tbuckley/cabot-search huggingface dataset:
Limited Predictability of Amino Acid Substitutions in Seasonal Influenza Viruses
Authors: Pierre Barrat-Charlaix, John Huddleston, Trevor Bedford, Richard A. Neher
Journal: Molecular Biology and Evolution (2021)

Seasonal influenza viruses repeatedly infect humans in part because they rapidly change their antigenic properties and evade host immune responses, necessitating frequent updates of the vaccine composition. Accurate predictions of strains circulating in the future could therefore improve the vaccine match. Here, we studied the predictability of frequency dynamics and fixation of amino acid substitutions. Current frequency was the strongest predictor of eventual fixation, as expected in neutral evolution. Other properties, such as occurrence in previously characterized epitopes or high Local Branching Index (LBI) had little predictive power. Parallel evolution was found to be moderately predictive of fixation. Although the LBI had little power to predict frequency dynamics, it was still successful at picking strains representative of future populations. The latter is due to a tendency of the LBI to be high for consensus-like sequences that are closer to the future than the average sequence. Simulations of models of adapting populations, in contrast, show clear signals of predictability. This indicates that the evolution of influenza HA and NA, while driven by strong selection pressure to change, is poorly described by common models of directional selection such as traveling fitness waves.
IDH1依存性α-KGはヒストンメチル化調節により褐色脂肪分化と機能を調節する【JST・京大機械翻訳】
Authors: Kang Hyun Sup, Lee Jae Ho, Oh Kyoung-Jin, Lee Eun Woo, Han Baek Soo, Park Kun-Young, Suh Jae Myoung, Min Jeong-Ki, Chi Seung-Wook, Lee Sang Chul, Bae Kwang-Hee, Kim Won Kon
Journal: Metabolism (2020)
Reply to “Cabbage and COVID‐19”
Authors: Josep M. Anto, Jean Bousquet
Journal: Allergy (2021)

To the Editor, We appreciate the interest and comments of Soriano and Ancochea1 regarding our papers.2 Further to the suggestion that "it would be of interest to repeat their statistics conducted during the first wave of COVID-19, again with the current estimates during the ongoing second wave, or later ones," we would like to emphasize that our geographical observation was a type of anecdotal evidence that contributed to formulating a hypothesis. In a previous paper, we found that after adjusting for potentially relevant country-level confounders, there was a negative ecological association between COVID-19 mortality and the consumption of cabbage and cucumber in European countries.3 In this study, we acknowledged that "As in any ecological study, any inference from the observed association should be made at the country level, as the possibility of ecological fallacy precludes inferences at the individual level; and that further testing in properly designed individual studies would be of interest." Indeed, it would be useful is testing the hypothesis in robust observational studies and/or clinical trials. Regarding our observation that COVID-19 could be considered as a disease of the Anthropocene,4 other authors have recently provided a more complete description of the links between the disruption of the natural ecosystems that characterize the Anthropocene and the occurrence of zoonosis.5, 6 The authors have no conflict of interest to declare.
Gut microbiota shape the inflammatory response in mice with an epithelial defect
Authors: Ran Wang, Md Moniruzzaman, Kuan Yau Wong, Percival Wiid, Alexa Harding, Rabina Giri, Wendy (Hui) Tong, Jackie Creagh, Jakob Begun, Michael A. McGuckin, Sumaira Z. Hasnain
Journal: Gut Microbes (2021)

