tbuckley/cabot-search huggingface dataset:
Scalable Empirical Mixture Models That Account for Across-Site Compositional Heterogeneity
Authors: Dominik Schrempf, Nicolas Lartillot, Gergely Szöllősi
Journal: Molecular Biology and Evolution (2020)

Abstract Biochemical demands constrain the range of amino acids acceptable at specific sites resulting in across-site compositional heterogeneity of the amino acid replacement process. Phylogenetic models that disregard this heterogeneity are prone to systematic errors, which can lead to severe long-branch attraction artifacts. State-of-the-art models accounting for across-site compositional heterogeneity include the CAT model, which is computationally expensive, and empirical distribution mixture models estimated via maximum likelihood (C10–C60 models). Here, we present a new, scalable method EDCluster for finding empirical distribution mixture models involving a simple cluster analysis. The cluster analysis utilizes specific coordinate transformations which allow the detection of specialized amino acid distributions either from curated databases or from the alignment at hand. We apply EDCluster to the HOGENOM and HSSP databases in order to provide universal distribution mixture (UDM) models comprising up to 4,096 components. Detailed analyses of the UDM models demonstrate the removal of various long-branch attraction artifacts and improved performance compared with the C10–C60 models. Ready-to-use implementations of the UDM models are provided for three established software packages (IQ-TREE, Phylobayes, and RevBayes).
The novel application of a tourniquet for reducing medical device–related pressure on the ears
Authors: Xiaodan Zhao, Ruiqi Liu, Xuan Zhou
Journal: Journal of the American Academy of Dermatology (2020)

The 2019 novel coronavirus broke out and spread worldwide quickly, leading to serious infection and the deaths of many people. To prevent and control this disease, it is especially important for health care workers to wear ear-looped face masks and spectacles to cut off transmission routes and protect themselves. However, there is a strong possibility of generating medical device–related pressure injuries on the ears when wearing protective equipment for a long time, putting users at higher risks of ulcers and infection. A novel application of a tourniquet (Fig 1) for reducing pressure injury on the ears can be used to solve this problem. First, cut a clean tourniquet into 4 pieces and set 2 of them on the spectacles frames. Second, cut through the other 2 segments and set them on the ear loops of the face mask (Fig 2).Fig 2The 4 segments of 1 tourniquet are set on ear loops of a face mask and spectacles frames.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This method has 3 advantages. First, it is simple and inexpensive to obtain the tourniquet, which can be disinfected with 75% alcohol repeatedly. Second, the tourniquet can largely relieve the pressure of face masks and spectacles on the ears, making users feel relatively comfortable. Third, the tourniquet increases the friction force between the ears and protective equipment, to a large extent preventing ear-looped face masks and spectacles from slipping off easily.
Abstract 5038: Limited inhibition of multiple nodes in a driver network blocks metastasis
Authors: Ali Ekrem Yesilkanal, Dongbo Yang, Payal Tiwari, Alan U. Sabino, Jiyoung Lee, Xiao-He Xie, Siqi Sun, Christopher Dann, Ethan Steinberg, Timothy Stuhlmiller, Casey Frankenberger, Elizabeth Goldsmith, Gary L. Johnson, Alexandre F. Ramos, Marsha Rosner
Journal: Cancer Research (2020)

Abstract High-dose, single-drug treatment is unsuccessful at suppressing metastasis due to cellular heterogeneity and feedback activation. Here we demonstrate that targeting driver network signaling capacity by limited inhibition at multiple nodes is a more effective anti-metastatic strategy. A physiological metastasis suppressor, Raf Kinase Inhibitory Protein, decreases the activity of multiple kinases in the stress-regulated MAP kinase (MAPK) network and reduces the output to metastatic transcription factor BACH1 that upregulates motility-related genes. This effect is mimicked by a low-dose four-drug cocktail (4D-MAPKi) that blocks metastatic colonization in mouse breast cancer models and increases survival. Drug treatment and network modeling show that 1) multi-kinase inhibition is required to suppress signaling output across cells with different MAPK network topologies, and 2) restricting inhibition of individual kinases prevents threshold activation of other compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of a driver network represents a transformative, clinically-relevant strategy for anti-metastatic treatment. Citation Format: Ali Ekrem Yesilkanal, Dongbo Yang, Payal Tiwari, Alan U. Sabino, Jiyoung Lee, Xiao-He Xie, Siqi Sun, Christopher Dann, Ethan Steinberg, Timothy Stuhlmiller, Casey Frankenberger, Elizabeth Goldsmith, Gary L. Johnson, Alexandre F. Ramos, Marsha Rosner. Limited inhibition of multiple nodes in a driver network blocks metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5038.
Association of Prefrontal-Striatal Functional Pathology With Alcohol Abstinence Days at Treatment Initiation and Heavy Drinking After Treatment Initiation
Authors: Sara K. Blaine, Stephanie Wemm, Nia Fogelman, Cheryl Lacadie, Dongju Seo, Dustin Scheinost, Rajita Sinha
Journal: American Journal of Psychiatry (2020)

