ea Your Salt Shaker May Prove Deadly, Study Finds By www.medicinenet.com Published On :: Tue, 12 Jul 2022 00:00:00 PDT Title: Your Salt Shaker May Prove Deadly, Study FindsCategory: Health NewsCreated: 7/11/2022 12:00:00 AMLast Editorial Review: 7/12/2022 12:00:00 AM Full Article
ea Are High-Tech Blood Pressure Monitors Really Worth It? By www.medicinenet.com Published On :: Tue, 16 Aug 2022 00:00:00 PDT Title: Are High-Tech Blood Pressure Monitors Really Worth It?Category: Health NewsCreated: 8/16/2022 12:00:00 AMLast Editorial Review: 8/16/2022 12:00:00 AM Full Article
ea When Should I Start Cleaning My Baby’s Mouth? By www.medicinenet.com Published On :: Thu, 11 Aug 2022 00:00:00 PDT Title: When Should I Start Cleaning My Baby’s Mouth?Category: Diseases and ConditionsCreated: 11/9/2020 12:00:00 AMLast Editorial Review: 8/11/2022 12:00:00 AM Full Article
ea Health Conditions a Dentist Might Find That Have Nothing to Do With Your Teeth By www.medicinenet.com Published On :: Fri, 12 Aug 2022 00:00:00 PDT Title: Health Conditions a Dentist Might Find That Have Nothing to Do With Your TeethCategory: Health NewsCreated: 8/11/2022 12:00:00 AMLast Editorial Review: 8/12/2022 12:00:00 AM Full Article
ea Moving Away From Opioids to Treat Dental Pain By www.medicinenet.com Published On :: Fri, 19 Aug 2022 00:00:00 PDT Title: Moving Away From Opioids to Treat Dental PainCategory: Health NewsCreated: 8/19/2022 12:00:00 AMLast Editorial Review: 8/19/2022 12:00:00 AM Full Article
ea Why Is My Period More Heavy Than Usual? By www.medicinenet.com Published On :: Tue, 28 Jun 2022 00:00:00 PDT Title: Why Is My Period More Heavy Than Usual?Category: Diseases and ConditionsCreated: 6/28/2022 12:00:00 AMLast Editorial Review: 6/28/2022 12:00:00 AM Full Article
ea Self-Employed Women Are Often Healthier: Study By www.medicinenet.com Published On :: Mon, 8 Aug 2022 00:00:00 PDT Title: Self-Employed Women Are Often Healthier: StudyCategory: Health NewsCreated: 8/8/2022 12:00:00 AMLast Editorial Review: 8/8/2022 12:00:00 AM Full Article
ea There's More MS in Northern Countries. Now, Researchers Find New Reason Why By www.medicinenet.com Published On :: Thu, 25 Aug 2022 00:00:00 PDT Title: There's More MS in Northern Countries. Now, Researchers Find New Reason WhyCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/25/2022 12:00:00 AM Full Article
ea 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
ea Yeast infections vs. STDs in Men and Women By www.medicinenet.com Published On :: Fri, 29 Jul 2022 00:00:00 PDT Title: Yeast infections vs. STDs in Men and WomenCategory: Diseases and ConditionsCreated: 1/8/2020 12:00:00 AMLast Editorial Review: 7/29/2022 12:00:00 AM Full Article
ea goldenseal By www.medicinenet.com Published On :: Thu, 18 Aug 2022 00:00:00 PDT Title: goldensealCategory: MedicationsCreated: 8/18/2022 12:00:00 AMLast Editorial Review: 8/18/2022 12:00:00 AM Full Article
ea When Hospital Patient & Doctor Speak Same Language, Outcomes Improve By www.medicinenet.com Published On :: Mon, 11 Jul 2022 00:00:00 PDT Title: When Hospital Patient & Doctor Speak Same Language, Outcomes ImproveCategory: Health NewsCreated: 7/11/2022 12:00:00 AMLast Editorial Review: 7/11/2022 12:00:00 AM Full Article
ea Helping Older Loved Ones in a Heat Wave By www.medicinenet.com Published On :: Mon, 25 Jul 2022 00:00:00 PDT Title: Helping Older Loved Ones in a Heat WaveCategory: Health NewsCreated: 7/25/2022 12:00:00 AMLast Editorial Review: 7/25/2022 12:00:00 AM Full Article
ea AHA News: How You Feel About Aging Could Affect Health. Here's How to Keep the Right Attitude. By www.medicinenet.com Published On :: Fri, 19 Aug 2022 00:00:00 PDT Title: AHA News: How You Feel About Aging Could Affect Health. Here's How to Keep the Right Attitude.Category: Health NewsCreated: 8/19/2022 12:00:00 AMLast Editorial Review: 8/19/2022 12:00:00 AM Full Article
ea You Could Live 9 Years Longer in Hawaii Than in Mississippi, New Data Shows By www.medicinenet.com Published On :: Tue, 23 Aug 2022 00:00:00 PDT Title: You Could Live 9 Years Longer in Hawaii Than in Mississippi, New Data ShowsCategory: Health NewsCreated: 8/23/2022 12:00:00 AMLast Editorial Review: 8/23/2022 12:00:00 AM Full Article
ea Steps to Long Life: Short Walk Each Day Helps Folks Over 85 By www.medicinenet.com Published On :: Thu, 25 Aug 2022 00:00:00 PDT Title: Steps to Long Life: Short Walk Each Day Helps Folks Over 85Category: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/25/2022 12:00:00 AM Full Article
