tbuckley/cabot-search huggingface dataset:
Compacting a synthetic yeast chromosome arm
Authors: Zhouqing Luo, Kang Yu, Shangqian Xie, Marco Monti, Daniel Schindler, Yuan Fang, Shijun Zhao, Zhenzhen Liang, Shuangying Jiang, Meiwei Luan, Chuanle Xiao, Yizhi Cai, Junbiao Dai
Journal: Genome biology (2021)

Abstract Background Redundancy is a common feature of genomes, presumably to ensure robust growth under different and changing conditions. Genome compaction, removing sequences nonessential for given conditions, provides a novel way to understand the core principles of life. The synthetic chromosome rearrangement and modification by loxP-mediated evolution (SCRaMbLE) system is a unique feature implanted in the synthetic yeast genome (Sc2.0), which is proposed as an effective tool for genome minimization. As the Sc2.0 project is nearing its completion, we have begun to explore the application of the SCRaMbLE system in genome compaction. Results We develop a method termed SCRaMbLE-based genome compaction (SGC) and demonstrate that a synthetic chromosome arm (synXIIL) can be efficiently reduced. The pre-introduced episomal essential gene array significantly enhances the compacting ability of SGC, not only by enabling the deletion of nonessential genes located in essential gene containing loxPsym units but also by allowing more chromosomal sequences to be removed in a single SGC process. Further compaction is achieved through iterative SGC, revealing that at least 39 out of 65 nonessential genes in synXIIL can be removed collectively without affecting cell viability at 30 °C in rich medium. Approximately 40% of the synthetic sequence, encoding 28 genes, is found to be dispensable for cell growth at 30 °C in rich medium and several genes whose functions are needed under specified conditions are identified. Conclusions We develop iterative SGC with the aid of eArray as a generic yet effective tool to compact the synthetic yeast genome.
A-to-I editing of miR-200b-3p in airway cells is associated with moderate-to-severe asthma
Authors: Kevin M. Magnaye, Katherine A. Naughton, Janel Huffman, D. Kyle Hogarth, Edward T. Naureckas, Steven R. White, Carole Ober
Journal: European Respiratory Journal (2021)

Background Asthma is a chronic lung disease characterised by persistent airway inflammation. Altered microRNA (miRNA)-mediated gene silencing in bronchial epithelial cells (BECs) has been reported in asthma, yet adenosine deaminase acting on RNA (ADAR)-mediated miRNA editing in asthma remains unexplored. Methods We first identified adenosine to inosine (A-to-I) edited sites in miRNAs in BECs from 142 adult asthma cases and controls. A-to-I edited sites were tested for associations with asthma severity and clinical measures of asthma. Paired RNA sequencing data were used to perform pathway enrichments and test for associations with bioinformatically predicted target genes of the unedited and edited miRNAs. Results Of 19 A-to-I edited sites detected in these miRNAs, one site at position 5 of miR-200b-3p was edited less frequently in cases compared with controls (p corrected =0.013), and especially compared with cases with moderate (p corrected =0.029) and severe (p corrected =3.9×10 −4 ), but not mild (p corrected =0.38), asthma. Bioinformatic prediction revealed 232 target genes of the edited miR-200b-3p, which were enriched for both interleukin-4 and interferon-γ signalling pathways, and included the SOCS1 (suppressor of cytokine signalling 1) gene. SOCS1 was more highly expressed in moderate (p corrected =0.017) and severe (p corrected =5.4×10 −3 ) asthma cases compared with controls. Moreover, both miR-200b-3p editing and SOCS1 were associated with bronchoalveolar lavage eosinophil levels. Conclusions Reduced A-to-I editing of position 5 of miR-200b-3p in lower airway cells from moderate-to-severe asthmatic subjects may lead to overexpression of SOCS1 and impaired cytokine signalling. We propose ADAR-mediated editing as an epigenetic mechanism contributing to features of moderate-to-severe asthma in adulthood.
Risk Stratification After Myocardial Infarction: Toward Novel Quantitative Assessment of Left Ventricular Mechanics?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Luc A. Piérard, Patrizio Lancellotti
Journal: Journal of the American College of Cardiology (2010)
Single-cell RNA sequencing reveals SARS-CoV-2 infection dynamics in lungs of African green monkeys
Authors: Emily Speranza, Brandi N. Williamson, Friederike Feldmann, Gail L. Sturdevant, Lizzette Pérez- Pérez, Kimberly Meade-White, Brian J. Smith, Jamie Lovaglio, Craig Martens, Vincent J. Munster, Atsushi Okumura, Carl Shaia, Heinz Feldmann, Sonja M. Best, Emmie de Wit
Journal: Science Translational Medicine (2021)