Alcohol use disorder (AUD) is associated with neuroadaptations in brain stress and reward circuits. It is not known whether such neuroadaptations are affected by number of days of alcohol abstinence and whether they influence heavy drinking during the early treatment phase. The authors used a novel functional MRI (fMRI) approach to assess brain responses during sustained exposure to standardized visual stimuli of stressful, alcohol cue, and neutral control images combined with prospective assessment of drinking outcomes during early outpatient treatment, in two related studies.In study 1, 44 treatment-entering patients with AUD and 43 demographically matched healthy control subjects participated in the fMRI experiment to identify dysfunctional responses associated with chronic alcohol abuse. In study 2, 69 treatment-entering patients with AUD were assessed for whether fMRI responses at treatment initiation were influenced by alcohol abstinence and were prospectively predictive of early heavy drinking outcomes.Relative to control subjects, patients with AUD showed significant hyperreactivity in the ventromedial prefrontal cortex (vmPFC) in response to neutral images, but significant hypoactivation in the vmPFC and ventral striatum in response to stress images and to alcohol cues relative to response to neutral images. In study 2, this specific prefrontal-ventral striatal dysfunction was associated with fewer days of alcohol abstinence and also predicted greater number heavy drinking days during the subsequent 2 weeks of treatment engagement.Number of days of alcohol abstinence at treatment initiation significantly affected functional disruption of the prefrontal-striatal responses to stress images and to alcohol cues in patients with AUD, and the severity of this disruption in turn predicted greater heavy drinking during early treatment. Treatments that target this functional prefrontal-striatal pathology could improve early treatment outcomes in AUD.
Abstract 315: Community Characteristics Associated With Out of Hospital Cardiac Arrest Mortality: The Intersection of Urbanicity, Poverty, and Race
Authors: John Barbe, David F Gaieski, Alexis M Zebrowski, David G Buckler, Marissa N Lang, Benjamin S Abella, Brendan G Carr
Journal: Circulation (2019)

Introduction: Variation in survival for out-of-hospital cardiac arrest (OHCA) has been described, but the intersection of urbanicity, race, and poverty and the impact on OHCA outcomes remains unclear. We sought to test whether rurality was associated with increased in-hospital mortality compared to urban and suburban communities when accounting for differences in poverty and race. Methods: We performed a retrospective analysis using 2013-2014 Medicare claims for inpatient stays originating in the emergency department. OHCA Patients (≥65 years) were identified by ICD-9-CM diagnosis code. Urbanicity was assigned based on county of residence using Rural-Urban Continuum Codes. Census data were used for county poverty and racial composition measures. Multivariate logistic regression was used to estimate the association of in-hospital mortality with urbanicity, percent of resident population in poverty, and percent black residency. Also included were individual, hospital, and community characteristics. Results: A total of 246,736 OHCA cases were identified of which 53% were male, 23% non-white, and 36% &gt;75 years. Survival to discharge was 22%. Over 95% of OHCA patients resided in urban (85%) or suburban (11%) areas. Predicted probabilities of death (Figure) were lowest in suburban communities with moderate poverty and small black populations (0.76, CI 0.75-0.76) and highest in urban areas with moderate poverty and larger black populations (0.80, CI 0.80-0.81). All areas with high poverty and larger black populations had similar predicted probabilities (0.77-0.78), regardless of urbanicity. Conclusions: Suburban residence was associated with lower odds of mortality, even in communities with high levels of poverty. Communities with moderate poverty showed the greatest spread of outcomes in all 3 urbanicity categories. Further work should explore access to care, social determinants of health, and hospital factors that lead to the observed disparities.
Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2
Authors: Sandra C.A. Nielsen, Fan Yang, Katherine J.L. Jackson, Ramona A. Hoh, Katharina Röltgen, Grace H. Jean, Bryan A. Stevens, Ji-Yeun Lee, Arjun Rustagi, Angela J. Rogers, Abigail E. Powell, Molly Hunter, Javaria Najeeb, Ana R. Otrelo-Cardoso, Kathryn E. Yost, Bence Daniel, Kari C. Nadeau, Howard Y. Chang, Ansuman T. Satpathy, Theodore S. Jardetzky, Peter S. Kim, Taia T. Wang, Benjamin A. Pinsky, Catherine A. Blish, Scott D. Boyd
Journal: Cell Host & Microbe (2020)
Predictive equations of maximum respiratory mouth pressures: A systematic review
Authors: S. Souto-Miranda, C. Jácome, A. Alves, A. Machado, C. Paixão, A. Oliveira, A. Marques
Journal: Pulmonology (2020)