Intestinal epithelial cell endoplasmic reticulum (ER) stress has been implicated in intestinal inflammation. It remains unclear whether ER stress is an initiator of or a response to inflammation. Winnie mice, carrying a Muc2 gene mutation resulting in intestinal goblet cell ER stress, develop spontaneous colitis with a depleted mucus barrier and increased bacterial translocation. This study aims to determine whether the microbiota was required for the development of Winnie colitis, and whether protein misfolding itself can initiate inflammation directly in absence of the microbiota. To assess the role of microbiota in driving Winnie colitis, WT and Winnie mice on the same background were rederived into the germ-free facility and housed in the Trexler-type soft-sided isolators. The colitis phenotype of these mice was assessed and compared to WT and Winnie mice housed within a specific pathogen-free facility. We found that Winnie colitis was substantially reduced but not abolished under germ-free conditions. Expression of inflammatory cytokine genes was reduced but several chemokines remained elevated in absence of microbiota. Concomitantly, ER stress was also diminished, although mucin misfolding persisted. RNA-Seq revealed that Winnie differentiated colon organoids have decreased expression of the negative regulators of the inflammatory response compared to WT. This data along with the increase in Mip2a chemokine expression, suggests that the epithelial cells in the Winnie mice are more responsive to stimuli. Moreover, the data demonstrate that intestinal epithelial intrinsic protein misfolding can prime an inflammatory response without initiating the unfolded protein response in the absence of the microbiota. However, the microbiota is necessary for the amplification of colitis in Winnie mice. Genetic predisposition to mucin misfolding in secretory cells initiates mild inflammatory signals. However, the inflammatory signal sets a forward-feeding cycle establishing progressive inflammation in the presence of microbiota.Abbreviations: Endoplasmic Reticulum: ER; Mucin-2: Muc-2; GF: Germ-Free; Inflammatory Bowel Disease: IBD
Enabling out-of-body experiences for living organs
Authors: Donald E. Ingber
Journal: The Journal of Experimental Medicine (2021)

In a 1937 issue of JEM, Carrel (1937. J. Exp. Med.https://doi.org/10.1084/jem.65.4.515) described a technique for culturing whole living organs outside the body. Here, Ingber reviews how this work led to a series of scientific, engineering, and medical breakthroughs that continue to this day.
CharPlant: A <i>De Novo</i> Open Chromatin Region Prediction Tool for Plant Genomes
Authors: Yin Shen, Ling-Ling Chen, Junxiang Gao
Journal: Genomics Proteomics & Bioinformatics (2021)

Chromatin accessibility is a highly informative structural feature for understanding gene transcription regulation, because it indicates the degree to which nuclear macromolecules such as proteins and RNAs can access chromosomal DNA. Studies have shown that chromatin accessibility is highly dynamic during stress response, stimulus response, and developmental transition. Moreover, physical access to chromosomal DNA in eukaryotes is highly cell-specific. Therefore, current technologies such as DNase-seq, ATAC-seq, and FAIRE-seq reveal only a portion of the open chromatin regions (OCRs) present in a given species. Thus, the genome-wide distribution of OCRs remains unknown. In this study, we developed a bioinformatics tool called CharPlant for the de novo prediction of OCRs in plant genomes. To develop this tool, we constructed a three-layer convolutional neural network (CNN) and subsequently trained the CNN using DNase-seq and ATAC-seq datasets of four plant species. The model simultaneously learns the sequence motifs and regulatory logics, which are jointly used to determine DNA accessibility. All of these steps are integrated into CharPlant, which can be run using a simple command line. The results of data analysis using CharPlant in this study demonstrate its prediction power and computational efficiency. To our knowledge, CharPlant is the first de novo prediction tool that can identify potential OCRs in the whole genome. The source code of CharPlant and supporting files are freely available from https://github.com/Yin-Shen/CharPlant.
Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection [see comments]
Authors: JM Pluda, R Yarchoan, PD Smith, N McAtee, LE Shay, D Oette, M Maha, SM Wahl, CE Myers, S Broder
Journal: Blood (1990)
Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development
Authors: Yuh‐Jin Liang, Wei Teng, Chih‐Li Chen, Cheng‐Pu Sun, Rui‐Dung Teng, Yen‐Hua Huang, Kung‐Hao Liang, Yi‐Wen Chen, Chung‐Chih Lin, Chien‐Wei Su, Mi‐Hua Tao, Jaw‐Ching Wu
Journal: Hepatology (2021)

Background and Aims PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion‐defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo . Approach and Results Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case–control follow‐up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072‐9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133‐6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real‐time ATP assay, and calcium staining of preS2ΔMT‐expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100‐fold lower in preS2ΔMT‐infected humanized Fah–/–/ Rag2–/–/Il2rg–/– triple knockout mice than in wild‐type HBV‐infected mice. PreS2ΔMT‐infected mice displayed up‐regulation of UPR and caspase‐3 and enhanced liver fibrosis. Conclusions PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.
Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study
Authors: Richard T. Bryan, Wenyu Liu, Sarah J. Pirrie, Rashid Amir, Jean Gallagher, Ana I. Hughes, Kieran P. Jefferson, Allen Knight, Veronica Nanton, Harriet P. Mintz, Ann M. Pope, James W.F. Catto, Prashant Patel, Nicholas D. James
Journal: European Urology (2021)
Is oxygen therapy beneficial for normoxemic patients with acute heart failure? A propensity score matched study
Authors: Yue Yu, Ren-Qi Yao, Yu-Feng Zhang, Su-Yu Wang, Wang Xi, Jun-Nan Wang, Xiao-Yi Huang, Yong-Ming Yao, Zhi-Nong Wang
Journal: Military Medical Research (2021)