ea Get Moving! Any Sports Can Lower Seniors' Odds of Early Death By www.medicinenet.com Published On :: Fri, 26 Aug 2022 00:00:00 PDT Title: Get Moving! Any Sports Can Lower Seniors' Odds of Early DeathCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/26/2022 12:00:00 AM Full Article
ea Health Care Plans Keep Allergy Rescue Injectors Pricey for Some By www.medicinenet.com Published On :: Fri, 15 Jul 2022 00:00:00 PDT Title: Health Care Plans Keep Allergy Rescue Injectors Pricey for SomeCategory: Health NewsCreated: 7/15/2022 12:00:00 AMLast Editorial Review: 7/15/2022 12:00:00 AM Full Article
ea Hepatitis C Infection Can Kill, But Less Than a Third of Patients Get Treatment By www.medicinenet.com Published On :: Wed, 10 Aug 2022 00:00:00 PDT Title: Hepatitis C Infection Can Kill, But Less Than a Third of Patients Get TreatmentCategory: Health NewsCreated: 8/10/2022 12:00:00 AMLast Editorial Review: 8/10/2022 12:00:00 AM Full Article
ea What Is the Main Cause of Leaky Gut, and How Do You Fix It? By www.medicinenet.com Published On :: Tue, 23 Aug 2022 00:00:00 PDT Title: What Is the Main Cause of Leaky Gut, and How Do You Fix It?Category: Diseases and ConditionsCreated: 8/23/2022 12:00:00 AMLast Editorial Review: 8/23/2022 12:00:00 AM Full Article
ea Cold, Flu, Allergy Treatments By www.medicinenet.com Published On :: Fri, 15 Jul 2022 00:00:00 PDT Title: Cold, Flu, Allergy TreatmentsCategory: Diseases and ConditionsCreated: 9/24/1999 12:00:00 AMLast Editorial Review: 7/15/2022 12:00:00 AM Full Article
ea 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
ea How Do I Increase Serotonin? By www.medicinenet.com Published On :: Tue, 5 Jul 2022 00:00:00 PDT Title: How Do I Increase Serotonin?Category: Diseases and ConditionsCreated: 5/24/2021 12:00:00 AMLast Editorial Review: 7/5/2022 12:00:00 AM Full Article
ea What Are 4 Symptoms of Seasonal Affective Disorder? By www.medicinenet.com Published On :: Wed, 6 Jul 2022 00:00:00 PDT Title: What Are 4 Symptoms of Seasonal Affective Disorder?Category: Diseases and ConditionsCreated: 12/10/2021 12:00:00 AMLast Editorial Review: 7/6/2022 12:00:00 AM Full Article
ea How Childhood Abuse Can Haunt the Senior Years By www.medicinenet.com Published On :: Fri, 8 Jul 2022 00:00:00 PDT Title: How Childhood Abuse Can Haunt the Senior YearsCategory: Health NewsCreated: 7/8/2022 12:00:00 AMLast Editorial Review: 7/8/2022 12:00:00 AM Full Article
ea Gardening Can Blossom Into Better Mental Health By www.medicinenet.com Published On :: Mon, 11 Jul 2022 00:00:00 PDT Title: Gardening Can Blossom Into Better Mental HealthCategory: Health NewsCreated: 7/11/2022 12:00:00 AMLast Editorial Review: 7/11/2022 12:00:00 AM Full Article
ea Most Post-Stroke Depression Still Goes Untreated By www.medicinenet.com Published On :: Mon, 25 Jul 2022 00:00:00 PDT Title: Most Post-Stroke Depression Still Goes UntreatedCategory: Health NewsCreated: 7/25/2022 12:00:00 AMLast Editorial Review: 7/25/2022 12:00:00 AM Full Article
ea Treating central sleep apnoea in heart failure: progressing one step at a time By err.ersjournals.com Published On :: 2024-10-30T01:30:15-07:00 Extract We read with great interest the correspondence by T. Bitter and co-workers in the European Respiratory Review, about our recently published review entitled "Central sleep apnoea: not just one phenotype" [1]. We first want to express our gratefulness to the authors for their support and appreciation of our work, particularly regarding the urgent need for an increasingly differentiated view of central sleep apnoea (CSA) in the context of precision medicine. Full Article
ea Treating central sleep apnoea in heart failure: is positive airway pressure and adaptive servo-ventilation in particular the gold standard? By err.ersjournals.com Published On :: 2024-10-30T01:30:15-07:00 Extract We read with great interest the review article by Randerath et al. [1] recently published in the European Respiratory Review. We would like to congratulate the authors on this clearly structured review, which emphasises the urgent need for an increasingly differentiated view of central sleep apnoea (CSA) in the context of precision medicine. Full Article
