tbuckley/cabot-search huggingface dataset:
Landscape of transcription termination in Arabidopsis revealed by single-molecule nascent RNA sequencing
Authors: Weipeng Mo, Bo Liu, Hong Zhang, Xianhao Jin, Dongdong Lu, Yiming Yu, Yuelin Liu, Jinbu Jia, Yanping Long, Xian Deng, Xiaofeng Cao, Hongwei Guo, Jixian Zhai
Journal: Genome biology (2021)

Abstract Background The dynamic process of transcription termination produces transient RNA intermediates that are difficult to distinguish from each other via short-read sequencing methods. Results Here, we use single-molecule nascent RNA sequencing to characterize the various forms of transient RNAs during termination at genome-wide scale in wildtype Arabidopsis and in atxrn3 , fpa , and met1 mutants. Our data reveal a wide range of termination windows among genes, ranging from ~ 50 nt to over 1000 nt. We also observe efficient termination before downstream tRNA genes, suggesting that chromatin structure around the promoter region of tRNA genes may block pol II elongation. 5′ Cleaved readthrough transcription in atxrn3 with delayed termination can run into downstream genes to produce normally spliced and polyadenylated mRNAs in the absence of their own transcription initiation. Consistent with previous reports, we also observe long chimeric transcripts with cryptic splicing in fpa mutant; but loss of CG DNA methylation has no obvious impact on termination in the met1 mutant. Conclusions Our method is applicable to establish a comprehensive termination landscape in a broad range of species.
Abstract 10464: Mental Health Conditions Are Associated with Underuse of Oral Anticoagulation Therapy in Patients with Atrial Fibrillation: The FinACAF Study
Authors: Jussi Jaakkola, Konsta Teppo, Juhani Airaksinen, Fausto Biancari, Jukka Putaala, Olli Halminen, Jari Haukka, Juha Hartikainen, Janne Kinnunen, Paula Tiili, Miika Linna, Pirjo Mustonen, Mika Lehto
Journal: Circulation (2021)

Introduction: Little is known about the effects of mental health conditions (MHC) on the utilization of oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF). We assessed the hypothesis that MHCs are associated with a lower rate of OAC initiation in patients with incident AF. Methods: The FinACAF registry included all 239 756 patients with incident AF during 2007-2018 in Finland identified from national registries covering all levels of care as well as their drug purchases. The main exposure was any MHC (previous diagnosis of depression, bipolar disorder, anxiety disorder or schizophrenia or fulfilled prescription of psychiatric medication within preceding year from first AF diagnosis) and the outcome OAC initiation (first fulfilled OAC prescription after AF diagnosis). Results: The patients’ mean age was 72.6 years (SD 13.2), 49.7% were female and 95.0% had CHA 2 DS 2 -VASc score ≥1. The prevalence of any MHC was 19.9%. A lower rate of OAC initiation was observed in patients with any MCH than in those without MHC (64.9% vs. 73.1%, p&lt;0.001) during the entire follow-up. Any MHC was associated with lower cumulative incidence of OAC initiation (adjusted subdistribution hazard ratio (aSHR) 0.783; 95% CI 0.774-0.794, Figure) during the entire follow-up, as were depression (aSHR 0.833; 95% CI 0.813-0.852), bipolar disorder (aSHR 0.807; 95% CI 0.778-0.838), anxiety disorder (aSHR 0.816; 95% CI 0.758-0.878) and schizophrenia (aSHR 0.743; 95% CI 0.698-0.792) individually. By 2018, 89.9% of OAC initiations were with a non-vitamin K antagonist oral anticoagulant (NOAC) in patients with any MHC and 92.4% in patients with no MHC. Any MHC remained associated with impaired cumulative incidence of OAC initiation also in the NOAC-era during 2015-2018 (aSHR 0.821; 95% CI 0.805-0.837). Conclusions: MHCs are common among AF patients, and they are associated with a lower rate of OAC initiation even during the NOAC-era.
Abstract 10603: Risk Factors for Development of Advanced Heart Failure: A Population-Based Study
Authors: Anna Subramaniam, Susan Weston, Jill Killian, Philip Schulte, Veronique L Roger, Margaret M Redfield, Saul Blecker, Shannon M Dunlay
Journal: Circulation (2021)