The clinical efficiency of routine oxygen therapy is uncertain in patients with acute heart failure (AHF) who do not have hypoxemia. The aim of this study was to investigate the association between oxygen therapy and clinical outcomes in normoxemic patients hospitalized with AHF using real-world data. Normoxemic patients diagnosed with AHF on ICU admission from the electronic ICU (eICU) Collaborative Research Database were included in the current study, in which the study population was divided into the oxygen therapy group and the ambient-air group. Propensity score matching (PSM) was applied to create a balanced covariate distribution between patients receiving supplemental oxygen and those exposed to ambient air. Linear regression and logistic regression models were performed to assess the associations between oxygen therapy and length of stay (LOS), and all-cause in-hospital as well as ICU mortality rates, respectively. A series of sensitivity and subgroup analyses were conducted to further validate the robustness of our findings. A total of 2922 normoxemic patients with AHF were finally included in the analysis. Overall, 42.1% (1230/2922) patients were exposed to oxygen therapy, and 57.9% (1692/2922) patients did not receive oxygen therapy (defined as the ambient-air group). After PSM analysis, 1122 pairs of patients were matched: each patient receiving oxygen therapy was matched with a patient without receiving supplemental oxygen. The multivariable logistic model showed that there was no significant interaction between the ambient air and oxygen group for all-cause in-hospital mortality [odds ratio (OR) 1.30; 95% confidence interval (CI) 0.92-1.82; P = 0.138] or ICU mortality (OR 1.39; 95% CI 0.83-2.32; P = 0.206) in the post-PSM cohorts. In addition, linear regression analysis revealed that oxygen therapy was associated with prolonged ICU LOS (OR 1.11; 95% CI 1.06-1.15; P < 0.001) and hospital LOS (OR 1.06; 95% CI 1.01-1.10; P = 0.009) after PSM. Furthermore, the absence of an effect of supplemental oxygen on mortality was consistent in all subgroups. Routine use of supplemental oxygen in AHF patients without hypoxemia was not found to reduce all-cause in-hospital mortality or ICU mortality.
Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference
Authors: Jason Gotlib, Tracy I. George, Melody C. Carter, K. Frank Austen, Bruce Bochner, Daniel F. Dwyer, Jonathan J. Lyons, Matthew J. Hamilton, Joseph Butterfield, Patrizia Bonadonna, Catherine Weiler, Stephen J. Galli, Lawrence B. Schwartz, Hanneke Oude Elberink, Anne Maitland, Theoharis Theoharides, Celalettin Ustun, Hans-Peter Horny, Alberto Orfao, Michael Deininger, Deepti Radia, Mohamad Jawhar, Hanneke Kluin-Nelemans, Dean D. Metcalfe, Michel Arock, Wolfgang R. Sperr, Peter Valent, Mariana Castells, Cem Akin
Journal: Journal of Allergy and Clinical Immunology (2021)
Silencing HBV transcription with SMC5/6: has a path been found?
Authors: John Tavis, Ranjit Chauhan
Journal: Gut (2021)