ea The deadly dance of alveolar macrophages and influenza virus By err.ersjournals.com Published On :: 2024-10-30T01:30:15-07:00 Influenza A virus (IAV) is one of the leading causes of respiratory infections. The lack of efficient anti-influenza therapeutics requires a better understanding of how IAV interacts with host cells. Alveolar macrophages are tissue-specific macrophages that play a critical role in lung innate immunity and homeostasis, yet their role during influenza infection remains unclear. First, our review highlights an active IAV replication within alveolar macrophages, despite an abortive viral cycle. Such infection leads to persistent alveolar macrophage inflammation and diminished phagocytic function, alongside direct mitochondrial damage and indirect metabolic shifts in the alveolar micro-environment. We also discuss the "macrophage disappearance reaction", which is a drastic reduction of the alveolar macrophage population observed after influenza infection in mice but debated in humans, with unclear underlying mechanisms. Furthermore, we explore the dual nature of alveolar macrophage responses to IAV infection, questioning whether they are deleterious or protective for the host. While IAV may exploit immuno-evasion strategies and induce alveolar macrophage alteration or depletion, this could potentially reduce excessive inflammation and allow for the replacement of more effective cells. Despite these insights, the pathophysiological role of alveolar macrophages during IAV infection in humans remains understudied, urging further exploration to unravel their precise contributions to disease progression and resolution. Full Article
ea 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
ea Breathing techniques to reduce symptoms in people with serious respiratory illness: a systematic review By err.ersjournals.com Published On :: 2024-10-30T01:30:15-07:00 Background In adults with serious respiratory illness, breathlessness is prevalent and associated with reduced health-related quality of life. The aim of this review was to assess the impact of breathing techniques on breathlessness in adults with serious respiratory illness. Methods Electronic databases were searched to identify randomised controlled trials testing breathing techniques (techniques that aim to alter the respiratory pattern, excluding respiratory muscle training) in people with serious respiratory illness. The primary outcome was breathlessness and secondary outcomes were health-related quality of life and adverse events. Two authors independently screened for inclusion, evaluated risk of bias and extracted data. Results 73 randomised controlled trials were included with 5479 participants, most with COPD or asthma. Breathing exercises (pursed lip and/or diaphragmatic breathing) reduced breathlessness measured by the modified Medical Research Council scale compared to usual care (mean difference (MD) –0.40 points, 95% CI –0.70– –0.11, eight studies, n=323), although the effect did not exceed the minimal important difference. Yoga breathing also improved modified Medical Research Council score compared to usual care (MD –1.05 points, 95% CI –2.45–0.35, three studies, n=175). Breathing techniques consistently improved health-related quality of life in people with COPD and asthma on multiple health-related quality of life measures in comparison to usual care, with effects that generally exceeded the minimal important difference. No adverse events related to breathing techniques were reported. Conclusion Breathing techniques may improve breathlessness, and consistently improve health-related quality of life, in people with serious respiratory illness. These findings support the use of breathing exercises in the care of people with serious respiratory illness. Full Article
ea Dynamic dysregulation of retrotransposons in neurodegenerative diseases at the single-cell level [RESOURCES] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 Retrotransposable elements (RTEs) are common mobile genetic elements comprising ~42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. Machine learning algorithms for predicting cell disease stage using a combination of RTE and gene expression features suggests dynamic regulation of RTEs in AD. Furthermore, we construct a single-cell atlas of retrotransposable elements in neurodegenerative disease (scARE) using these data sets and features. scARE has six feature analysis modules to explore RTE dynamics in a user-defined condition. To our knowledge, scARE represents the first systematic investigation of RTE dynamics at the single-cell level within the context of neurodegenerative diseases. Full Article
ea 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
