tbuckley/cabot-search huggingface dataset:
Evolution-Based Protein Engineering for Antifungal Peptide Improvement
Authors: Jing Gu, Noriyoshi Isozumi, Shouli Yuan, Ling Jin, Bin Gao, Shinya Ohki, Shunyi Zhu
Journal: Molecular Biology and Evolution (2021)

Antimicrobial peptides (AMPs) have been considered as the alternatives to antibiotics because of their less susceptibility to microbial resistance. However, compared with conventional antibiotics they show relatively low activity and the consequent high cost and nonspecific cytotoxicity, hindering their clinical application. What's more, engineering of AMPs is a great challenge due to the inherent complexity in their sequence, structure, and function relationships. Here, we report an evolution-based strategy for improving the antifungal activity of a nematode-sourced defensin (Cremycin-5). This strategy utilizes a sequence-activity comparison between Cremycin-5 and its functionally diverged paralogs to identify sites associated with antifungal activity for screening of enhanceable activity-modulating sites for subsequent saturation mutagenesis. Using this strategy, we identified a site (Glu-15) whose mutations with nearly all other types of amino acids resulted in a universally enhanced activity against multiple fungal species, which is thereby defined as a Universally Enhanceable Activity-Modulating Site (UEAMS). Especially, Glu15Lys even exhibited >9-fold increased fungicidal potency against several clinical isolates of Candida albicans through inhibiting cytokinesis. This mutant showed high thermal and serum stability and quicker killing kinetics than clotrimazole without detectable hemolysis. Molecular dynamic simulations suggest that the mutations at the UEAMS likely limit the conformational flexibility of a distant functional residue via allostery, enabling a better peptide-fungus interaction. Further sequence, structural, and mutational analyses of the Cremycin-5 ortholog uncover an epistatic interaction between the UEAMS and another site that may constrain its evolution. Our work lights one new road to success of engineering AMP drug leads.
Factors related to liver impairment during SARS-CoV-2 infection
Authors: L. Canillas, G. Pagano, T. Broquetas, J. Romero, E. Garrido, A. Viu, J. A. Carrion, N. C. Hidalgo, S. Coll, X. Bessa, M. Garcia-Retortillo, M. Puigvehi
Journal: Journal of Hepatology (2021)
Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota
Authors: Thomas Vogl, Shelley Klompus, Sigal Leviatan, Iris N. Kalka, Adina Weinberger, Cisca Wijmenga, Jingyuan Fu, Alexandra Zhernakova, Rinse K. Weersma, Eran Segal
Journal: Nature Medicine (2021)
Several miRNAs derived from serum extracellular vesicles are potential biomarkers for early diagnosis and progression of Parkinson’s disease
Authors: Shulei He, Lu Huang, Ci Shao, Tiejian Nie, Li Xia, Bozhou Cui, Fangfang Lu, Lin Zhu, Bolin Chen, Qian Yang
Journal: Translational Neurodegeneration (2021)

