tbuckley/cabot-search huggingface dataset:
Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes
Authors: Helen K. Reddel, Leonard B. Bacharier, Eric D. Bateman, Christopher E. Brightling, Guy G. Brusselle, Roland Buhl, Alvaro A. Cruz, Liesbeth Duijts, Jeffrey M. Drazen, J. Mark FitzGerald, Louise J. Fleming, Hiromasa Inoue, Fanny W. Ko, Jerry A. Krishnan, Mark L. Levy, Jiangtao Lin, Kevin Mortimer, Paulo M. Pitrez, Aziz Sheikh, Arzu A. Yorgancioglu, Louis-Philippe Boulet
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting β2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ⩾60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting β2-agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.
KaKs_Calculator 3.0: Calculating Selective Pressure on Coding and Non-Coding Sequences
Authors: Zhang Zhang
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract KaKs_Calculator 3.0 is an updated toolkit that is capable of calculating selective pressure on both coding and non-coding sequences. Similar to the nonsynonymous/synonymous substitution rate ratio for coding sequences, selection on non-coding sequences can be quantified as the ratio of non-coding nucleotide substitution rate to synonymous substitution rate of adjacent coding sequences. As testified on empirical data, KaKs_Calculator 3.0 shows effectiveness to detect the strength and mode of selection operated on molecular sequences, accordingly demonstrating its great potential to achieve genome-wide scan of natural selection on diverse sequences and identification of potentially functional elements at a whole-genome scale. The package of KaKs_Calculator 3.0 is freely available for academic use only at https://ngdc.cncb.ac.cn/biocode/tools/BT000001.
Use of host lipids by the Lyme disease spirochete may lead to biomarkers
Authors: Gunjan Arora, Thomas Hart, Erol Fikrig
Journal: Journal of Clinical Investigation (2022)

Lyme disease is the most common tick-borne disease in North America and Europe, however, current biomarkers inconsistently detect the disease. In this issue of the JCI, Gwynne et al. revealed how the Lyme disease agent Borrelia burgdorferi relies on host lipids for growth. The authors used a murine model to show that B. burgdorferi infection led to the production of antibodies against phospholipids, possibly as a consequence of incorporation into the spirochete membrane. Antibodies were induced against phosphatidic acid, phosphatidylcholine, and phosphatidylserine. Notably, no antibodies against cardiolipin were found, distinguishing Lyme disease from syphilis and some other diseases. Sera samples from patients with Lyme disease suggested that these antibodies may help diagnose B. burgdorferi infection and that antibody titers may effectively indicate the response to treatment. These findings suggest that B. burgdorferi–induced anti-lipid antibodies, in conjunction with a careful clinical assessment, may aid in the diagnosis of Lyme disease.
Application of nanomaterials in proteomics-driven precision medicine
Authors: Yong Zhang, Haonan Yang, Yanbao Yu, Ying Zhang
Journal: Theranostics (2022)

Nanostructured devices and nanoparticles have fundamentally reshaped the development of precision healthcare in recent decades.Meanwhile, mass spectrometry (MS)-based proteomics has evolved from simple protein sequencing to a powerful approach that identifies disease patterns and signatures, reveals molecular mechanisms of pathological processes, and develops therapeutic or preventive drugs.Significantly, the two distinct disciplines have synergized and expanded our knowledge about human health and disease, as evidenced by a variety of nanotechnology-assisted sample processing strategies, facilitating in-depth proteome profiling and post-translational modifications (PTMs) characterization.This review summarizes recent advances in nanoparticle design for better enrichment of marker proteins and their PTMs from various bio-specimens and emerging nanotechnologies that are applied to MS-based proteomics for precision medicine discovery.
Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms
Authors: Sheng Chen, Donghao Gan, Sixiong Lin, Yiming Zhong, Mingjue Chen, Xuenong Zou, Zengwu Shao, Guozhi Xiao
Journal: Theranostics (2022)

Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities.Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence.In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases.We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.
Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway
Authors: Jin-Zhu Wang, Hong Zhu, Pu You, Hui Liu, Wei-Kang Wang, Xiaojuan Fan, Yun Yang, Keren Xu, Yingfeng Zhu, Qunyi Li, Ping Wu, Chao Peng, Catherine C.L. Wong, Kaicheng Li, Yufeng Shi, Nu Zhang, Xiuxing Wang, Rong Zeng, Ying Huang, Liusong Yang, Zefeng Wang, Jingyi Hui
Journal: Journal of Clinical Investigation (2022)