ea Seamless, rapid, and accurate analyses of outbreak genomic data using split k-mer analysis [METHODS] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 Sequence variation observed in populations of pathogens can be used for important public health and evolutionary genomic analyses, especially outbreak analysis and transmission reconstruction. Identifying this variation is typically achieved by aligning sequence reads to a reference genome, but this approach is susceptible to reference biases and requires careful filtering of called genotypes. There is a need for tools that can process this growing volume of bacterial genome data, providing rapid results, but that remain simple so they can be used without highly trained bioinformaticians, expensive data analysis, and long-term storage and processing of large files. Here we describe split k-mer analysis (SKA2), a method that supports both reference-free and reference-based mapping to quickly and accurately genotype populations of bacteria using sequencing reads or genome assemblies. SKA2 is highly accurate for closely related samples, and in outbreak simulations, we show superior variant recall compared with reference-based methods, with no false positives. SKA2 can also accurately map variants to a reference and be used with recombination detection methods to rapidly reconstruct vertical evolutionary history. SKA2 is many times faster than comparable methods and can be used to add new genomes to an existing call set, allowing sequential use without the need to reanalyze entire collections. With an inherent absence of reference bias, high accuracy, and a robust implementation, SKA2 has the potential to become the tool of choice for genotyping bacteria. SKA2 is implemented in Rust and is freely available as open-source software. Full Article
ea Contrasting and combining transcriptome complexity captured by short and long RNA sequencing reads [METHODS] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 Mapping transcriptomic variations using either short- or long-read RNA sequencing is a staple of genomic research. Long reads are able to capture entire isoforms and overcome repetitive regions, whereas short reads still provide improved coverage and error rates. Yet, open questions remain, such as how to quantitatively compare the technologies, can we combine them, and what is the benefit of such a combined view? We tackle these questions by first creating a pipeline to assess matched long- and short-read data using a variety of transcriptome statistics. We find that across data sets, algorithms, and technologies, matched short-read data detects ~30% more splice junctions, such that ~10%–30% of the splice junctions included at ≥20% by short reads are missed by long reads. In contrast, long reads detect many more intron-retention events and can detect full isoforms, pointing to the benefit of combining the technologies. We introduce MAJIQ-L, an extension of the MAJIQ software, to enable a unified view of transcriptome variations from both technologies and demonstrate its benefits. Our software can be used to assess any future long-read technology or algorithm and can be combined with short-read data for improved transcriptome analysis. Full Article
ea Complete genomes of Asgard archaea reveal diverse integrated and mobile genetic elements [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 Asgard archaea are of great interest as the progenitors of Eukaryotes, but little is known about the mobile genetic elements (MGEs) that may shape their ongoing evolution. Here, we describe MGEs that replicate in Atabeyarchaeia, a wetland Asgard archaea lineage represented by two complete genomes. We used soil depth–resolved population metagenomic data sets to track 18 MGEs for which genome structures were defined and precise chromosome integration sites could be identified for confident host linkage. Additionally, we identified a complete 20.67 kbp circular plasmid and two family-level groups of viruses linked to Atabeyarchaeia, via CRISPR spacer targeting. Closely related 40 kbp viruses possess a hypervariable genomic region encoding combinations of specific genes for small cysteine-rich proteins structurally similar to restriction-homing endonucleases. One 10.9 kbp integrative conjugative element (ICE) integrates genomically into the Atabeyarchaeum deiterrae-1 chromosome and has a 2.5 kbp circularizable element integrated within it. The 10.9 kbp ICE encodes an expressed Type IIG restriction-modification system with a sequence specificity matching an active methylation motif identified by Pacific Biosciences (PacBio) high-accuracy long-read (HiFi) metagenomic sequencing. Restriction-modification of Atabeyarchaeia differs from that of another coexisting Asgard archaea, Freyarchaeia, which has few identified MGEs but possesses diverse defense mechanisms, including DISARM and Hachiman, not found in Atabeyarchaeia. Overall, defense systems and methylation mechanisms of Asgard archaea likely modulate their interactions with MGEs, and integration/excision and copy number variation of MGEs in turn enable host genetic versatility. Full Article