Abstract Background Blood-based test for predicting disease progression and early diagnosis of Parkinson’s disease (PD) is an unmet need in the clinic. The profiles of microRNAs (miRNAs) are regarded as potential diagnostic biomarkers for human diseases, whereas miRNAs in the periphery are susceptible to the influence of various components. MiRNAs enriched in serum extracellular vesicles (EVs) have demonstrated disease-specific advantages in diagnosis due to their high abundance, stability and resistance to degradation. This study was aimed to screen differentially expressed EV-derived miRNAs between healthy controls and PD patients to aid in diagnosis of PD. Methods A total of 31 healthy controls and 72 patients with a diagnosis of PD at different Hoehn and Yahr stages in Tangdu Hospital were included. In total, 185 differentially expressed miRNAs were obtained through RNA sequencing of serum EVs as well as edgeR and t -test analyses. Subsequently, the weighted gene co-expression network analysis (WGCNA) was utilized to identify the commonly expressed miRNAs in all stages of PD by constructing connections between modules, and specifically expressed miRNAs in each stage of PD by functional enrichment analysis. After aligning these miRNAs with PD-related miRNAs in Human miRNA Disease Database, the screened miRNAs were further validated by receiver operating characteristic (ROC) curves and quantitative real-time polymerase chain reaction (qRT-PCR) using peripheral blood EVs from 40 more participants. Results WGCNA showed that 4 miRNAs were commonly associated with all stages of PD and 13 miRNAs were specifically associated with different stages of PD. Of the 17 obtained miRNAs, 7 were validated by ROC curve analysis and 7 were verified in 40 more participants by qRT-PCR. Six miRNAs were verified by both methods, which included 2 miRNAs that were commonly expressed in all stages of PD and 4 miRNAs that were specifically expressed in different stages of PD. Conclusions The 6 serum EV-derived miRNAs, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-199a-3p, hsa-miR-28-5p, hsa-miR-22-5p and hsa-miR-151a-5p, may potentially be used as biomarkers for PD progression and for early diagnosis of PD in populations.
Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults
Authors: Philip S. Insel, Brian S. Mohlenhoff, Thomas C. Neylan, Andrew D. Krystal, R. Scott Mackin
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology. <h3>Objective</h3> To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults. <h3>Design, Setting, and Participants</h3> In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had<i>APOE</i>genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021. <h3>Exposures</h3> Self-reported daytime and nighttime sleep duration. <h3>Main Outcomes and Measures</h3> Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio. <h3>Results</h3> Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive). Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (<i>F</i><sub>1, 4419</sub> = 5.0;<i>P</i> = .03), a 0.009 reduction of medial orbitofrontal Aβ (<i>F</i><sub>1, 4419</sub> = 17.4;<i>P</i> &lt; .001), and a 0.011 reduction of anterior cingulate Aβ (<i>F</i><sub>1, 4419</sub> = 15.9;<i>P</i> &lt; .001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (<i>F</i><sub>1,2910</sub> = 16.9;<i>P</i> &lt; .001) and a 0.005 reduction of anterior cingulate Aβ (<i>F</i><sub>1,2910</sub> = 7.6;<i>P</i> = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (<i>F</i><sub>1,2910</sub> = 7.3;<i>P</i> = .03) and a 0.024 increase of posterior cingulate Aβ (<i>F</i><sub>1,2910</sub> = 14.2;<i>P</i> = .001) in participants who tested Aβ negative. <h3>Conclusions and Relevance</h3> In this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.
Abstract 13767: Centhaquine Attenuates Acute Kidney Injury Following Hemorrhagic Shock
Authors: Amaresh Ranjan, Vivek Cherian, Seema Briyal, Zhong Zhang, Megan Kotsko, Anil Gulati
Journal: Circulation (2019)

Introduction: Hemorrhagic shock is often complicated by acute kidney injury. We have demonstrated that centhaquine is an effective resuscitative agent and currently in clinical phase III (CTRI/2019...
PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer
Authors: Alexander Stein, Donjete Simnica, Christoph Schultheiß, Rebekka Scholz, Joseph Tintelnot, Eray Gökkurt, Lisa von Wenserski, Edith Willscher, Lisa Paschold, Markus Sauer, Sylvie Lorenzen, Jorge Riera-Knorrenschild, Reinhard Depenbusch, Thomas J Ettrich, Steffen Dörfel, Salah-Eddin Al-Batran, Meinolf Karthaus, Uwe Pelzer, Lisa Waberer, Axel Hinke, Marcus Bauer, Chiara Massa, Barbara Seliger, Claudia Wickenhauser, Carsten Bokemeyer, Susanna Hegewisch-Becker, Mascha Binder
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration. Methods We treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing. Results Circulating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion. Conclusion The addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation. Trial registration number NCT03174405 .
Even Cowboys Work in Teams
Authors: Debbie Summers
Journal: Circulation (2011)

The title and inspiration for this presentation are taken from an address by Dr. Atul Gawande at the Harvard Medical School Graduation, 2011. Dr. Gawande stated, “The core structure of medicine emerged in an era when doctors could hold all the key information patients needed in their heads and manage everything required themselves. One needed only an ethic of hard work, a prescription pad, a secretary, and a hospital willing to serve as one's workshop…………But you can't hold all the information in your head any longer, and you can't master all the skills.” He goes on to say that in our current healthcare environment, “places that function most like a system (diverse people working together to direct their specialized capabilities toward common goals for patients) are most successful.” That defines a high functioning team or group of teams. Underpinning the success of a team are three skills described by Dr. Gawande: use of data to understand performance, self reflection and finding solutions to system problems based on data, and implementing the systems and team approach at scale. Optimal stroke care requires a diverse group of people working together as a highly functional team or group of teams. This presentation will discuss both the system and teams that have organized in the region around Kansas City to assure the best possible outcome for each stroke patient by getting as many patients as possible to the right place at the right time.
Controversy and Progress in Alzheimer’s Disease — FDA Approval of Aducanumab
Authors: Gil D. Rabinovici
Journal: New England Journal of Medicine (2021)