Y-box-binding protein 1 (YB-1) is a multifunctional RNA binding protein involved in virtually every step of RNA metabolism. However, the functions and mechanisms of YB-1 in one of the most aggressive cancers, glioblastoma, are not well understood. In this study, we found that YB-1 protein was markedly overexpressed in glioblastoma and acted as a critical activator of both mTORC1 and mTORC2 signaling. Mechanistically, YB-1 bound the 5'UTR of CCT4 mRNA to promote the translation of CCT4, a component of the CCT chaperone complex, that in turn activated the mTOR signaling pathway by promoting mLST8 folding. In addition, YB-1 autoregulated its own translation by binding to its 5'UTR, leading to sustained activation of mTOR signaling. In patients with glioblastoma, high protein expression of YB-1 correlated with increased expression of CCT4 and mLST8 and activated mTOR signaling. Importantly, the administration of RNA decoys specifically targeting YB-1 in a mouse xenograft model resulted in slower tumor growth and better survival. Taken together, these findings uncover a disrupted proteostasis pathway involving a YB-1/CCT4/mLST8/mTOR axis in promoting glioblastoma growth, suggesting that YB-1 is a potential therapeutic target for the treatment of glioblastoma.
Abstract EP07: A Longitudinal Lipidomics Profiling For Risk Of Chronic Kidney Disease In American Indians: The Strong Heart Family Study
Authors: Wenjie Zeng, Guanhong Miao, Pooja Subedi, Shelley Cole, Jason G Umans, Nora Franceschini, Elisa T Lee, Barbara V Howard, Oliver Fiehn
Journal: Circulation (2022)

Background: Dyslipidemia is associated with and often precedes the onset of chronic kidney disease (CKD). However, standard lipid panels fail to describe the full spectrum of blood lipidome. A longitudinal profiling of the full spectrum of blood lipidome associated with the risk of CKD is still lacking in any racial/ethnic group, including American Indians, a population that suffered a disproportionately high burden of CKD. Objective: To identify novel lipids and lipidomic signatures associated with risk of CKD in American Indians, independent of traditional risk factors. Methods: We included 1,910 American Indians who attended two examinations (~5.5 years apart) and were free of CKD and cardiovascular disease (CVD) at baseline. CKD was defined based on the estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI formula. Fasting plasma levels of 1,542 lipids in 3,916 samples at two-time points were repeatedly measured by untargeted LC-MS. Machine learning (elastic net) was used to identify lipidomic predictors of CKD beyond traditional risk factors (age, sex, center, BMI, hypertension, diabetes, urinary albumin/creatinine ratio, HDL, triglyceride, and use of lipid-lowering medications). Mixed-effect linear models were used to examine the relationship between changes (baseline to 5-year follow-up) in lipidome and change in kidney function (eGFR), adjusting for traditional risk factors mentioned above, baseline lipid, and baseline eGFR. Multivariate analysis was conducted to identify discriminatory lipidomic signatures that can differentiate between high- and low-risk individuals. Results: Of 1,910 participants free of CKD and CVD (17.8% diabetic) at baseline, 55 (2.9%) developed incident CKD by the end of a 5-year follow-up. Elastic net identified 106 (24 known) lipids, largely glycerophospholipids (GPs), sphingomyelins (SMs), triacylglycerols (TAGs), fatty acids (FAs), and acylcarnitines (ACs), whose altered baseline levels were associated with the risk of CKD, independent of traditional risk factors. A composite lipid score composed of the 24 known lipids improved CKD risk prediction beyond traditional risk factors (AUROC improved from 0.944 to 0.963, P = 0.006). Longitudinal changes in 182 lipids (75 known) lipids, largely GPs, FAs, SMs, TAGs, ACs, and diacylglycerols (DAGs), explained up to 4.8% of the variation of the eGFR change. Multivariate analysis identified distinct lipidomic signatures that separated high- from low-risk participants. Conclusion: We identified novel molecular lipids that significantly predict CKD onset and progression among American Indians beyond traditional risk factors. Our findings shed light on the mechanisms by which dyslipidemia affects CKD and provide instrumental data for biomarker identification, risk prediction and stratification, prognosis, and potential therapeutics.
Mechanosensation by endothelial PIEZO1 is required for leukocyte diapedesis
Authors: ShengPeng Wang, Bianbian Wang, Yue Shi, Tanja Möller, Rebekka I. Stegmeyer, Boris Strilic, Ting Li, Zuyi Yuan, Changhe Wang, Nina Wettschureck, Dietmar Vestweber, Stefan Offermanns
Journal: Blood (2022)