Single-cell RNA sequencing of lungs of SARS-CoV-2–infected African green monkeys reveals virus replication and host response dynamics in vivo.
T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes
Authors: Tiepeng Li, Lingdi Zhao, Yonghao Yang, Yao Wang, Yong Zhang, Jindong Guo, Guangyu Chen, Peng Qin, Benling Xu, Baozhen Ma, Fang Zhang, Yiman Shang, Qingjun Li, Kai Zhang, Dongfeng Yuan, Chaojie Feng, Yan Ma, Zhiyong Liu, Zhichao Tian, Hongle Li, Shengdian Wang, Quanli Gao
Journal: Cancer Research (2021)

Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-β (TCRβ) repertoires of the TILs and T cells expanded from paired PD-1+ PBLs, and whether T cells expanded from PD-1+ PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1+ PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRβ sequencing data revealed that an average of 11.29% (1.32%-29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1+ PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1+ PBLs was 35.11% (7.23%-78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1+ PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1+ PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes. SIGNIFICANCE: This study harnesses the tumor reactivity of PD-1+ PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer.See related commentary by Ladle, p. 1940.
Automated screening of COVID-19 preprints: can we help authors to improve transparency and reproducibility?
Authors: Tracey Weissgerber, Nico Riedel, Halil Kilicoglu, Cyril Labbé, Peter Eckmann, Gerben ter Riet, Jennifer Byrne, Guillaume Cabanac, Amanda Capes-Davis, Bertrand Favier, Shyam Saladi, Peter Grabitz, Alexandra Bannach-Brown, Robert Schulz, Sarah McCann, Rene Bernard, Anita Bandrowski
Journal: Nature Medicine (2021)
Brain 18F-FDG and 18F-Flumetamol PET Imaging of Fragile X-Associated Tremor Ataxia Syndrome
Authors: Ruggero Bacchin, Matteo Salgarello, Michela Trentin, Giampietro Zanette, Stefano Tamburin
Journal: Clinical Nuclear Medicine (2021)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare movement disorder caused by a 55-to-200 CGG-trinucleotide expansion premutation in the FMR1 gene. Core diagnostic criteria are tremor, ataxia, and T2-weighted hyperintensity of the middle cerebellar peduncles on MRI, but FXTAS encompass a broad spectrum of neurological symptoms. FXTAS pathophysiology is largely unknown, and some animal models and neuropathology findings suggest possible overlap with Alzheimer disease. We report the combined PET imaging of a genetically confirmed FXTAS patient, presenting reduced temporal-frontal 18F-FDG uptake, and pathological cortical deposition of amyloid to 18F-flumetamol PET scan. This report may offer clues to FXTAS pathophysiology.
Association of Female Reproductive Factors With Incidence of Fracture Among Postmenopausal Women in Korea
Authors: Jung Eun Yoo, Dong Wook Shin, Kyungdo Han, Dahye Kim, Ji Won Yoon, Dong-Yun Lee
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Although estrogen level is positively associated with bone mineral density, there are limited data on the risk of fractures after menopause. <h3>Objective</h3> To investigate whether female reproductive factors are associated with fractures among postmenopausal women. <h3>Design, Setting, and Participants</h3> This population-based retrospective cohort study used data from the Korean National Health Insurance Service database on 1 272 115 postmenopausal women without previous fracture who underwent both cardiovascular and breast and/or cervical cancer screening from January 1 to December 31, 2009. Outcome data were obtained through December 31, 2018. <h3>Exposures</h3> Information was obtained about reproductive factors (age at menarche, age at menopause, parity, breastfeeding, and exogenous hormone use) by self-administered questionnaire. <h3>Main Outcomes and Measures</h3> Incidence of any fractures and site-specific fractures (vertebral, hip, and others). <h3>Results</h3> Among the 1 272 115 participants, mean (SD) age was 61.0 (8.1) years. Compared with earlier age at menarche (≤12 years), later age at menarche (≥17 years) was associated with a higher risk of any fracture (adjusted hazard ratio [aHR], 1.24; 95% CI, 1.17-1.31) and vertebral fracture (aHR, 1.42; 95% CI, 1.28-1.58). Compared with earlier age at menopause (&lt;40 years), later age at menopause (≥55 years) was associated with a lower risk of any fracture (aHR, 0.89; 95% CI, 0.86-0.93), vertebral fracture (aHR, 0.77; 95% CI, 0.73-0.81), and hip fracture (aHR, 0.88; 95% CI, 0.78-1.00). Longer reproductive span (≥40 years) was associated with lower risk of fractures compared with shorter reproductive span (&lt;30 years) (any fracture: aHR, 0.86; 95% CI, 0.84-0.88; vertebral fracture: aHR, 0.73; 95% CI, 0.71-0.76; and hip fracture: aHR, 0.87; 95% CI, 0.80-0.95). Parous women had a lower risk of any fracture than nulliparous women (aHR, 0.96; 95% CI, 0.92-0.99). Although breastfeeding for 12 months or longer was associated with a higher risk of any fractures (aHR, 1.05; 95% CI, 1.03-1.08) and vertebral fractures (aHR, 1.22; 95% CI, 1.17-1.27), it was associated with a lower risk of hip fracture (aHR, 0.84; 95% CI, 0.76-0.93). Hormone therapy for 5 years or longer was associated with lower risk of any factures (aHR, 0.85; 95% CI, 0.83-0.88), while use of oral contraceptives for 1 year or longer was associated with a higher risk of any fractures (aHR, 1.03; 95% CI, 1.01-1.05). <h3>Conclusions and Relevance</h3> The findings of this cohort study suggest that female reproductive factors are independent risk factors for fracture, with a higher risk associated with shorter lifetime endogenous estrogen exposure. Interventions to reduce fracture risk may be needed for women at high risk, including those without osteoporosis.
Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70
Authors: Seung Yeob Hyun, Huong Thuy Le, Hye-Young Min, Honglan Pei, Yijae Lim, Injae Song, Yen T. K. Nguyen, Suckchang Hong, Byung Woo Han, Ho-Young Lee
Journal: Theranostics (2021)