Introduction: Some patients with heart failure (HF) will go on to develop advanced HF, characterized by severe HF symptoms despite attempts to optimize medical therapy. Our understanding of advanced HF at a population level remains limited. The goals of this study were to determine the risk of developing advanced HF in patients with newly diagnosed HF, identify risk factors for developing advanced HF, and evaluate the impact of advanced HF on outcomes. Methods: This was a population-based, retrospective cohort study of Olmsted County, Minnesota residents with a new clinical diagnosis of HF between 2007-2017. The primary outcome was development of advanced HF, defined using the 2018 European Society of Cardiology Criteria. Risk factors for development of advanced HF from the time of incident HF diagnosis were examined using cause-specific Cox proportional hazard regression models. The associations of development of advanced HF with risks of hospitalization and mortality were examined using Andersen-Gill and Cox models, respectively, with advanced HF treated as a time dependent covariate. Results: There were 4597 residents with incident HF from 2007 to 2017. The cumulative incidence of advanced HF was 6.0%, 9.1%, and 11.5% at 2, 4, and 6 years after incident HF diagnosis. Characteristics independently associated with development of advanced HF included older age, male sex, diabetes, chronic obstructive pulmonary disease, peripheral vascular disease, lower serum sodium, worse right ventricular function, left atrial enlargement, higher estimated filling pressures, and higher right ventricular systolic pressure (p&lt;0.05 for each). Development of advanced HF was associated with increased risks of all-cause hospitalization (adjusted HR 3.00; 95% CI 2.65-3.41, p&lt;0.001), HF hospitalization (HR 10.24, 95% CI 8.67-12.10), all-cause mortality (HR 5.00, 95% CI 4.46-5.59, p&lt;0.001), and cardiovascular mortality (HR 7.84, 95% CI 6.74-9.12). Conclusions: In this population-based study, clinical, laboratory and echocardiographic characteristics at the time of incident HF diagnosis were associated with future risk of advanced HF. Development of advanced HF was associated with markedly increased morbidity and mortality.
Apart, together: reflections from the Trends editorial team on the COVID-19 pandemic
Journal: Trends in Neurosciences (2021)

December 2021 marks approximately 2 years since the early reports of a respiratory virus outbreak (as described at the time), later named COVID-19. Few could have envisioned what would transpire over the coming months. None can accurately predict how things will unfold in the years to come. The pandemic continues, diminished in some places, unabated in others, and periodically re-emerging throughout. Although the future remains uncertain, we have chosen at the Trends portfolio of journals to use this opportunity to reflect on some of the indelible aspects of this difficult epoch and our hopes for the future.
Gut microbiota: a key regulator of ageing-associated atrial fibrillation?
Authors: Na Li, David J Durgan, Xander H T Wehrens
Journal: Cardiovascular Research (2021)

Changes in the composition of the gut microbiota have been linked to various disorders including obesity, hypertension, and chronic kidney disease. Interestingly, aging together with the abovementioned conditions are risk factors for atrial fibrillation. The gut microbiota interacts with the host through various pathways including those that affect cardiac metabolism, inflammatory responses, and fibrogenesis. The paper by Zhang et al. in this issue of Cardiovascular Research reveals that age-associated gut microbiota dysbiosis causes elevated lipopolysaccharide levels and impaired glucose tolerance, which in turn promotes AF development. In this commentary, we will briefly discuss potential gut microbiota-derived signals that may underlie age-dependent AF development.
Cytogenetic Monitoring of Farmers Exposed to Pesticides in Colombia
Authors: Luz Stella Hoyos, Silvio Carvajal, Lila Solano, Janet Rodriguez, Lourdes Orozco, Yanneth Lopez, William W. Au
Journal: Environmental Health Perspectives (1996)

