bluuebunny/crossref_metadata_2025_split huggingface dataset:
SHP2 Inhibition Abrogates Adaptive Resistance to KRASG12C-Inhibition and Remodels the Tumor Microenvironment ofKRAS-Mutant Tumors
Authors: Fedele Carmine , Li Shuai , Teng Kai Wen , Foster Connor , Peng David , Ran Hao , Mita Paolo , Geer Mitchell , Hattori Takamitsu , Koide Akiko , Wang Yubao , Tang Kwan H. , Leinwand Joshua , Wang Wei , Diskin Brian , Deng Jiehui , Chen Ting , Dolgalev Igor , Ozerdem Ugur , Miller George , Koide Shohei , Wong Kwok-Kin , Neel Benjamin G. 
Published: May 2020

ABSTRACTKRASis the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime therapeutic goal. Recently, inhibitors (G12C-Is) that bind KRASG12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRASG12Cactivation and inhibitor engagement, we found that, reflecting its action upstream of SOS1/2, SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and blocked adaptive resistance to G12C-Isin vitro, in xenografts, and in syngeneicKRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. Biochemical analysis revealed enhanced suppression of ERK-, MYC-, anti-apoptotic-, and cell-cycle genes, and increased pro-apoptotic gene expression in tumors from combination-treated mice. SHP2-I/G12C-I also evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but also revealed direct inhibitory effects on angiogenesis resulting in decreased tumor vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional combination strategies for enhancing the efficacy of G12C-Is.
Single cell atlas of beige remodeling of white adipose tissue reveals a myeloid to lymphoid shift during cold exposure compared to beta 3 adrenergic stimulation
Authors: Rabhi Nabil , Belkina Anna C. , Desevin Kathleen , Cortez Briana Noel , Farmer Stephen R. 
Published: May 2020

SUMMARYWhite adipose tissue (WAT) is a dynamic tissue, which responds to environmental stimuli and dietary cues by changing its morphology and metabolic capacity. The ability of WAT to undergo a beige remodeling has become an appealing strategy to combat obesity and its related metabolic complications. Within the cell mixture that constitutes the stromal vascular fraction (SVF), WAT beiging is initiated through expansion and differentiation of adipocytes progenitor cells, however, the extent of the SVF cellular changes is still poorly understood. Additionally, direct beta 3 adrenergic receptor (Adrb3) stimulation has been extensively used to mimic physiological cold- induced beiging, yet it is still unknown whether Adrb3 activation induces the same WAT remodeling as cold exposure. Here, by using single cell RNA sequencing, we provide a comprehensive atlas of the cellular dynamics during beige remodeling within white adipose tissue. We reveal drastic changes both in the overall cellular composition and transcriptional states of individual cell subtypes between Adrb3- and cold-induced beiging. Moreover, we demonstrate that cold exposure induces a myeloid to lymphoid shift of the immune compartment compared to Adrb3 activation. Further analysis, showed that Adrb3 stimulation leads to activation of the interferon/Stat1 pathways favoring infiltration of myeloid immune cells, while repression of this pathway by cold promotes lymphoid immune cells recruitment. These findings provide new insight into the cellular dynamics during WAT beige remodeling and could ultimately lead to novel strategies to identify translationally-relevant drug targets to counteract obesity and T2D.
Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines
Authors: Boyoglu-Barnum Seyhan , Ellis Daniel , Gillespie Rebecca A. , Hutchinson Geoffrey B. , Park Young-Jun , Moin Syed M. , Acton Oliver , Ravichandran Rashmi , Murphy Mike , Pettie Deleah , Matheson Nick , Carter Lauren , Creanga Adrian , Watson Michael J. , Kephart Sally , Vaile John R. , Ueda George , Crank Michelle C. , Stewart Lance , Lee Kelly K. , Guttman Miklos , Baker David , Mascola John R. , Veesler David , Graham Barney S. , King Neil P. , Kanekiyo Masaru 
Published: May 2020

AbstractInfluenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health. However, next-generation vaccine design efforts have been complicated by challenges including the genetic plasticity of the virus and the immunodominance of certain epitopes in its glycoprotein antigens. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in a highly immunogenic array, and their assemblyin vitroenables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited hemagglutination inhibition and neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to commercial QIV in mice, ferrets, and nonhuman primates. The nanoparticle immunogens—but not QIV—simultaneously induced broadly protective antibody responses to heterologous viruses, including H5N1 and H7N9, by targeting the subdominant yet conserved HA stem. Unlike previously reported influenza vaccine candidates, our nanoparticle immunogens can alter the intrinsic immunodominance hierarchy of HA to induce both potent receptor-blocking and broadly cross-reactive stem-directed antibody responses and are attractive candidates for a next-generation influenza vaccine that could replace current seasonal vaccines.One Sentence SummaryNanoparticle immunogens displaying four seasonal influenza hemagglutinins elicit neutralizing antibodies directed at both the immunodominant head and the conserved stem and confer broad protective immunity.
Stop the crop: insights into the insecticidal mode of action of cinnamodial against mosquitoes
Authors: Kalsi Megha , Walter Anton , Lee Beenhwa , DeLaat Andrew , Trigueros Renata Rusconi , Happel Katharina , Sepesy Rose , Nguyen Bao , Manwill Preston K. , Rakotondraibe H. Liva , Piermarini Peter M. 
Published: May 2020