Rationale: Cancer stem cells (CSCs) are known to cause tumor recurrence and drug resistance. The heat shock protein (HSP) system plays a major role in preserving expression and function of numerous oncoproteins, including those involved in the CSC activities. We explored novel anticancer drugs, especially those targeting HSP components required for the functional role of CSCs. Methods: Investigation of the role of the HSP system in CSCs and screening of a natural product chemical library were performed by utilizing cancer cell lines, primary cultures of patient-derived xenografts (PDXs), and their putative CSC subpopulations (i.e., those grown under sphere-forming conditions, stably transfected with reporter vectors carrying NANOG or POUSF1 promoters, or carrying high ALDH activity) in vitro and PDX and KrasG12D/+-driven tumor models in vivo. Regulation of the HSP system was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. Results: The HSP system was activated in CSCs via transcriptional upregulation of the HSP system components, especially HSP70. Evodiamine (Evo) was identified to induce apoptosis in both CSC and bulk non-CSC populations in human lung, colon, and breast cancer cells and their sublines with chemoresistance. Evo administration decreased the multiplicity, volume, and load of lung tumors in KrasG12D/+ transgenic mice and the growth of cancer cell line- and PDX-derived tumors without detectable toxicity. Mechanistically, Evo disrupted the HSP system by binding the N-terminal ATP-binding pocket of HSP70 and causing its ubiquitin-mediated degradation. Conclusions: Our findings illustrate HSP70 as a potential target for eliminating CSCs and Evo as an effective HSP70-targeting anticancer drug eradicating both CSCs and non-CSCs with a minimal toxicity.
Risk Factors Associated With All-Cause 30-Day Mortality in Nursing Home Residents With COVID-19
Authors: Orestis A. Panagiotou, Cyrus M. Kosar, Elizabeth M. White, Leonidas E. Bantis, Xiaofei Yang, Christopher M. Santostefano, Richard A. Feifer, Carolyn Blackman, James L. Rudolph, Stefan Gravenstein, Vincent Mor
Journal: JAMA Internal Medicine (2021)