Maximum inspiratory (Pimax) and expiratory (Pemax) mouth pressures are commonly used to detect respiratory muscle weakness resorting to predictive equations established for healthy people. There are several predictive equations, but they are widespread in the literature. This study aimed to review the existent predictive equations of maximum inspiratory (Pimax) and expiratory (Pemax) mouth pressures for adults. Additionally, we aimed to identify which ones were generated based on international standards. A systematic review of predictive equations of Pimax and Pemax for healthy adults was conducted. A comprehensive search was performed of Cochrane Library, EBSCO, PubMed, Scopus and Web of Science to identify studies that presented at least one equation for Pimax or Pemax developed for healthy adults. The quality of studies was assessed by two reviewers with the Quality Assessment of Diagnostic Accuracy Studies (Quadas-2). Risk of bias was high in 8 of the 20 studies included. Forty-two Pimax and 34 Pemax equations were found, mostly using the variables age (n = 39), weight (n = 20) and height (n = 8). These equations explained 3 to 96% of the Pimax/Pemax variance. They were developed with individuals from 11 countries (Portugal not included). Twelve Pimax and eight Pemax equations complied with international standards. This review gathered the predictive equations that have been developed for both Pimax and Pemax, however most were generated from unstandardized procedures. Future studies should explore the suitability of these equations for populations for which specific ones are not available, such as the Portuguese population, and develop new equations if necessary.
Mining social media data to investigate patient perceptions regarding DMARD pharmacotherapy for rheumatoid arthritis
Authors: Chanakya Sharma, Samuel Whittle, Pari Delir Haghighi, Frada Burstein, Roee Sa'adon, Helen Isobel Keen
Journal: Annals of the Rheumatic Diseases (2020)

We hypothesise that patients have a positive sentiment regarding biological/targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) and a negative sentiment towards conventional synthetic agents (csDMARDs). We analysed discussions on social media platforms regarding DMARDs to understand the collective sentiment expressed towards these medications.Treato analytics were used to download all available posts on social media about DMARDs in the context of rheumatoid arthritis. Strict filters ensured that user generated content was downloaded. The sentiment (positive or negative) expressed in these posts was analysed for each DMARD using sentiment analysis. We also analysed the reason(s) for this sentiment for each DMARD, looking specifically at efficacy and side effects.Computer algorithms analysed millions of social media posts and included 54 742 posts about DMARDs. We found that both classes had an overall positive sentiment. The ratio of positive to negative posts was higher for b/tsDMARDs (1.210) than for csDMARDs (1.048). Efficacy was the most commonly mentioned reason in posts with a positive sentiment and lack of efficacy was the most commonly mentioned reason for a negative sentiment. These were followed by the presence/absence of side effects in negative or positive posts, respectively.Public opinion on social media is generally positive about DMARDs. Lack of efficacy followed by side effects were the most common themes in posts with a negative sentiment. There are clear reasons why a DMARD generates a positive or negative sentiment, as the sentiment analysis technology becomes more refined, targeted studies could be done to analyse these reasons and allow clinicians to tailor DMARDs to match patient needs.
Biofunctional Elements Incorporated Nano/Microstructured Coatings on Titanium Implants with Enhanced Osteogenic and Antibacterial Performance
Authors: Na Xu, Jijiang Fu, Lingzhou Zhao, Paul K. Chu, Kaifu Huo
Journal: Advanced Healthcare Materials (2020)

