tbuckley/cabot-search huggingface dataset:
More Than One-to-Four via 2R: Evidence of an Independent Amphioxus Expansion and Two-Gene Ancestral Vertebrate State for MyoD-Related Myogenic Regulatory Factors (MRFs)
Authors: Madeleine E Aase-Remedios, Clara Coll-Lladó, David E K Ferrier
Journal: Molecular Biology and Evolution (2020)

The evolutionary transition from invertebrates to vertebrates involved extensive gene duplication, but understanding precisely how such duplications contributed to this transition requires more detailed knowledge of specific cases of genes and gene families. Myogenic differentiation (MyoD) has long been recognized as a master developmental control gene and member of the MyoD family of bHLH transcription factors (myogenic regulatory factors [MRFs]) that drive myogenesis across the bilaterians. Phylogenetic reconstructions within this gene family are complicated by multiple instances of gene duplication and loss in several lineages. Following two rounds of whole-genome duplication (2R WGD) at the origin of the vertebrates, the ancestral function of MRFs is thought to have become partitioned among the daughter genes, so that MyoD and Myf5 act early in myogenic determination, whereas Myog and Myf6 are expressed later, in differentiating myoblasts. Comparing chordate MRFs, we find an independent expansion of MRFs in the invertebrate chordate amphioxus, with evidence for a parallel instance of subfunctionalization relative to that of vertebrates. Conserved synteny between chordate MRF loci supports the 2R WGD events as a major force in shaping the evolution of vertebrate MRFs. We also resolve vertebrate MRF complements and organization, finding a new type of vertebrate MRF gene in the process, which allowed us to infer an ancestral two-gene state in the vertebrates corresponding to the early- and late-acting types of MRFs. This necessitates a revision of previous conclusions about the simple one-to-four origin of vertebrate MRFs.
Analysis of 1321 Eubacterium rectale genomes from metagenomes uncovers complex phylogeographic population structure and subspecies functional adaptations
Authors: Nicolai Karcher, Edoardo Pasolli, Francesco Asnicar, Kun D. Huang, Adrian Tett, Serena Manara, Federica Armanini, Debbie Bain, Sylvia H. Duncan, Petra Louis, Moreno Zolfo, Paolo Manghi, Mireia Valles-Colomer, Roberta Raffaetà, Omar Rota-Stabelli, Maria Carmen Collado, Georg Zeller, Daniel Falush, Frank Maixner, Alan W. Walker, Curtis Huttenhower, Nicola Segata
Journal: Genome biology (2020)

Eubacterium rectale is one of the most prevalent human gut bacteria, but its diversity and population genetics are not well understood because large-scale whole-genome investigations of this microbe have not been carried out.
Infographic. Cooling strategies to attenuate PPE-induced heat strain during the COVID-19 pandemic
Authors: Coen CWG Bongers, Johannus Q de Korte, Milene Catoire, Job Greefhorst, Maria T E Hopman, Boris Kingma, Thijs M H Eijsvogels
Journal: British Journal of Sports Medicine (2020)

In order to determine the cause of a perinatal death it is important to correlate the postmortem findings with the clinical histories of both mother and infant. The postmortem examination of a newborn infant differs from that of an adult in a number of ways, especially in the method of removal and dissection of the brain, the examination of the cervical spine, the dissection of the cardiovascular system for congenital abnormalities, and the examination of the placenta. A systematic technique for performing a perinatal necropsy is described. Stress is laid on measurement of the size of the infant and of the individual organs and comparison of these with known standards, allowance being made for the maturity of the infant.
THU0378 DO COMORBIDITIES DECREASE THE FIRST TNF-INHIBITOR RETENTION AND TREATMENT RESPONSE IN AXIAL SPONDYLOARTHRITIS PATIENTS? DATA FROM TURKBIO
Authors: Y. Erez, A. Karakas, S. B. Kocaer, T. Yüce İnel, S. Gulle, A. Köken Avşar, S. Uslu, G. Can, İ. Sari, M. Birlik, E. Dalkiliç, Y. Pehlivan, S. Senel, S. Akar, S. S. Koca, A. Tufan, A. Yazici, S. Yilmaz, N. Inanc, D. Solmaz, N. Akkoc, F. Onen
Journal: Annals of the Rheumatic Diseases (2020)