Interview with Dr. Gil Rabinovici on the FDA’s controversial approval of a new treatment for Alzheimer’s disease. (16:39)Download The FDA’s accelerated approval of aducanumab represents a landmark moment, though the drug’s road to the clinic has been rocky and contentious. The hope is that despite its limitations, this first-in-class drug will open the door to more efficacious therapies.
Angiotensin IV attenuates diabetic cardiomyopathy <i>via</i> suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis
Authors: Meng Zhang, Wenhai Sui, Yanqiu Xing, Jing Cheng, Cheng Cheng, Fei Xue, Jie Zhang, Xiaohong Wang, Cheng Zhang, Panpan Hao, Yun Zhang
Journal: Theranostics (2021)

Rationale:The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear.This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy.Methods: In vivo, diabetic mice were treated with low-, medium-and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations.In vitro, H9C2 cardiomyocytes and cardiac fibroblasts were treated with different concentrations of glucose, low-, medium-and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS, or their combinations.Results: Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice.Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment.However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration.Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups.Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice.In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiac fibroblasts, which were substantially attenuated by Ang IV treatment.However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS.Conclusions: Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.
Undermined and undervalued: how the pandemic exacerbated moral injury and burnout in the NHS
Authors: Jo Best
Journal: BMJ (2021)

This article provides a detailed analysis of the theoretical, statistical, and implementation challenges related to factor investing in the US sovereign bond markets, with a focus on the level factor, which explains for any maturity the largest fraction of differences in bond returns over time. Using a comprehensive database of individual bond returns in the United States covering the 1975–2018 sample period, the authors find that a conditional version of a carry strategy based on a time-varying exposure to the level factor can generate up to 210 bps of excess performance (gross of transaction costs) over the benchmark and a significantly higher Sharpe ratio. Overall, their results suggest that even in a single-issuer universe with highly correlated bond returns, and after accounting for transaction costs, conditional investing strategies based on second-generation return-predicting factors can lead to robust benefits from both asset-only and asset-liability management perspectives. <b>TOPICS:</b>Analysis of individual factors/risk premia, factor-based models, style investing <b>Key Findings</b> • Conditional carry strategies based on second-generation return-predicting factors generate excess performance with respect to both unconditional carry strategies and conditional carry strategies based on the slope of the yield curve. • These strategies remain profitable when implemented at a CUSIP level, even when transaction costs and long-only constraints are accounted for, and show particularly strong levels of outperformance in increasing interest rate environments and in bear equity markets. • For liability-driven investors, these conditional carry strategies can be used to generate dynamic active duration bets with respect to the liability benchmark and substantially outperform a strict duration-matching strategy with relatively modest levels of tracking error.
Patient-Reported Outcome Measures Modestly Enhance Prediction of Readmission in Patients with Cirrhosis
Authors: Eric S. Orman, Marwan S. Ghabril, Archita P. Desai, Lauren Nephew, Kavish R. Patidar, Sujuan Gao, Chenjia Xu, Naga Chalasani
Journal: Clinical Gastroenterology and Hepatology (2021)
Association Between Mood Disorders and Risk of COVID-19 Infection, Hospitalization, and Death
Authors: Felicia Ceban, Danica Nogo, Isidro P. Carvalho, Yena Lee, Flora Nasri, Jiaqi Xiong, Leanna M. W. Lui, Mehala Subramaniapillai, Hartej Gill, Rene N. Liu, Prianca Joseph, Kayla M. Teopiz, Bing Cao, Rodrigo B. Mansur, Kangguang Lin, Joshua D. Rosenblat, Roger C. Ho, Roger S. McIntyre
Journal: JAMA Psychiatry (2021)