Abstract Bone fracture is prevalent among athletes and senior citizens and may require surgical insertion of bone implants. Titanium (Ti) and its alloys are widely used in orthopedics due to its high corrosion resistance, good biocompatibility, and modulus compatible with natural bone tissues. However, bone repair and regrowth are impeded by the insufficient intrinsic osteogenetic capability of Ti and Ti alloys and potential bacterial infection. The physicochemical properties of the materials and nano/microstructures on the implant surface are crucial for clinical success and loading with biofunctional elements such as Sr, Zn, Cu, Si, and Ag into nano/microstructured TiO 2 coating has been demonstrated to enhance bone repair/regeneration and bacterial resistance of Ti implants. In this review, recent advances in biofunctional element‐incorporated nano/microstructured coatings on Ti and Ti alloy implants are described and the prospects and limitations are discussed.
Abstract 3427: Finding critical cancer driving and cancer suppressing genes using functional genomics screening <i>in vivo</i>
Authors: Marco Josef Herold, Shinsuke Mizutani, Yexuan Deng, Ana Janic, Andrew Kueh, Martin Pal, Stephen Wilcox, Lin Tai, Gemma L. Kelly, Andreas Strasser
Journal: Cancer Research (2020)

Abstract P53 is one of the most potent tumour suppressors and its activity is also required for cancer cells to respond to diverse chemotherapeutic drugs. Focused functional genetic screens in haematopoietic cells in vivo revealed DNA repair to be one of the most critical downstream pathways for p53's tumour suppressive function. Recently, we extended our search for novel tumour suppressor genes acting potentially outside the p53 tumour suppressor pathway. To this end, we performed whole genome CRISPR/Cas9 knockout screening in vivo, using the Eµ-Myc transgenic mouse model. This identified previously unknown genes and hence pathways, which upon deletion/mutation lead to the acceleration of tumour onset. Amongst these novel tumour suppressor genes, we identified the GATOR1 members DEPDC5 and NPRL3, which are known inhibitors of the mTOR pathway. Interestingly, drug mediated inhibition of mTOR activity with rapamycin or Torin1 in GATOR1 deficient Eµ-Myc cells led to efficient killing of these malignant cells, which was in striking contrast to control Eµ-Myc lymphoma cells that were resistant to this treatment. In parallel we conducted CRISPR/Cas9 screens for identifying p53 bound promoter and enhancer elements in haematopoietic cells in vivo. Excitingly, we observed that targeting the NPRL3 promoter led to accelerated tumour onset in the Eµ-Myc transgenic model, suggesting that NPRL3 is under direct transcriptional control of p53. These results indicate that p53 mediated shutdown of the mTOR pathway through upregulation of the GATOR1 member NPRL3 is a critical tumour suppressive function of p53. Citation Format: Marco Josef Herold, Shinsuke Mizutani, Yexuan Deng, Ana Janic, Andrew Kueh, Martin Pal, Stephen Wilcox, Lin Tai, Gemma L. Kelly, Andreas Strasser. Finding critical cancer driving and cancer suppressing genes using functional genomics screening in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3427.
Abstract PS19-21: Tak1 signaling regulates p53 through a mechanism involving ribosomal stress
Authors: Andrei Bakin, Justin Zonneville
Journal: Cancer Research (2021)