The coronavirus disease 2019 (COVID-19) pandemic has severely affected nursing homes. Vulnerable nursing home residents are at high risk for adverse outcomes, but improved understanding is needed to identify risk factors for mortality among nursing home residents. To identify risk factors for 30-day all-cause mortality among US nursing home residents with COVID-19. This cohort study was conducted at 351 US nursing homes among 5256 nursing home residents with COVID-19-related symptoms who had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction testing between March 16 and September 15, 2020. Resident-level characteristics, including age, sex, race/ethnicity, symptoms, chronic conditions, and physical and cognitive function. Death due to any cause within 30 days of the first positive SARS-CoV-2 test result. The study included 5256 nursing home residents (3185 women [61%]; median age, 79 years [interquartile range, 69-88 years]; and 3741 White residents [71%], 909 Black residents [17%], and 586 individuals of other races/ethnicities [11%]) with COVID-19. Compared with residents aged 75 to 79 years, the odds of death were 1.46 (95% CI, 1.14-1.86) times higher for residents aged 80 to 84 years, 1.59 (95% CI, 1.25-2.03) times higher for residents aged 85 to 89 years, and 2.14 (95% CI, 1.70-2.69) times higher for residents aged 90 years or older. Women had lower risk for 30-day mortality than men (odds ratio [OR], 0.69 [95% CI, 0.60-0.80]). Two comorbidities were associated with mortality: diabetes (OR, 1.21 [95% CI, 1.05-1.40]) and chronic kidney disease (OR, 1.33 [95%, 1.11-1.61]). Fever (OR, 1.66 [95% CI, 1.41-1.96]), shortness of breath (OR, 2.52 [95% CI, 2.00-3.16]), tachycardia (OR, 1.31 [95% CI, 1.04-1.64]), and hypoxia (OR, 2.05 [95% CI, 1.68-2.50]) were also associated with increased risk of 30-day mortality. Compared with cognitively intact residents, the odds of death among residents with moderate cognitive impairment were 2.09 (95% CI, 1.68-2.59) times higher, and the odds of death among residents with severe cognitive impairment were 2.79 (95% CI, 2.14-3.66) times higher. Compared with residents with no or limited impairment in physical function, the odds of death among residents with moderate impairment were 1.49 (95% CI, 1.18-1.88) times higher, and the odds of death among residents with severe impairment were 1.64 (95% CI, 1.30-2.08) times higher. In this cohort study of US nursing home residents with COVID-19, increased age, male sex, and impaired cognitive and physical function were independently associated with mortality. Understanding these risk factors can aid in the development of clinical prediction models of mortality in this population.
Effect of Lowering V<scp>t</scp> on Mortality in Acute Respiratory Distress Syndrome Varies with Respiratory System Elastance
Authors: Ewan C. Goligher, Eduardo L. V. Costa, Christopher J. Yarnell, Laurent J. Brochard, Thomas E. Stewart, George Tomlinson, Roy G. Brower, Arthur S. Slutsky, Marcelo P. B. Amato
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: If the risk of ventilator-induced lung injury in acute respiratory distress syndrome (ARDS) is causally determined by driving pressure rather than by Vt, then the effect of ventilation with lower Vt on mortality would be predicted to vary according to respiratory system elastance (Ers). Objectives: To determine whether the mortality benefit of ventilation with lower Vt varies according to Ers. Methods: In a secondary analysis of patients from five randomized trials of lower- versus higher-Vt ventilation strategies in ARDS and acute hypoxemic respiratory failure, the posterior probability of an interaction between the randomized Vt strategy and Ers on 60-day mortality was computed using Bayesian multivariable logistic regression. Measurements and Main Results: Of 1,096 patients available for analysis, 416 (38%) died by Day 60. The posterior probability that the mortality benefit from lower-Vt ventilation strategies varied with Ers was 93% (posterior median interaction odds ratio, 0.80 per cm H2O/[ml/kg]; 90% credible interval, 0.63-1.02). Ers was classified as low (<2 cm H2O/[ml/kg], n = 321, 32%), intermediate (2-3 cm H2O/[ml/kg], n = 475, 46%), and high (>3 cm H2O/[ml/kg], n = 224, 22%). In these groups, the posterior probabilities of an absolute risk reduction in mortality ≥ 1% were 55%, 82%, and 92%, respectively. The posterior probabilities of an absolute risk reduction ≥ 5% were 29%, 58%, and 82%, respectively. Conclusions: The mortality benefit of ventilation with lower Vt in ARDS varies according to elastance, suggesting that lung-protective ventilation strategies should primarily target driving pressure rather than Vt.
Subcutaneous Rituximab-MiniCHOP Compared With Subcutaneous Rituximab-MiniCHOP Plus Lenalidomide in Diffuse Large B-Cell Lymphoma for Patients Age 80 Years or Older
Authors: Lucie Oberic, Frederic Peyrade, Mathieu Puyade, Christophe Bonnet, Peggy Dartigues-Cuillères, Bettina Fabiani, Philippe Ruminy, Hervé Maisonneuve, Julie Abraham, Catherine Thieblemont, Pierre Feugier, Gilles Salles, Fontanet Bijou, Gian-Matteo Pica, Gandhi Damaj, Corinne Haioun, René-Olivier Casasnovas, Hassan Farhat, Ronan Le Calloch, Agathe Waultier-Rascalou, Sandra Malak, Jerome Paget, Elodie Gat, Hervé Tilly, Fabrice Jardin
Journal: Journal of Clinical Oncology (2021)