AbstractCinnamodial (CDIAL) is a drimane sesquiterpene dialdehyde found in the bark of Malagasy medicinal plants (Cinnamosmaspecies; family Canellaceae). We previously demonstrated that CDIAL was insecticidal, antifeedant, and repellent againstAedes aegyptimosquitoes. The goal of the present study was to generate insights into the insecticidal mode of action for CDIAL, which is presently unknown. We evaluated the effects of CDIALin vitroon the contractility of the ventral diverticulum (crop) in adult femaleAe. aegypti. The crop is a food storage organ surrounded by visceral muscle that spontaneously contractsin vitro. We found that CDIAL completely inhibited spontaneous contractions of the crop as well as those stimulated by the agonist 5-hydroxytryptamine. Several derivatives of CDIAL with known insecticidal activity also inhibited crop contractions. Morphometric analyses of crops suggested that CDIAL induced a tetanic paralysis that was dependent on extracellular Ca2+and inhibited by Gd3+, a non-specific blocker of plasma membrane Ca2+channels. Screening of numerous pharmacological agents revealed that a Ca2+ionophore (A23187) was the only compound other than CDIAL to completely inhibit crop contractions via a tetanic paralysis. Taken together, our results suggest that CDIAL inhibits crop contractility by elevating intracellular Ca2+through the activation of plasma membrane Ca2+channels thereby leading to a tetanic paralysis, which may explain the insecticidal effects of CDIAL against mosquitoes. Our pharmacological screening efforts also revealed the presence of two regulatory pathways in mosquito crop contractility not previously described: an inhibitory glutamatergic pathway and a stimulatory octopaminergic pathway. The latter was also completely inhibited by CDIAL.
Large-Scale Sparse Regression for Multiple Responses with Applications to UK Biobank
Authors: Qian Junyang , Tanigawa Yosuke , Li Ruilin , Tibshirani Robert , Rivas Manuel A. , Hastie Trevor 
Published: May 2020

AbstractIn high-dimensional regression problems, often a relatively small subset of the features are relevant for predicting the outcome, and methods that impose sparsity on the solution are popular. When multiple correlated outcomes are available (multitask), reduced rank regression is an effective way to borrow strength and capture latent structures that underlie the data. Our proposal is motivated by the UK Biobank population-based cohort study, where we are faced with large-scale, ultrahigh-dimensional features, and have access to a large number of outcomes (phenotypes): lifestyle measures, biomarkers, and disease outcomes. We are hence led to fit sparse reduced-rank regression models, using computational strategies that allow us to scale to problems of this size. We use an iterative algorithm that alternates between solving the sparse regression problem and solving the reduced rank decomposition. For the sparse regression component, we propose a scalable iterative algorithm based on adaptive screening that leverages the sparsity assumption and enables us to focus on solving much smaller sub-problems. The full solution is reconstructed and tested via an optimality condition to make sure it is a valid solution for the original problem. We further extend the method to cope with practical issues such as the inclusion of confounding variables and imputation of missing values among the phenotypes. Experiments on both synthetic data and the UK Biobank data demonstrate the effectiveness of the method and the algorithm. We presentmultiSnpnetpackage, available athttp://github.com/junyangq/multiSnpnetthat works on top of PLINK2 files, which we anticipate to be a valuable tool for generating polygenic risk scores from human genetic studies.
The dynamic modular fingerprints of the human brain at rest
Authors: Kabbara Aya , Paban Veronique , Hassan Mahmoud 
Published: May 2020

AbstractThe human brain is a dynamic modular network that can be decomposed into a set of modules and its activity changes permanently over time. At rest, several brain networks, known as Resting-State Networks (RSNs), emerge and cross-communicate even at sub-second temporal scale. Here, we seek to decipher the fast reshaping in spontaneous brain modularity and its relationship to RSNs. We use Electro/Magneto-Encephalography (EEG/MEG) to track dynamics of modular brain networks, in three independent datasets (N= 568) of healthy subjects at rest. We show the presence of striking spatiotemporal network pattern consistent over participants. We also show that some RSNs, such as default mode network and temporal network, are not necessary ‘unified units’ but rather can be divided into multiple sub-networks over time. Using the resting state questionnaire, our results revealed also that brain network dynamics are strongly correlated to mental imagery at rest. These findings add new perspectives to brain dynamic analysis and highlight the importance of tracking fast reconfiguration of electrophysiological networks at rest.
Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA
Authors: Islam Ariful , Rahman Mohammad Atiqur , Brenner Megan B. , Moore Allamar , Kellmyer Alyssa , Buechler Harley , DiGiorgio Frank , Verchio Vincent , McCracken Laura , Sumi Mousumi , Hartley Robert , Lizza Joseph R. , Moura-Letts Gustavo , Fischer Bradford D. , Keck Thomas M. 
Published: May 2020