ea Global characterization of somatic mutations and DNA methylation changes during vegetative propagation in strawberries [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 Somatic mutations arise and accumulate during tissue culture and vegetative propagation, potentially affecting various traits in horticultural crops, but their characteristics are still unclear. Here, somatic mutations in regenerated woodland strawberry derived from tissue culture of shoot tips under different conditions and 12 cultivated strawberry individuals are analyzed by whole genome sequencing. The mutation frequency of single nucleotide variants is significantly increased with increased hormone levels or prolonged culture time in the range of 3.3 x 10–8–3.0 x 10–6 mutations per site. CG methylation shows a stable reduction (0.71%–8.03%) in regenerated plants, and hypoCG-DMRs are more heritable after sexual reproduction. A high-quality haplotype-resolved genome is assembled for the strawberry cultivar "Beni hoppe." The 12 "Beni hoppe" individuals randomly selected from different locations show 4731–6005 mutations relative to the reference genome, and the mutation frequency varies among the subgenomes. Our study has systematically characterized the genetic and epigenetic variants in regenerated woodland strawberry plants and different individuals of the same strawberry cultivar, providing an accurate assessment of somatic mutations at the genomic scale and nucleotide resolution in plants. Full Article
ea Evolutionary dynamics of polyadenylation signals and their recognition strategies in protists [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 The poly(A) signal, together with auxiliary elements, directs cleavage of a pre-mRNA and thus determines the 3' end of the mature transcript. In many species, including humans, the poly(A) signal is an AAUAAA hexamer, but we recently found that the deeply branching eukaryote Giardia lamblia uses a distinct hexamer (AGURAA) and lacks any known auxiliary elements. Our discovery prompted us to explore the evolutionary dynamics of poly(A) signals and auxiliary elements in the eukaryotic kingdom. We use direct RNA sequencing to determine poly(A) signals for four protists within the Metamonada clade (which also contains G. lamblia) and two outgroup protists. These experiments reveal that the AAUAAA hexamer serves as the poly(A) signal in at least four different eukaryotic clades, indicating that it is likely the ancestral signal, whereas the unusual Giardia version is derived. We find that the use and relative strengths of auxiliary elements are also plastic; in fact, within Metamonada, species like G. lamblia make use of a previously unrecognized auxiliary element where nucleotides flanking the poly(A) signal itself specify genuine cleavage sites. Thus, despite the fundamental nature of pre-mRNA cleavage for the expression of all protein-coding genes, the motifs controlling this process are dynamic on evolutionary timescales, providing motivation for future biochemical and structural studies as well as new therapeutic angles to target eukaryotic pathogens. Full Article
ea De novo genome assemblies of two cryptodiran turtles with ZZ/ZW and XX/XY sex chromosomes provide insights into patterns of genome reshuffling and uncover novel 3D genome folding in amniotes [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 Understanding the evolution of chromatin conformation among species is fundamental to elucidate the architecture and plasticity of genomes. Nonrandom interactions of linearly distant loci regulate gene function in species-specific patterns, affecting genome function, evolution, and, ultimately, speciation. Yet, data from nonmodel organisms are scarce. To capture the macroevolutionary diversity of vertebrate chromatin conformation, here we generate de novo genome assemblies for two cryptodiran (hidden-neck) turtles via Illumina sequencing, chromosome conformation capture, and RNA-seq: Apalone spinifera (ZZ/ZW, 2n = 66) and Staurotypus triporcatus (XX/XY, 2n = 54). We detected differences in the three-dimensional (3D) chromatin structure in turtles compared to other amniotes beyond the fusion/fission events detected in the linear genomes. Namely, whole-genome comparisons revealed distinct trends of chromosome rearrangements in turtles: (1) a low rate of genome reshuffling in Apalone (Trionychidae) whose karyotype is highly conserved when compared to chicken (likely ancestral for turtles), and (2) a moderate rate of fusions/fissions in Staurotypus (Kinosternidae) and Trachemys scripta (Emydidae). Furthermore, we identified a chromosome folding pattern that enables "centromere–telomere interactions" previously undetected in turtles. The combined turtle pattern of "centromere–telomere interactions" (discovered here) plus "centromere clustering" (previously reported in sauropsids) is novel for amniotes and it counters previous hypotheses about amniote 3D chromatin structure. We hypothesize that the divergent pattern found in turtles originated from an amniote ancestral state defined by a nuclear configuration with extensive associations among microchromosomes that were preserved upon the reshuffling of the linear genome. Full Article