Abstract Triple-negative breast cancer (TNBC) is among the most aggressive forms of breast cancer with limited therapeutic options. TAK1 is implicated in aggressive behavior of TNBC, while means are not fully understood. Here, we report that pharmacological blockade of TAK1 signaling hampered ribosome biogenesis (RBG) by reducing expression of RBG regulators such as RRS1, while not changing expression of ribosomal core proteins. Importantly, TAK1 blockade upregulated expression of p53 target genes in cell lines carrying wild type (wt) TP53 but not in p53-mutant cells. By examining involvement of the ribosomal stress response, we found that p53 activation by blockade of TAK1 was prevented by depletion of ribosomal protein RPL11. Further, siRNA-mediated depletion of TAK1 or RELA resulted in activation of p53 signaling and this response was dependent on RPL11. Knockdown of RRS1 disrupted nucleolar organization and resulted in activation of p53. Genomic TCGA data showed that TNBCs express high levels of ribosome biogenesis regulators, and elevated RRS1 levels correlate with unfavorable prognosis. Cytotoxicity data showed that TNBC cell lines are more sensitive to TAK1 inhibitor compared to luminal and HER2+ cell lines. Together, the data indicate that TAK1 regulates p53 activation by controlling ribosome biogenesis factors, and the TAK1-ribosome axis is a potential therapeutic target in TNBC. Citation Format: Andrei Bakin, Justin Zonneville. Tak1 signaling regulates p53 through a mechanism involving ribosomal stress [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-21.
Abstract 3876: Multiplex immunohistochemistry accurately defines the immune compositional change of tumor microenvironment to predict hyperprogressive disease
Authors: Seoree Kim, Sang Hoon Chun, Sang-Yeob Kim, Junyoung Seo, Chan Kwon Jung, Jinhyoung Kang
Journal: Cancer Research (2020)

Abstract Introduction: To retrospectively assess hyperprogressive disease(HPD) in patients who underwent immune checkpoint blockade therapy and explore the heterogenous nature of tumor microenvironment of hyperprogressive patients using multiplex immunohistochemistry. Method: We retrospectively reviewed medical records of non-small cell lung cancer patients (n=243) treated with anti-PD-1 or anti-PD-L1 monotherapy at 5 institutes of St. Mary's Hospitals between January 2014 and May 2018. HPD was defined as a tumor growth kinetics ratio (TGKr) exceeding two during anti-PD-1 / PD-L1 therapy and a time-to-failure (TTF) of less than 2 months. We also analyzed the association of Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and CRP-albumin ratio (CAR) with HPD. To evaluate the difference of immune composition in TME by multiplex IHC(mIHC). Panel 1/2 composed of T cell markers and co-inhibitory signal markers. Panel 3/4 examined macrophages, NK cells and dendritic cells. Results: Overall, 231 patients were included. Overall, 26 patients (11.3%) met the criteria for hyperprogression. Multiplex IHX data quantitated immune subset number present intra-tumor vs the tumor stroma. there was a difference in immune cell composition between the HPD, poor responders (PRs) and good responders (GRs). High levels of CD4 + Teff cells, FOXP3 Treg cells were associated with HPD(p &amp;lt; 0.052, &amp;lt;0.017) and CD4 to CD45RO ratio indicated a potential predictive value to develop HPD(p &amp;lt; 0.042). Key observation was that there was a tendency to M2 polarization in patients with HPD when the macrophage M1/2 markers of CD14, CD68 and CD163 were observed. And the myeloid markers, such as CD11c, expressed by CAFs, tend to increase in the intra-tumor lesion of the HPD group (p &amp;lt; 0.501). Conclusion: This study was important in investigating the HPD-related immune prognostic factors in NSCLC patients in korea. According to these data, HPD is a unique biologic process distinct from a non HPD-PR. Multiplex IHC can be used not only to predict HPD, but also to understand the dynamicity and the complexed immune compositional change within TME. Furthermore, based on these findings, we are undergoing study the TME by serially collected pre- and post-treatment tissue samples, it may be helpful to shed light on the mechanisms of HPD. Citation Format: Seoree Kim, Sang Hoon Chun, Sang-Yeob Kim, Junyoung Seo, Chan Kwon Jung, Jinhyoung Kang. Multiplex immunohistochemistry accurately defines the immune compositional change of tumor microenvironment to predict hyperprogressive disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3876.
OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING
Authors: Yunyun Guo, Fei Jiang, Lingli Kong, Haifeng Wu, Honghai Zhang, Xiaorong Chen, Jian Zhao, Baoshan Cai, Yanqi Li, Chunhong Ma, Fan Yi, Lei Zhang, Bingyu Liu, Yi Zheng, Lingqiang Zhang, Chengjiang Gao
Journal: Cellular and Molecular Immunology (2020)