We have monitored 30 pesticide-exposed workers and 30 matched controls for expression of chromosome aberrations (CA) and sister chromatid exchanges (SCE) in their lymphocytes.Peripheral blood cultures were set up within 3 hr after the collection of samples, and four cultures were set up from each donor.For CA analysis, 100 complete metaphase cells from each donor were evaluated.For the SCE assay, 50 complete metaphase cells from each donor were analyzed.The CA and SCE data were analyzed for differences between the two groups using the x2 and the Student's t-test, respectively.From the CA analysis it was obvious that the overwhelming majority of aberrations were chromatid breaks and isochromatid breaks; therefore, only these data are presented and used for statistical analysis.Isochromatid breaks were counted as two breaks each and chromatid breaks as one in calculating the total chromatid break frequencies.Statistical evaluation of the data indicates that there is no significant difference (p> 0.05; X2 test) between the exposed and the nonexposed groups based on chromatid breaks per 100 cells (1.2 ± 0.3 and 1.5 ±0.2, respectively) and total chromatid breaks per 100 cells (1.7 ±0.3 and 2.1 ± 0.2, respectively).No significant difference between the two groups (p>0.05,Student's t-test) was observed with SCE frequencies (5.0 ± 1.1 and 4.8 ± 0.9, respectively).Linear regression analysis indicates that the data were not influenced by age, cigarette smoking, or alcohol consumption.It is assuring that the exposure conditions among these Indian farmers have not caused detectable increases of chromosome damage using standard assays; this suggests the lack of serious long-term health problems.However, periodic monitoring of such exposed populations should be conducted using the same or other more sensitive assays.In addition, other populations with exposure to different types of pesticides in Colombia should also be investigated.
Reference Values of Human Bone Marrow and Peripheral Blood Levels of 49 Cytokines According to Age and Clonal Hematopoiesis
Authors: Noemie Ravalet, Hélène Guermouche, Pierre Hirsch, Frederic Picou, Nathalie Gallay, Amelie Foucault, Jenny Beaud, Valérie Gissot, Jean-Alain Martignoles, Ludovic Suner, Caroline Deswarte, Sebastien Lachot, Emmanuelle Rault, Laetitia Largeaud, Emmanuel Gyan, Francois Delhommeau, Olivier Herault
Journal: Blood (2021)
Ritlecitinib and brepocitinib demonstrate significant improvement in scalp alopecia areata biomarkers
Authors: Emma Guttman-Yassky, Ana B. Pavel, Aisleen Diaz, Ning Zhang, Ester Del Duca, Yeriel Estrada, Brett King, Anindita Banerjee, Christopher Banfield, Lori Ann Cox, Martin E. Dowty, Karen Page, Michael S. Vincent, Weidong Zhang, Linda Zhu, Elena Peeva
Journal: Journal of Allergy and Clinical Immunology (2021)

Janus kinase (JAK) inhibitors have shown encouraging results in the treatment of alopecia areata (AA), an autoimmune form of hair loss, in small, uncontrolled studies and case reports.We conducted a biopsy substudy during the randomized, double-blind, placebo-controlled first 24 weeks of a phase 2a clinical trial that evaluated the efficacy and safety of ritlecitinib, an inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and brepocitinib, an inhibitor of tyrosine kinase 2 (TYK2)/JAK1 in the treatment of AA.Change in biomarkers in lesional scalp biopsy samples between baseline and weeks 12 and 24 was an exploratory end point, and 46 patients participated from the ritlecitinib (n = 18), brepocitinib (n = 16), and placebo (n = 12) groups. Correlations of biomarkers with hair regrowth, measured using the Severity of Alopecia Tool (SALT) score, were also evaluated.NCT02974868.At week 24, both ritlecitinib and brepocitinib demonstrated improvement exceeding 100% in the lesional scalp transcriptome toward a nonlesional profile. At week 12, the improvements in scalp tissue were greater with brepocitinib than ritlecitinib; however, at week 24, the improvements were greater with ritlecitinib.For both ritlecitinib and brepocitinib, improvement in the SALT scores was positively associated with expression of TH1 markers and negatively associated with expression of hair keratins. Larger, long-term clinical trials are warranted.
Independent SAGE replies to<i>The BMJ</i>
Authors: Deenan Pillay
Journal: BMJ (2021)

We read The BMJ ’s article on whether the Independent Scientific Advisory Group for Emergencies (Independent SAGE) has been a success with interest,1 as well as a little irritation, given that it began with a major factual error that set the tone for the remainder of the text (as described in our rapid response).2

We are not “rebel scientists” but internationally recognised academics and health practitioners seeking to communicate science to the public, press, and policy makers. Our main activity is delivering public briefings through live broadcasting and written reports, in which we seek to present often complex information in a timely manner and an easily understandable form. Key to these briefings is expert interpretation of the latest epidemiological data from the government daily dashboard, NHS England, public health bodies from each home nation, NHS Test and Trace, the Office for National Statistics, the REACT study, and other reputable sources, acknowledging the work of those who do so much to curate them. The people responsible for …
Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
Authors: Yongguo Zhang, Destiny Ogbu, Shari Garrett, Yinglin Xia, Jun Sun
Journal: Gut Microbes (2021)