ea 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
ea Evidence for compensatory evolution within pleiotropic regulatory elements [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is owing to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs. Full Article
ea Chromatin interaction maps identify oncogenic targets of enhancer duplications in cancer [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 As a major type of structural variants, tandem duplication plays a critical role in tumorigenesis by increasing oncogene dosage. Recent work has revealed that noncoding enhancers are also affected by duplications leading to the activation of oncogenes that are inside or outside of the duplicated regions. However, the prevalence of enhancer duplication and the identity of their target genes remains largely unknown in the cancer genome. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identify 881 duplication hotspots in 13 major cancer types, most of which do not contain protein-coding genes. We show that the hotspots are enriched with distal enhancer elements and are highly lineage-specific. We develop a HiChIP-based methodology that navigates enhancer–promoter contact maps to prioritize the target genes for the duplication hotspots harboring enhancer elements. The methodology identifies many novel enhancer duplication events activating oncogenes such as ESR1, FOXA1, GATA3, GATA6, TP63, and VEGFA, as well as potentially novel oncogenes such as GRHL2, IRF2BP2, and CREB3L1. In particular, we identify a duplication hotspot on Chromosome 10p15 harboring a cluster of enhancers, which skips over two genes, through a long-range chromatin interaction, to activate an oncogenic isoform of the NET1 gene to promote migration of gastric cancer cells. Focusing on tandem duplications, our study substantially extends the catalog of noncoding driver alterations in multiple cancer types, revealing attractive targets for functional characterization and therapeutic intervention. Full Article
ea Targeted and complete genomic sequencing of the major histocompatibility complex in haplotypic form of individual heterozygous samples [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 The human major histocompatibility complex (MHC) is a ~4 Mb genomic segment on Chromosome 6 that plays a pivotal role in the immune response. Despite its importance in various traits and diseases, its complex nature makes it challenging to accurately characterize on a routine basis. We present a novel approach allowing targeted sequencing and de novo haplotypic assembly of the MHC region in heterozygous samples, using long-read sequencing technologies. Our approach is validated using two reference samples, two family trios, and an African-American sample. We achieved excellent coverage (96.6%–99.9% with at least 30x depth) and high accuracy (99.89%–99.99%) for the different haplotypes. This methodology offers a reliable and cost-effective method for sequencing and fully characterizing the MHC without the need for whole-genome sequencing, facilitating broader studies on this important genomic segment and having significant implications in immunology, genetics, and medicine. Full Article
ea 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
ea The Priority Updates from the Research Literature (PURLs) Methodology By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Full Article
ea Only One Quarter of Family Physicians Are Very Satisfied with Their Electronic Health Records Platform By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Two decades into the era of Electronic Health Records (EHRs), the promise of streamlining clinical care, reducing burden, and improving patient outcomes has yet to be realized. A cross-sectional family physician census conducted by the American Board of Family Medicine in 2022 and 2023 included self-reported physician EHR satisfaction. Of the nearly 10,000 responding family physicians, only one-in-four (26.2%) report being very satisfied and one-in-three (33.8%) were not satisfied. These low levels of satisfaction point to the need for greater transparency in the marketplace and pressure to increase user-centric EHR design. Full Article