Background: The frequency of comorbidities has increased in spondyloarthritis patients compared to the general population. The effect of comorbidities on tumour necrosis factor alpha inhibitor (TNFi) drug retention and treatment response has not been well evaluated. Objectives: The purpose of this study to assess the impact of comorbidities on the first TNFi drug survival and treatment response in patients with axial spondyloarthritis (axSpA) registered in the TURKBIO database. Methods: In this study, the frequency of comorbidities, disease activity scores at baseline and month 6 and drug retention were recorded in AxSpA patients iniating first TNFi treatment between 2011 and 2019. Kaplan Meier plot and log rank tests were used for drug survival analysis. Cox regression analysis with HR was performed to evaluate the correlation between comorbidities and drug survival. Results: There were 2428 patients with AxSpA (39.3% female) who used their first TNFi during the study period. Among them, a total of 770 (31%) had at least one comorbid disease. Hypertension was the most common comorbidity (9.7%), followed by the affective disorders (8%) and chronic lung disease (5.8%). The baseline characteristics of patients are shown in Table 1.The presence of any comorbidity did not impact the first TNFi retention (Figure 1). When comorbidities were analysed seperately, we found that only history of cerebrovascular event was negatively associated with drug retention rate (HR: 6.9, p:0.008). There was no statistically significant difference in Bath AS Disease Activity Index 50% (BASDAI50) response between patients with and without comorbidity at 6 months. Less axSpA patients with comorbidity achieved a ASDAS score ≤ 2.1 compared to patients without comorbidity at 6 months. Table 1. Baseline Characteristics of Patients Radiographic Spondyloarthritis, n (%) 2318 (95.5) Female, n(%) 954 (39.3) Age, year 42.2±11.8 Age at diagnosis, years 32.5± 11.3 Age at initial TNFi, years 39.4 ± 11.1 Symptom duration, years 9.7± 7.5 Time to initial TNFi, years 7±6.8 HLA-B27- positivity, n (%) 1144 (47.1) Smokers, n (%) 1068 (44) Baseline BASDAI 35.5±22.2 Baseline ASDAS-CRP 2.8±1.1 Baseline CRP (mg/L) 15.7±24.4 VAS global patient 46.6±28.7 -Quantitative variables are presented as mean ± SD, and qualitative variables are presented as frequency and percentage -ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score using C-reactive protein VAS, visual analogue scale Conclusion: The results of this study demonstrated that the presence of previous cerebrovascular event decreased the first TNFi survival in patients with axSpA. It also suggested that comorbidities might decrease TNFi treatment response. Disclosure of Interests: None declared
Telomere Dysfunction Activates p53 and Represses HNF4α Expression Leading to Impaired Human Hepatocyte Development and Function
Authors: Michael Munroe, Evandro Luis Niero, Wilson Chun Fok, Alexandre Teixeira Vessoni, Ho‐Chang Jeong, Kirsten Ann Brenner, Luis Francisco Zirnberger Batista
Journal: Hepatology (2020)

Background and Aims Telomere attrition is a major risk factor for end‐stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro , stage‐specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo . Approach and Results Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down‐regulation, immediately after endoderm differentiation and completely absent in in vitro –derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening prevents the up‐regulation and activation of human hepatocyte nuclear factor 4 alpha ( HNF4α ) in a p53‐dependent manner. Both reactivation of telomerase and silencing of p53 rescued hepatocyte formation in telomerase mutants. Likewise, the conditional expression (doxycycline‐controlled) of HNF4α , even in cells that retained short telomeres, accrued DNA damage, and exhibited p53 stabilization, successfully restored hepatocyte formation from hESCS. Conclusions Our data show that telomere dysfunction acts as a major regulator of HNF4α during hepatocyte development, pointing to a target in the treatment of liver disease in telomere‐syndrome patients.
Outcomes for Pressure Ulcer Trials (OUTPUTs) project: review and classification of outcomes reported in pressure ulcer prevention research
Authors: A. Lechner, J. Kottner, S. Coleman, D. Muir, D. Beeckman, W. Chaboyer, J. Cuddigan, Z. Moore, C. Rutherford, J. Schmitt, J. Nixon, K. Balzer
Journal: British Journal of Dermatology (2020)