Chronic hepatitis B virus (HBV) infection is maintained by the viral nuclear covalently closed circular DNA (cccDNA) that is the transcriptional template for HBV’s mRNAs. The cccDNA is durable during current therapies, but a functional cure for HBV infections will require stable, off-treatment silencing of any cccDNA remaining in the body after treatment cessation.1 The cccDNA is silenced naturally during infection by binding of the structural maintenance of chromosome 5/6 (SMC5/6) complex to the cccDNA, and HBV antagonises this silencing with the HBx protein that binds to SMC5/6 and triggers its proteasomal degradation.2 In Gut , Allweiss and Giersch et al 3 explored what happens to HBV mRNA transcription during and after suppression of viral mRNA and antigen levels in HBV-infected chimeric mice carrying humanised livers. Suppressing all HBV mRNAs with a small interfering RNA (siRNA) or with pegylated interferon α (Peg-IFNα) increased SMC5/6 binding to the cccDNA, suppressed HBV transcription and reduced HBV protein production. Withdrawal of siRNA and Peg-IFNα led to degradation of SMC5/6 and rebound of viral transcription and protein levels. Finally, treating the mice with the potent HBV entry inhibitor myrcludex B (bulevirtide, Hepcludex) after cessation of siRNA or Peg-IFNα treatment greatly increased durability of SMC5/6-mediated transcriptional repression. This is a …
Expanded Access to Lung Cancer Screening—Implementing Wisely to Optimize Health
Authors: Anne C. Melzer, Timothy J. Wilt
Journal: JAMA Network Open (2021)

Daniel E. Jonas, MD, MPH; Daniel S. Reuland, MD, MPH; Shivani M. Reddy, MD, MSc; Max Nagle, MD, MPH; Stephen D. Clark, MD, MPH; Rachel Palmieri Weber, PhD; Chineme Enyioha, MD, MPH; Teri L. Malo, PhD, MPH; Alison T. Brenner, PhD, MPH; Charli Armstrong, BA; Manny Coker-Schwimmer, MPH; Jennifer Cook Middleton, PhD; Christiane Voisin, MSLS; Russell P. Harris, MD, MPH
Analysis of PFS2 by subsequent therapy in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as 1L therapy for advanced urothelial carcinoma (UC).
Authors: Mustafa Ozguroglu, Ajjai Shivaram Alva, Tibor Csőszi, Nobuaki Matsubara, Lajos Geczi, Susanna Y. Cheng, Yves Fradet, Stephane Oudard, Christof Vulsteke, Rafael Morales-Barrera, Aude Flechon, Seyda Gunduz, Yohann Loriot, Alejo Rodriguez-Vida, Ronac Mamtani, Evan Y. Yu, Kijoeng Nam, Kentaro Imai, Blanca Homet Moreno, Thomas Powles
Journal: Journal of Clinical Oncology (2021)

448 Background: 1L pembro + chemo did not show statistically superior PFS and OS vs chemo for pts with advanced UC in the phase III KEYNOTE-361 study; OS for pembro vs chemo was not formally tested. We analyzed PFS2 (time from randomization to progressive disease [PD] on first subsequent therapy, or death from any cause, whichever occurs first) by study treatment and subsequent therapy in KEYNOTE-361 (NCT02853305) to determine the effects, if any, of therapy sequence on PFS2. Methods: PFS2 was estimated for pts in each treatment arm, who received any subsequent therapy including any anti–PD-(L)1, any therapy other than anti–PD-(L)1, or no therapy. These were exploratory analyses; no formal comparisons were done. Results: 1010 pts were randomized: 351 pts to receive pembro + chemo, 307 to pembro, and 352 to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. Subsequent therapy was received by 124/351 (35%), 126/307 (41%), and 215/352 (61%) pts in the pembro + chemo, pembro, and chemo arms, respectively. Subsequent anti–PD-(L)1 therapy was received by 169/352 (48%) pts in the chemo arm vs 23/351 (7%) in the pembro + chemo arm and 14/307 (5%) in the pembro arm. Of pts in the pembro arm who received subsequent therapy, &gt;90% received 2L cisplatin-based or carboplatin-based treatment. Median (m) PFS2 (95% CI) for all pts by treatment arm was 14.1 mo (12.6-16.2) with pembro + chemo, 10.9 mo (9.5-12.9) with pembro, and 10.4 mo (9.8-11.2) with chemo. Across treatment arms, pts in the pembro + chemo arm had the longest mPFS2 with any subsequent therapy (14.5 mo [95% CI 13.1-16.6]) (Table). Pts in the pembro arm who received no subsequent therapy had a longer mPFS2 (12.9 mo [95% CI 8.1-17.9]) vs pts in the chemo arm who received no subsequent therapy (9.4 mo [95% CI 7.6-10.6]). Finally, pts treated with 1L pembro in the trial followed by 2L therapy other than anti−PD-(L)1 had comparable mPFS2 (10.2 mo [95% CI 8.6-12.1]) to pts treated with 1L chemo in the trial followed by 2L anti−PD-(L)1 (11.1 mo [95% CI 10.2-12.9]). Conclusions: In this exploratory analysis, treatment sequence of chemo followed by anti−PD-(L)1 upon PD vs anti–PD-(L)1 followed by chemo upon PD did not appear to impact mPFS2. Among pts who did not receive 2L therapy, 1L pembro appeared to be associated with longer mPFS2 than chemo, potentially driven by long-term responders to pembro. Clinical trial information: NCT02853305 . [Table: see text]
Office-Based Addiction Treatment Retention and Mortality Among People Experiencing Homelessness
Authors: Danielle R. Fine, Elizabeth Lewis, Karen Weinstock, Joseph Wright, Jessie M. Gaeta, Travis P. Baggett
Journal: JAMA Network Open (2021)