Amyotrophic Lateral Sclerosis is a neuromuscular disease characterized by the progressive death of motor neurons and muscle atrophy. The gastrointestinal symptoms in ALS patients were largely ignored or underestimated. The relationship between the enteric neuromuscular system and microbiome in ALS progression is unknown. We performed longitudinal studies on the enteric neuron system (ENS) and microbiome in the ALS human-SOD1G93A (Superoxide Dismutase 1) transgenic mice. We treated age-matched wild-type and ALS mice with butyrate or antibiotics to investigate the microbiome and neuromuscular functions. We examined intestinal mobility, microbiome, an ENS marker GFAP (Glial Fibrillary Acidic Protein), a smooth muscle marker (SMMHC, Smooth Muscle Myosin Heavy Chain), and human colonoids. The distribution of human-G93A-SOD1 protein was tested as an indicator of ALS progression. At 2-month-old before ALS onset, SOD1G93A mice had significantly lower intestinal mobility, decreased grip strength, and reduced time in the rotarod. We observed increased GFAP and decreased SMMHC expression. These changes correlated with consistent increased aggregation of mutated SOD1G93A in the colon, small intestine, and spinal cord. Butyrate or antibiotics treated SOD1G93A mice had a significantly longer latency to fall in the rotarod test, reduced SOD1G93A aggregation, and enhanced enteric neuromuscular function. Feces from 2-month-old SOD1G93A mice significantly enhanced SOD1G93A aggregation in human colonoids transfected with a SOD1G93A-GFP plasmid. Longitudinal studies of microbiome data further showed the altered bacterial community related to autoimmunity (e.g., Clostridium sp. ASF502, Lachnospiraceae bacterium A4), inflammation (e.g., Enterohabdus Muris,), and metabolism (e.g., Desulfovibrio fairfieldensis) at 1- and 2-month-old SOD1G93A mice, suggesting the early microbial contribution to the pathological changes. We have demonstrated a novel link between the microbiome, hSOD1G93A aggregation, and intestinal mobility. Dysbiosis occurred at the early stage of the ALS mice before observed mutated-SOD1 aggregation and dysfunction of ENS. Manipulating the microbiome improves the muscle performance of SOD1G93A mice. We provide insights into the fundamentals of intestinal neuromuscular function and microbiome in ALS.
Abstract 10409: Assessment of Left Ventricular Ejection Fraction From Echocardiographic Images Using Deep Learning Algorithm
Authors: Kenya Kusunose, Akihiro Haga, Takashi Abe, Daiju Fukuda, Hirotsugu Yamada, Masataka Sata
Journal: Circulation (2019)

Introduction: Precise and reliable echocardiographic assessment of left ventricular ejection fraction (LVEF) is needed for clinical decision-making. LVEF is currently determined through an observer...
Abstract 12801: Heart Failure as an Independent Predictor of Insomnia Symptoms
Authors: Rida Gharzeddine, Margaret McCarthy, Gary Yu, Victoria V Dickson
Journal: Circulation (2021)

Background: Heart failure (HF) is accompanied with several untoward outcomes including insomnia symptoms. Many factors including comorbidities, experienced symptoms, and psychosocial characteristics associated with HF were attributed to the high prevalence of insomnia symptoms in persons with HF. However, it is not yet clear if HF itself contributes to insomnia symptoms regardless of these associated factors. Purpose: The purpose of this analysis was to investigate the association of HF with insomnia symptoms in adjusted models for sociodemographic, clinical, and lifestyle factors. Methods: A secondary data analysis guided by the neurocognitive model of insomnia was conducted on data from the health and retirement study using multiple logistic regression. The total sample size included 17,910 subjects of which 1,189 were identified to have HF. Results: The results showed that those with HF were approximately two times more likely to have insomnia symptoms (OR:1.95, p &lt;0.001) in the unadjusted model. After adjusting for age, sex, race, ethnicity, education, marital status, income, poverty level, sleep-disordered breathing, obesity, depression symptoms, comorbid diseases, smoking, alcohol consumption, and physical activity using block-wise selection, HF maintained a significant association with insomnia symptoms (OR:1.15, p&lt;0.05). When looking at each insomnia symptom separately, HF significantly predicted difficulty initiating sleep (OR: 1.23, p &lt; 0.01) in the fully adjusted model, but maintained a trend with difficulty maintaining sleep and early morning awakening. Conclusion: These results are suggestive of an alerting effect in HF which could be attributed to its pathophysiology. Specifically, the neurohormonal compensatory mechanism and the increased sympathetic stimulation in heart failure may exert an alerting effect during the day and contribute to a hyper-arousal state and difficulty initiating sleep before it partially wears off after sleep. Further studies are needed to investigate this hypothesis.
Abstract 11612: The Different Impact of Disproportionately Low B-Type Natriuretic Peptide Levels on Outcome in Patients of Acute Decompensated Heart Failure Between Sinus Rhythm and Atrial Fibrillation
Authors: Kazushi Sakane, Yumiko Kanzaki, Kosuke Tsuda, Masaaki Hoshiga
Journal: Circulation (2021)