In order to overcome inconsistencies in the reporting of outcomes in clinical trials, core outcome sets (COSs) have been developed in many clinical areas and the awareness of this concept is growing steadily. The Outcomes for Pressure Ulcer Trials (OUTPUTs) project aims to improve the quality of evidence from pressure ulcer prevention trials by developing a COS. As an initial step in the COS process we aimed to identify and classify both outcomes and concepts that represent potential outcomes for future trials that have been reported in pressure ulcer prevention research. A review was conducted in 12 major databases covering the literature indexed until 2016. Outcomes and relevant concepts reported in primary studies and/or reviews on pressure ulcer prevention in adult patients were extracted as presented in the articles, and afterwards inductively grouped into outcome domains. The domains were then categorized according to the outcome domain taxonomy recently proposed by the COMET group. In total 332 studies were included and 68 outcome domains were identified, covering multiple aspects of pressure ulcer prevention. Pressure ulcer occurrence was reported in 71% of all included studies, representing the most frequent outcome, followed by costs (22% of all studies) and acceptability of intervention and comfort (18% of all studies). A plethora of different outcomes are applied in pressure ulcer prevention research and substantial variations in definitions and reporting of similar outcomes were observed. A COS for pressure ulcer prevention trials is needed to overcome the noncomparability of outcomes.
The phenomenology of gender dysphoria in adults: A systematic review and meta-synthesis
Authors: Kate Cooper, Ailsa Russell, William Mandy, Catherine Butler
Journal: Clinical Psychology Review (2020)

Gender dysphoria is distress due to a discrepancy between one's assigned gender and gender identity. Adults who wish to access gender clinics are assessed to ensure they meet the diagnostic criteria for gender dysphoria. Therefore, the definition of gender dysphoria has a significant impact on the lives of individuals who wish to undergo physical gender transition. This systematic review aimed to identify and synthesize all existing qualitative research literature about the lived experience of gender dysphoria in adults. A pre-planned systematic search identified 1491 papers, with 20 of those meeting full inclusion criteria, and a quality assessment of each paper was conducted. Data pertaining to the lived experience of gender dysphoria were extracted from each paper and a meta-ethnographic synthesis was conducted. Four overarching concepts were identified; distress due to dissonance of assigned and experienced gender; interface of assigned gender, gender identity and society; social consequences of gender identity; internal processing of rejection, and transphobia. A key finding was the reciprocal relationship between an individual's feelings about their gender and societal responses to transgender people. Other subthemes contributing to distress were misgendering, mismatch between gender identity and societal expectations, and hypervigilance for transphobia.
“Abandoned” Nursing Homes Continue to Face Critical Supply and Staff Shortages as COVID-19 Toll Has Mounted
Authors: Jennifer Abbasi
Journal: JAMA (2020)

Jose F. Figueroa, MD, MPH; Rishi K. Wadhera, MD, MPP; Irene Papanicolas, PhD; Kristen Riley, BA; Jie Zheng, PhD; E. John Orav, PhD; Ashish K. Jha, MD, MPH
Treating asthma in the COVID-19 pandemic
Authors: Ran Wang, Andras Bikov, Stephen J Fowler
Journal: Thorax (2020)

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated from Wuhan, China, at the end of 2019 and has rapidly spread to cause a global pandemic associated with substantial morbidity and mortality.1 By mid-April 2020, nearly two million confirmed cases of COVID-19 had been reported from 210 countries, resulting in over 100 000 deaths. Similar to previous novel coronavirus diseases (severe acute respiratory syndrome and Middle East respiratory syndrome), COVID-19 often leads to severe respiratory failure, and it might be assumed that patients with chronic respiratory diseases such as asthma would be at higher risk of developing severe illness. It is perhaps surprising then that, thus far, no clear association has been found2–5; asthma was reported in less than 1% of patients with COVID-19 from Wuhan,2 3 and chronic airway diseases, including asthma, in 10%–13% of nearly 2400 patients hospitalised in New York City.4 5 Although Williamson et al reported a modest increase in risk of COVID-19-related hospital deaths in asthma, this was mainly in patients recently receiving oral corticosteroids.6 It seems unlikely that respiratory comorbidities would be under-reported, so what other explanations may be offered?