PURPOSE: The prognosis of elderly patients with diffuse large B-cell lymphoma (DLBCL) is worse than that of young patients. An attenuated dose of chemotherapy—cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-miniCHOP)—is a good compromise between efficacy and safety in very elderly patients. In combination with R-CHOP (R2-CHOP), lenalidomide has an acceptable level of toxicity and may mitigate the negative prognosis of the non–germinal center B-cell–like phenotype. The Lymphoma Study association conducted a multicentric, phase III, open-label, randomized trial to compare R-miniCHOP and R2-miniCHOP. PATIENTS AND METHODS: Patients of age 80 years or older with untreated DLBCL were randomly assigned into the R-miniCHOP21 group or the R2-miniCHOP21 group for six cycles and stratified according to CD10 expression and age. The first cycle of rituximab was delivered by IV on D1 after a prephase and then delivered subcutaneously on D1 of cycles 2-6. Lenalidomide was delivered at a dose of 10 mg once daily on D1-D14 of each cycle. The primary end point was overall survival (OS). RESULTS: A total of 249 patients with new DLBCL were randomly assigned (127 R-miniCHOP and 122 R2-miniCHOP). The median age was 83 years (range, 80-96), and 55% of the patients were classified as non-GCB. The delivered dose for each R-miniCHOP compound was similar in both arms. Over a median follow-up of 25.1 months, the intention-to-treat analysis revealed that R2-miniCHOP did not improve OS (2-year OS 66% in R-miniCHOP and 65.7% in R2-miniCHOP arm, P = .98) in the overall population or in the non-GCB population. Grade 3-4 adverse events occurred in 53% of patients with R-miniCHOP and in 81% of patients with R2-miniCHOP. CONCLUSION: The addition of lenalidomide to R-miniCHOP does not improve OS. Rituximab delivered subcutaneously was safe in this population.
Cytokine Regulation and Function in T Cells
Authors: Chen Dong
Journal: Annual Review of Immunology (2021)

T lymphocytes, the major effector cells in cellular immunity, produce cytokines in immune responses to mediate inflammation and regulate other types of immune cells. Work in the last three decades has revealed significant heterogeneity in CD4+ T cells, in terms of their cytokine expression, leading to the discoveries of T helper 1 (Th1), Th2, Th17, and T follicular helper (Tfh) cell subsets. These cells possess unique developmental and regulatory pathways and play distinct roles in immunity and immune-mediated pathologies. Other types of T cells, including regulatory T cells and γδ T cells, as well as innate lymphocytes, display similar features of subpopulations, which may play differential roles in immunity. Mechanisms exist to prevent cytokine production by T cells to maintain immune tolerance to self-antigens, some of which may also underscore immune exhaustion in the context of tumors. Understanding cytokine regulation and function has offered innovative treatment of many human diseases.
Social Behavior as a Transdiagnostic Marker of Resilience
Authors: Ruth Feldman
Journal: Annual Review of Clinical Psychology (2021)

The recent shift from psychopathology to resilience and from diagnosis to functioning requires the construction of transdiagnostic markers of adaptation. This review describes a model of resilience that is based on the neurobiology of affiliation and the initial condition of mammals that mature in the context of the mother's body and social behavior. The model proposes three tenets of resilience-plasticity, sociality, and meaning-and argues that coordinated social behavior stands at the core sustaining resilience. Two lines in the maturation of coordinated social behavior are charted, across animal evolution and throughout human development, culminating in the mature human reciprocity of empathy, mutuality, and perspective-taking. Cumulative evidence across ages and clinical conditions and based on our behavioral coding system demonstrates that social reciprocity, defined by plasticity at the individual, dyadic, and group levels, denotes resilience, whereas the two poles of disengagement/avoidance and intrusion/rigidity characterize specific psychopathologies, each with a distinct behavioral signature. Attention to developmentally sensitive markers and to the dimension of meaning in human sociality may open new, behavior-based pathways to resilience.