Importance People experiencing homelessness have been disproportionately affected by the opioid overdose crisis. To mitigate morbidity and mortality, several office-based addiction treatment (OBAT) programs designed for this population have been established across the US, but studies have not yet evaluated their outcomes. Objective To evaluate treatment retention and mortality in an OBAT program designed specifically for individuals experiencing homelessness with opioid use disorder (OUD). Design, Setting, and Participants A retrospective cohort study was conducted in the Boston Health Care for the Homeless Program (BHCHP). Participants included all adult patients (N = 1467) who had 1 or more OBAT program encounter at BHCHP from January 1, 2008, to December 31, 2018. Data analysis was conducted from January 13 to December 14, 2020. Exposures Sociodemographic, clinical, and addiction treatment–related characteristics were abstracted from the BHCHP electronic health record. Main Outcomes and Measures The primary outcome was all-cause mortality, identified by linkage to the Massachusetts Department of Public Health vital records. Multivariable Cox proportional hazards regression analyses were performed to evaluate baseline and time-varying variables associated with all-cause mortality. Secondary addiction treatment–related outcomes were abstracted from the electronic health record and included (1) BHCHP OBAT program retention, (2) buprenorphine continuation and adherence verified by toxicology testing, and (3) opioid abstinence verified by toxicology testing. Results Of 1467 patients in the cohort, 1046 were men (71.3%) and 731 (49.8%) were non-Hispanic White; mean (SD) age was 42.2 (10.6) years. Continuous retention in the OBAT program was 45.2% at 1 month, 21.7% at 6 months, and 11.3% at 12 months. Continuous buprenorphine adherence was 41.5% at 1 month, 17.6% at 6 months, and 10.2% at 12 months, and continuous opioid abstinence was 28.3% at 1 month, 6.1% at 6 months, and 2.9% at 12 months. The all-cause mortality rate was 29.0 deaths per 1000 person-years, with 51.8% dying from drug overdose. Past-month OBAT program attendance was associated with lower mortality risk (adjusted hazard ratio, 0.34; 95% CI, 0.21-0.55). Conclusions and Relevance Mortality rates were high in this cohort of addiction treatment–seeking homeless and unstably housed individuals with OUD. Although continuous OBAT program retention was low, past-month attendance in care was associated with reduced mortality risk. Future work should examine interventions to promote increased OBAT attendance to mitigate morbidity and mortality in this vulnerable population.
Sex differences in acute cardiovascular care: a review and needs assessment
Authors: Saraschandra Vallabhajosyula, Dhiran Verghese, Viral K Desai, Pranathi R Sundaragiri, Virginia M Miller
Journal: Cardiovascular Research (2021)

Abstract Despite significant progress in the care of patients suffering from cardiovascular disease, there remains a persistent sex disparity in the diagnosis, management, and outcomes of these patients. These sex disparities are seen across the spectrum of cardiovascular care, but, are especially pronounced in acute cardiovascular care. The spectrum of acute cardiovascular care encompasses critically ill or tenuous patients with cardiovascular conditions that require urgent or emergent decision-making and interventions. In this narrative review, the disparities in the clinical course, management, and outcomes of six commonly encountered acute cardiovascular conditions, some with a known sex-predilection will be discussed within the basis of underlying sex differences in physiology, anatomy, and pharmacology with the goal of identifying areas where improvement in clinical approaches are needed.