Introduction: B-type natriuretic peptide (BNP) has been widely used for the diagnosis of heart failure. Previous data suggest a lower diagnostic accuracy of BNP in HF patients with atrial fibrillation (AF). However, little is known about disproportionately low BNP levels in AF patients even during acute heart failure conditions. Hypothesis: The factors related to disproportionately low BNP might be different between AF and sinus rhythm (SR) in patients with acute decompensated heart failure (ADHF). Methods: Among 424 patients hospitalized for ADHF between January 2015 and December 2017, we divided into two groups based on the rhythm at hospital admission (AF group, n=201 and SR group, n=223) and subdivided them into four groups (Q1-Q4) according to each quartile of BNP levels at hospital admission (BNP lowest quartile (Q1) group (LB): &lt; 320 pg/mL in SR; Q1 &lt; 240 pg/mL in AF). Results: The proportion of patients with unexpectedly low BNP (BNP &lt; 200 pg/mL) was higher in AF group (19.9%) than in SR group (12.1%, p=0.03). BNP was correlated with left ventricular end-diastolic volume index (LVEDVi), left ventricular ejection fraction (LVEF) in both groups (AF: r=0.28, p&lt;0.01; r=-0.43, p&lt;0.01, SR: r=0.41, p&lt;0.01; r=-0.39, p&lt;0.01, respectively) . On the other hand, BNP was positively correlated with left atrial diameter in SR group but negatively correlated in AF group (r=0.14, p=0.039 vs. r=-0.21, p&lt;0.01, respectively, Figure). Furthermore, survival rates significantly increased along BNP tertiles in SR group. On the contrary, in AF group, Q1 (LB) did not show the highest survival rates (p=0.02, Figure). Conclusions: A higher proportion of ADHF with disproportionately low BNP was seen in AF than in SR group. In ADHF patients with AF, LB may be reflected by LA structural remodeling. Furthermore, LB was related to good prognosis in SR group, but not in AF group.
EPID-18. USING GERMLINE VARIANTS FOR DIFFERENTIAL DIAGNOSIS OF INDETERMINATE BRAIN LESIONS: EVALUATING THE EFFECT OF TUMOR TYPE AND RACE ON SENSITIVITY AND SPECIFICITY OF GLIOMA polygenic risk models
Authors: Jeanette Eckel-passow, Decker Paul, Matthew Kosel, Thomas Kollmeyer, Kristen Drucker, Gian Marco Conte, Bradley Erickson, Susan Slager, Daniel Lachance, Robert Jenkins, Oliver Tobin
Journal: Neuro-Oncology (2021)

Abstract Abnormalities on brain MRI may be identified in ~15% of individuals aged 50-66. It can be difficult to discriminate glioma, CNS lymphoma, Inflammatory Demyelinating Disease (CNSIDD) and solitary metastasis, and misdiagnosis may expose patients to unnecessary anxiety, surgery, or radiotherapy. CNS lymphoma requires only biopsy, solitary metastasis may be resected and radiated or radiated empirically, and high-grade glioma requires maximal safe resection followed by chemoradiation. CNSIDD should only be biopsied when diagnostic uncertainty requires it, and resection and radiotherapy are unnecessary, introducing unwarranted morbidity. Polygenic risk models can identify patients at the highest risk of developing glioma; we hypothesized that these polygenic models could help with differential diagnosis of indeterminate brain lesions. We also hypothesized that race would be an important contributing factor in the models. In the initial discovery and validation European (EUR) cohorts the mean probability of glioma for IDHmut non-codeleted glioma was 0.55 and 0.52, respectively, and in healthy controls was 0.19 and 0.21, respectively. To further evaluate sensitivity, we analyzed additional genotype data from 867 gliomas (764 EUR, 54 AFR, 24 AMR, 15 EAS, 10 SAS) from The Cancer Genome Atlas (TCGA). Across 764 EUR IDHmut non-codeleted glioma, the mean probability 0.53, whereas across 54 AFR and 24 AMR the mean was 0.22 and 0.32, respectively. To evaluate specificity, we analyzed 3200 TCGA patients with primary tumor types that commonly metastasize to the brain (2676 EUR, 365 AFR, 46 AMR, 95 EAS, 18 SAS), and 236 AFR healthy controls. For patients with non-CNS primary tumors, the mean probability ranged from 0.09-0.18 for EUR and 0.04-0.07 for AFR. For AFR healthy controls, the mean was 0.05. Overall, race is a significant factor for polygenic risk models. Further work entails evaluating polygenic risk models in IDHwt glioma, CNS lymphoma and CNSIDD cohorts as well as in additional races.