The extravasation of leukocytes is a critical step during inflammation that requires the localized opening of the endothelial barrier. This process is initiated by the close interaction of leukocytes with various adhesion molecules such as ICAM-1 on the surface of endothelial cells. Here we reveal that mechanical forces generated by leukocyte-induced clustering of ICAM-1 synergize with fluid shear stress exerted by the flowing blood to increase endothelial plasma membrane tension and to activate the mechanosensitive cation channel PIEZO1. This leads to increases in [Ca2+]i and activation of downstream signaling events including phosphorylation of tyrosine kinases sarcoma (SRC) and protein tyrosine kinase 2 (PYK2), as well as of myosin light chain, resulting in opening of the endothelial barrier. Mice with endothelium-specific Piezo1 deficiency show decreased leukocyte extravasation in different inflammation models. Thus, leukocytes and the hemodynamic microenvironment synergize to mechanically activate endothelial PIEZO1 and subsequent downstream signaling to initiate leukocyte diapedesis.
Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis
Authors: Biqing Wang, Xuening Tang, Liu Yao, Yuxin Wang, Zhipeng Chen, Mengqi Li, Naishi Wu, Dawei Wu, Xiangchen Dai, Hongfeng Jiang, Ding Ai
Journal: Journal of Clinical Investigation (2022)

Subendothelial macrophage internalization of modified lipids and foam cell formation are hallmarks of atherosclerosis. Deubiquitinating enzymes (DUBs) are involved in various cellular activities; however, their role in foam cell formation is not fully understood. Here, using a loss-of-function lipid accumulation screening, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a factor that suppressed lipid uptake in macrophages. We found that USP9X expression in lesional macrophages was reduced during atherosclerosis development in both humans and rodents. Atherosclerotic lesions from macrophage USP9X-deficient mice showed increased macrophage infiltration, lipid deposition, and necrotic core content than control apolipoprotein E–KO (Apoe–/–) mice. Additionally, loss-of-function USP9X exacerbated lipid uptake, foam cell formation, and inflammatory responses in macrophages. Mechanistically, the class A1 scavenger receptor (SR-A1) was identified as a USP9X substrate that removed the K63 polyubiquitin chain at the K27 site. Genetic or pharmacological inhibition of USP9X increased SR-A1 cell surface internalization after binding of oxidized LDL (ox-LDL). The K27R mutation of SR-A1 dramatically attenuated basal and USP9X knockdown–induced ox-LDL uptake. Moreover, blocking binding of USP9X to SR-A1 with a cell-penetrating peptide exacerbated foam cell formation and atherosclerosis. In this study, we identified macrophage USP9X as a beneficial regulator of atherosclerosis and revealed the specific mechanisms for the development of potential therapeutic strategies for atherosclerosis.
Abstract P126: The 2020 Us Presidential Election, Sociopolitical Stress And Acute Cardiovascular Disease Hospitalizations
Authors: Matthew T Mefford, Jamal S Rana, Kristi Reynolds, Omesh N Ranasinghe, Murray A Mittleman, Jennifer Liu, Lei Qian, Hui Zhou, Teresa N Harrison, Alan C Geller, Richard P Sloan, Elizabeth Mostofsky, David R Williams, Stephen Sidney
Journal: Circulation (2022)

Background: Prior studies demonstrated a higher risk of acute cardiovascular disease (CVD) around population-wide psychosocial or environmental stressors. Less is known about the impact of sociopolitical events. The objective of the current study was to examine acute CVD hospitalizations following the 2020 presidential election. Methods: We examined hospitalizations for acute CVD around the 2020 presidential election, among adults enrolled in Kaiser Permanente Southern and Northern California, two integrated health care delivery systems that provide care for &gt;9 million persons. CVD was defined as hospitalizations for acute myocardial infarction (AMI), heart failure (HF) or stroke. Rate ratios (RR) and 95% confidence intervals (CIs) were calculated comparing rates in the five days following the 2020 election to the same five days two weeks prior. Results: Among 6,396,830 members ≥18 years, rates of hospitalization for CVD following the election (666 hospitalizations; rate = 760.5 per 100,00 person-years [PY]) were 1.17 times higher (95% CI 1.05, 1.31) compared to the same five days two weeks prior (569 hospitalizations; rate = 648.0 per 100,000 PY). (Table) RR for AMI, stroke, and HF were 1.42 (95% CI 1.13, 1.79), 1.02 (95% CI 0.86, 1.21) and 1.18 (95% CI 0.98, 1.42), respectively. Conclusions: Higher rates of acute CVD were observed following the 2020 presidential election. Awareness of the heightened risk of CVD and strategies to mitigate risk during significant sociopolitical events are needed.
Quality of Life After Fractional Flow Reserve–Guided PCI Compared With Coronary Bypass Surgery
Authors: William F. Fearon, Frederik M. Zimmermann, Victoria Y. Ding, Jo M. Zelis, Zsolt Piroth, Giedrius Davidavicius, Samer Mansour, Rajesh Kharbanda, Nikolaos Östlund-Papadogeorgos, Keith G. Oldroyd, Olaf Wendler, Michael J. Reardon, Y. Joseph Woo, Alan C. Yeung, Nico H.J. Pijls, Bernard De Bruyne, Manisha Desai, Mark A. Hlatky
Journal: Circulation (2022)