Preexisting noncommunicable diseases (eg, diabetes) increase the risk of COVID-19 infection, hospitalization, and death. Mood disorders are associated with impaired immune function and social determinants that increase the risk of COVID-19. Determining whether preexisting mood disorders represent a risk of COVID-19 would inform public health priorities.To assess whether preexisting mood disorders are associated with a higher risk of COVID-19 susceptibility, hospitalization, severe complications, and death.Systematic searches were conducted for studies reporting data on COVID-19 outcomes in populations with and without mood disorders on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, LitCovid, and select reference lists. The search timeline was from database inception to February 1, 2021.Primary research articles that reported quantitative COVID-19 outcome data in persons with mood disorders vs persons without mood disorders of any age, sex, and nationality were selected. Of 1950 articles identified through this search strategy, 21 studies were included in the analysis.The modified Newcastle-Ottawa Scale was used to assess methodological quality and risk of bias of component studies. Reported adjusted odds ratios (ORs) were pooled with unadjusted ORs calculated from summary data to generate 4 random-effects summary ORs, each corresponding to a primary outcome.The 4 a priori primary outcomes were COVID-19 susceptibility, COVID-19 hospitalization, COVID-19 severe events, and COVID-19 death. The hypothesis was formulated before study search. Outcome measures between individuals with and without mood disorders were compared.This review included 21 studies that involved more than 91 million individuals. Significantly higher odds of COVID-19 hospitalization (OR, 1.31; 95% CI, 1.12-1.53; P = .001; n = 26 554 397) and death (OR, 1.51; 95% CI, 1.34-1.69; P < .001; n = 25 808 660) were found in persons with preexisting mood disorders compared with those without mood disorders. There was no association between mood disorders and COVID-19 susceptibility (OR, 1.27; 95% CI, 0.73-2.19; n = 65 514 469) or severe events (OR, 0.94; 95% CI, 0.87-1.03; n = 83 240). Visual inspection of the composite funnel plot for asymmetry indicated the presence of publication bias; however, the Egger regression intercept test result was not statistically significant.The results of this systematic review and meta-analysis examining the association between preexisting mood disorders and COVID-19 outcomes suggest that individuals with preexisting mood disorders are at higher risk of COVID-19 hospitalization and death and should be categorized as an at-risk group on the basis of a preexisting condition.
Generation of the tumor-suppressive secretome from tumor cells
Authors: Shengzhi Liu, Xun Sun, Kexin Li, Rongrong Zha, Yan Feng, Tomohiko Sano, Chuanpeng Dong, Yunlong Liu, Uma K. Aryal, Akihiro Sudo, Bai-Yan Li, Hiroki Yokota
Journal: Theranostics (2021)

Rationale:The progression of cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option.We previously created tumor-suppressive secretomes by activating Wnt signaling in MSCs.Here, we examined whether the anti-tumor secretomes can be produced from tumor cells. Methods:Wnt signaling was activated in tumor cells by overexpressing β-catenin or administering BML284, a Wnt activator.Their conditioned medium (CM) was applied to cancer cells or tissues, and the effects of CM were evaluated.Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through µCT imaging and histology.Whole-genome proteomics analysis was conducted to determine and characterize novel tumor-suppressing proteins, which were enriched in CM. Results:The overexpression of β-catenin or the administration of BML284 generated tumor-suppressive secretomes from breast, prostate and pancreatic cancer cells.In the mouse model, β-catenin-overexpressing CM reduced tumor growth and tumor-driven bone destruction.This inhibition was also observed with BML284-treated CM.Besides p53 and Trail, proteomics analysis revealed that CM was enriched with enolase 1 (Eno1) and ubiquitin C (Ubc) that presented notable tumor-suppressing actions.Importantly, Eno1 immunoprecipitated CD44, a cell-surface adhesion receptor, and its silencing suppressed Eno1-driven tumor inhibition.A pan-cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes (p < 0.00001).CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator. Conclusions:The tumor-suppressive secretome can be generated from tumor cells, in which β-catenin presented two opposing roles, as an intracellular tumor promoter in tumor cells and a generator of extracellular tumor suppressor in CM.Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-tumor action.Besides presenting a potential option for treating primary cancers and metastases, the result indicates that aggressive tumors may inhibit the growth of less aggressive tumors via tumor-suppressive secretomes.