Shielding and self-isolation may be helping to reduce acquisition of SARS-CoV-2, but there is no reason to think this …
Abstract A02: Detection of circulating cell-free DNA in renal cancer using renal cancer-specific DNA mutations and methylation changes
Authors: Martyna J. Adamowicz, John Thomson, Sophie J. Warlow, Utsa Patra, Helen Thain, Sophie Marion de Proce, Alexander Laird, Timothy J. Aitman
Journal: Clinical Cancer Research (2020)

Abstract Renal cell cancer (RCC) is the most deadly of urologic malignancies. It is a very invasive and chemoresistant disease that is often treated by surgical resection as it also responds poorly to radiotherapy. Importantly, more than 30% of RCCs recur or metastasize following treatment and in the cases believed to be curable by nephrectomy, distant metastasis can develop even 10 years post-surgery. There is therefore a significant focus on tissue-based biomarkers from the primary kidney tumors to help predict which patients are likely to recur, though there are no biomarkers used in routine clinical practice. Over recent years, much research has aimed at the utilization of blood-based biomarkers, mainly circulating cell-free DNA (cfDNA), as a method of noninvasive disease diagnosis and monitoring. cfDNA is detected through the identification of tumor-specific cfDNA mutations, although cfDNA methylation may be a more specific biomarker as many CpG sites can be tested in parallel. We have collected tumor tissue and pre- and post-surgery blood samples from renal cancer patients and generated exome sequencing and EPIC array data of 20 tumors with matched blood samples to detect tumor-specific DNA mutations and methylation patterns. We have identified well-known driver mutations in renal cancer in VHL in 11 tumors at 0.12-0.51 variant allele fraction (VAF); PBRM1 in 8 tumors at 0.12-0.45 VAF; BAP-1 in 2 tumors at 0.45 and 0.3 VAF; and SETD2 at 0.39 VAF; KDM5C at 0.27 VAF, and CTNNA2 at 0.2 VAF in one out of 20 patients. We aim to validate these changes using droplet digital PCR (ddPCR) in tumor and circulating tumor DNA (ctDNA) pre- and post-surgery. We next plan to combine the result of the exome sequencing with EPIC array data as well in house-developed cfDNA profiles based on publicly available tissue and individual cell type DNA methylation data. This approach will allow us to select the best mutation and methylation diagnostic and prognostic markers to aid the monitoring of early disease and relapse as well as the treatment of renal cell cancer. Citation Format: Martyna J. Adamowicz, John Thomson, Sophie J. Warlow, Utsa Patra, Helen Thain, Sophie Marion de Proce, Alexander Laird, Timothy J. Aitman. Detection of circulating cell-free DNA in renal cancer using renal cancer-specific DNA mutations and methylation changes [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A02.
Physiological Modeling and Simulation—Validation, Credibility, and Application
Authors: W. Andrew Pruett, John S. Clemmer, Robert L. Hester
Journal: Annual Review of Biomedical Engineering (2020)

In this review, we discuss the science of model validation as it applies to physiological modeling. There is widespread disagreement and ambiguity about what constitutes model validity. In areas in which models affect real-world decision-making, including within the clinic, in regulatory science, or in the design and engineering of novel therapeutics, this question is of critical importance. Without an answer, it impairs the usefulness of models and casts a shadow over model credibility in all domains. To address this question, we examine the use of nonmathematical models in physiological research, in medical practice, and in engineering to see how models in other domains are used and accepted. We reflect on historic physiological models and how they have been presented to the scientific community. Finally, we look at various validation frameworks that have been proposed as potential solutions during the past decade.
Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations
Authors: Lindsay Fernández-Rhodes, Kristin L. Young, Adam G. Lilly, Laura M. Raffield, Heather M. Highland, Genevieve L. Wojcik, Cary Agler, Shelly-Ann M. Love, Samson Okello, Lauren E. Petty, Mariaelisa Graff, Jennifer E. Below, Kimon Divaris, Kari E. North
Journal: Circulation Research (2020)

Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.
Uncovering the secretes of allergic inflammation
Authors: Michael Brusilovsky, Mark Rochman, Nurit P. Azouz, Lydia E. Mack, Marc E. Rothenberg
Journal: Journal of Clinical Investigation (2020)

Allergic asthma is a chronic inflammatory lung disease associated with increased cytokine secretion. Aspects of airway inflammation are also linked to a common genetic variant that corresponds to the small GTPase, Rab27, a protein involved in vesicular trafficking in immune cells. However, the mechanisms by which Rab27 contributes to airway inflammation and cytokine release remain ambiguous. In this issue of the JCI, Okunishi et al. explored the role that the Rab27 effector, exophilin-5, has in allergic inflammation. Exophilin-5-deficient mice and asthma mouse models revealed that exophilin-5 regulates IL-33 production and the Th2 response. Notably, exophilin-5 deletion enhanced IL-33 release and pathogenic Th2 responsiveness through the mTOR pathway and altered intracellular IL-33 trafficking. This work provides insights into the molecular mechanisms that underlie inflammatory lung disease.