Previous studies have shown that quality of life improves after coronary revascularization more so after coronary artery bypass grafting (CABG) than after percutaneous coronary intervention (PCI). This study aimed to evaluate the effect of fractional flow reserve guidance and current generation, zotarolimus drug-eluting stents on quality of life after PCI compared with CABG.The FAME 3 trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) is a multicenter, international trial including 1500 patients with 3-vessel coronary artery disease who were randomly assigned to either CABG or fractional flow reserve-guided PCI. Quality of life was measured using the European Quality of Life-5 Dimensions (EQ-5D) questionnaire at baseline and 1 and 12 months. The Canadian Cardiovascular Class angina grade and working status were assessed at the same time points and at 6 months. The primary objective was to compare EQ-5D summary index at 12 months. Secondary end points included angina grade and work status.The EQ-5D summary index at 12 months did not differ between the PCI and CABG groups (difference, 0.001 [95% CI, -0.016 to 0.017]; P=0.946). The trajectory of EQ-5D during the 12 months differed (P<0.001) between PCI and CABG: at 1 month, EQ-5D was 0.063 (95% CI, 0.047 to 0.079) higher in the PCI group. A similar trajectory was found for the EQ (EuroQol) visual analogue scale. The proportion of patients with Canadian Cardiovascular Class 2 or greater angina at 12 months was 6.2% versus 3.1% (odds ratio, 2.5 [95% CI, 0.96-6.8]), respectively, in the PCI group compared with the CABG group. A greater percentage of younger patients (<65 years old) were working at 12 months in the PCI group compared with the CABG group (68% versus 57%; odds ratio, 3.9 [95% CI, 1.7-8.8]).In the FAME 3 trial, quality of life after fractional flow reserve-guided PCI with current generation drug-eluting stents compared with CABG was similar at 1 year. The rate of significant angina was low in both groups and not significantly different. The trajectory of improvement in quality of life was significantly better after PCI, as was working status in those <65 years old.URL: https://www.gov; Unique identifier: NCT02100722.
mTOR-Dependent ARID1A Degradation: A New Twist in the Genetic–Epigenetic Interplay Driving Hepatocellular Carcinoma
Authors: David R. Pease, Martin E. Fernandez-Zapico
Journal: Cancer Research (2021)

Abstract The importance of the cross-talk between the genetic and epigenetic alterations promoting cancer development is well understood; however, the molecular details underlying the mechanism of how oncogenic signaling remodels the epigenome to generate a procancer transcriptome require further elucidation. The study by Zhang and colleagues in this issue of Cancer Research reveals a novel role for oncogenic mTOR signaling leading to the degradation of a prominent chromatin remodeler, ARID1a, establishing an altered, protumor chromatin landscape in hepatocellular carcinoma (HCC) controlling tumor deve-lopment and treatment resistance. These findings highlight oncogenic effects on chromatin remodelers as an important factor in both HCC pathobiology and therapeutic response. As strategies for cancer therapy begin to move in an increasingly individualized direction, increased knowledge into the impact of restoring the function of chromatin remodelers on response to therapy is warranted. See related article by Zhang et al., p. 5652
Regulating Drug Prices while Increasing Innovation
Authors: Rena M. Conti, Richard G. Frank, Jonathan Gruber
Journal: New England Journal of Medicine (2021)

Interview with Dr. Rena Conti on strategies for regulating drug prices while promoting the development of new pharmaceuticals. (09:08)Download To save money on drugs while encouraging high-value pharmaceutical innovation, we need to better reward value, increase NIH funding for early-stage research, and reduce expenses and risks for developers of drugs whose social value exceeds their financial value.
The economics of organellar gene loss and endosymbiotic gene transfer
Authors: Steven Kelly
Journal: Genome biology (2021)

The endosymbiosis of the bacterial progenitors of the mitochondrion and the chloroplast are landmark events in the evolution of life on Earth. While both organelles have retained substantial proteomic and biochemical complexity, this complexity is not reflected in the content of their genomes. Instead, the organellar genomes encode fewer than 5% of the genes found in living relatives of their ancestors. While many of the 95% of missing organellar genes have been discarded, others have been transferred to the host nuclear genome through a process known as endosymbiotic gene transfer.