence of trans-interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture. Full Article
ia Mutational scanning of CRX classifies clinical variants and reveals biochemical properties of the transcriptional effector domain [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human CRX variants cause degenerative retinopathies, but most are variants of uncertain significance. We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitutions in CRX using a cell-based transcriptional reporter assay, curating a high-confidence list of nearly 2000 variants with altered transcriptional activity. In the structured homeodomain, activity scores closely aligned to a predicted structure and demonstrated position-specific constraints on amino acid substitution. In contrast, the intrinsically disordered transcriptional effector domain displayed a qualitatively different pattern of substitution effects, following compositional constraints without specific residue position requirements in the peptide chain. These compositional constraints were consistent with the acidic exposure model of transcriptional activation. We evaluated the performance of the DMS assay as a clinical variant classification tool using gold-standard classified human variants from ClinVar, identifying pathogenic variants with high specificity and moderate sensitivity. That this performance could be achieved using a synthetic reporter assay in a foreign cell type, even for a highly cell type-specific TF like CRX, suggests that this approach shows promise for DMS of other TFs that function in cell types that are not easily accessible. Together, the results of the CRX DMS identify molecular features of the CRX effector domain and demonstrate utility for integration into the clinical variant classification pipeline. Full Article
ia AGAP duplicons associate with structural diversity at Chromosome 10q11.22 [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 The 10q11.22 chromosomal region is a duplication-rich interval of the human genome and one of the last to be fully assembled. It carries copy number–variable genes associated with intellectual disability, bipolar disorder, and obesity. In this study, we characterized the structural diversity at this locus by analyzing 64 haploid assemblies produced by the Human Pangenome Reference Consortium. We identified 11 alternative haplotypes that differ in the copy number and/or orientation of large genomic segments, ranging from hundreds of kilobase pairs (kbp) to over one megabase pair (Mbp). We uncovered a 2.4 Mbp size difference between the shortest and longest haplotypes. Breakpoint analysis revealed that genomic instability results from nonallelic homologous recombination between segmental duplication (SD) pairs with varying similarity (94.4%–99.6%). Nonetheless, these pairs generally recombine at positions where their identity is higher (>99.6%). Recurrent inversions occur with different breakpoints within the same inverted SD pair. Inversion polymorphisms shuffle the entire SD arrangement, creating new predispositions to copy-number variations. The SD architecture is associated with a catarrhine-specific subgroup of the AGAP gene family, which likely triggered the accumulation of SDs at this locus over the past 25 million years of human evolution. Our results reveal extensive structural diversity and genomic instability at the 10q11.22 locus, and expand the general understanding of the mutational mechanisms behind SD-mediated rearrangements. Full Article