ea Potential Drawbacks of Noninvasive Diagnostic Methods for Nonalcoholic Fatty Liver Disease By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 The rising obesity epidemic is a phenomenon that has gained increasing attention from health providers and health policy makers. This led to recognition of nonalcoholic fatty liver disease (MASLD). The standard for its assessment has been histologic, which is neither practical nor acceptable by patients. Subsequently, a number of noninvasive assessment methods have been developed. However, despite ease of implementation, their confounding variables do hinder their accuracy. Nonetheless, the development of the liver stiffness measurement (LSM) and incorporation of other biological parameters has minimized but not eliminated the need for liver biopsy. Imaging methods are useful in evaluation, estimation, and following the progression of steatosis and fibrosis with particular attention to controlled attenuation parameter (CAP) and MRI–Proton Density Fat Fraction (MRI-PDFF). The choices for the family physician are broad and rely on tests’ availability, cost, and patient acceptance. Great efforts have been undertaken to produce more robust and novel noninvasive markers that indicate fibrinogenesis directly in an implementable and cost-effective way. Full Article
ea Headache Treatment Options By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Family medicine physicians often see headache as the chief complaint when meeting patients within their practice. The goal is to try different treatment modalities without having to send the patient to a specialist. Headaches affect different individuals during their lifetime. Before any treatment begins, it is best that one rules out possible causes of the headache, for example, drug interactions or structural cerebrum conditions. Nonpharmacological treatment is recommended first before attempting a stepwise approach to cost-effective pharmacological treatment options. Pharmacological treatment options should include preventive and on-demand options. A family physician has all the resources to assist patients with different types of headaches. Full Article
ea Assessing Patient Readiness for Hospital Discharge, Discharge Communication, and Transitional Care Management By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Background: Discharge communication between hospitalists and primary care clinicians is essential to improve care coordination, minimize adverse events, and decrease unplanned health services use. Health-related social needs are key drivers of health, and hospitalists and primary care clinicians value communicating social needs at discharge. Objective: To 1) characterize the current state of discharge communications between an academic medical center hospital and primary care clinicians at associated clinics; 2) seek feedback about the potential usefulness of discharge readiness information to primary care clinicians. Design: Exploratory, convergent mixed methods. Participants: Primary care clinicians from Family Medicine and General Internal Medicine of an academic medical center in the US Intermountain West. Approach: Literature-informed REDCap survey. Semistructured interview guide developed with key informants, grounded in current literature. Survey data were descriptively summarized; interview data were deductively and inductively coded, organized by topics. Results: Two key topics emerged: 1) discharge communication, with interrelated topics of transitional care management and follow-up appointment challenges, and recommendations for improving discharge communication; and 2) usefulness of the discharge readiness information, included interrelated topics related to lack of shared understanding about roles and responsibilities across settings and ethical concerns related to identifying problems that may not have solutions. Conclusions: While reiterating perennial discharge communication and transitional care management challenges, this study reveals new evidence about how these issues are interrelated with assessing and responding to patients’ lack of readiness for discharge and unmet social needs during care transitions. Primary care clinicians had mixed views on the usefulness of discharge readiness information. We offer recommendations for improving discharge communication and transitional care management (TCM) processes, which may be applicable in other care settings. Full Article