ABSTRACTRationaleIBNtxA (3-iodobenzoyl naltrexamine) is a novel μ opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in antinociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants but further evaluation of its in vivo pharmacological profile is necessary to evaluate its potential.ObjectiveThe purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to more completely examine the rewarding properties and discriminative stimulus effects of IBNtxA. These results will allow broader assessment of IBNtxA as a translational candidate or lead compound for further development.ResultsIBNtxA was synthesized and compared to morphine in a variety of mouse behavioral assays. 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and DMSO/saline vehicle, the κ agonist U-50488 fully substituted for IBNtxA. Classical μ agonist morphine, δ agonist SNC162, NOP agonist SCH 221510, and μ/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal.ConclusionsOverall IBNtxA has a complicated opioid receptor pharmacologyin vivo. These results indicate that IBNtxA produces potent antinociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.
Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast
Authors: Fan Jinbo , Jin Hui , Koch Bailey A. , Yu Hong-Guo 
Published: May 2020

AbstractThe linker of the nucleoskeleton and cytoskeleton (LINC) protein complex is composed of a pair of transmembrane proteins: the KASH-domain protein localized to the outer nuclear membrane and the SUN-domain protein to the inner nuclear membrane. In budding yeast, the sole SUN-domain protein, Mps3, is thought to pair with either Csm4 or Mps2, two KASH-like proteins, to form two separate LINC complexes. Here we show that Mps2 mediates the interaction between Csm4 and Mps3 to form a heterotrimeric telomere-associated LINC (t-LINC) in budding yeast meiosis. Mps2 binds to Csm4 and Mps3, and all three are localized to the telomere. Telomeric localization of Csm4 depends on both Mps2 and Mps3; in contrast, Mps2’s localization depends on Mps3 but not Csm4. Mps2-mediated t-LINC regulates telomere movement and meiotic recombination. By ectopically expressingCSM4in vegetative yeast cells, we reconstitute the heterotrimeric t-LINC and demonstrate its ability to tether telomeres. Our findings therefore reveal the heterotrimeric composition of t-LINC in budding yeast and have implications for understanding LINC variant formation.
Diagrammatic Theory of RNA Structures and Ensembles with Trinucleotide Repeats
Authors: Mak Chi H. , Phan Ethan N. H. 
Published: May 2020

ABSTRACTTrinucleotide repeat expansion disorders (TRED) are associated with the overexpansion of (CNG) repeats on the genome. mRNA transcripts of sequences with greater than 60 to 100 (CNG) tandem units have been implicated in TRED pathogenesis. In this paper, we develop a diagrammatic theory to study the structural diversity of these (CNG)nRNA sequences. Representing structural elements on the chain’s conformation by a set of graphs and employing elementary diagrammatic methods, we have formulated a renormalization procedure to resum these graphs and arrive at a closed-form expression for the ensemble partition function. With a simple approximation for the renormalization and applied to extended (CNG)nsequences, this theory can comprehensively capture an infinite set of conformations with any number and any combination of duplexes, hairpins and 2-way junctions. To quantify the diversity of different (CNG)nensembles, the analytical equations derived from the diagrammatic theory were solved numerically to derive equilibrium estimates for the secondary structural contents of the chains. The results suggest that the structural ensembles of (CNG)nrepeat sequence with n ~ 60 are surprisingly diverse, and they are dominated largely by open segments, with only a small fraction of the nucleotides forming base pairs. At the same time, the variance in the secondary-structural contents on the chains is also quite large, indicating that their structures can undergo strong equilibrium fluctuations and are expected to be rather suspectable to perturbations.STATEMENT OF SIGNIFICANCETrinucleotide repeat expansion disorders (TRED) are associated with the overexpansion of (CNG) repeats on the genome. mRNA transcripts of sequences with critical length greater than 60 to 100 (CNG) tandem units have been implicated in TRED pathogenesis, though their structures remain poorly characterized. Conventional view has tacitly assumed that conformations with maximal C:G base pairing dominate at equilibrium, but here we demonstrate that (CNG) repeat sequences are characterized by diverse ensembles of structurally heterogeneous folds and with a large variance of secondary structural contents. These ensembles of structures also undergo strong equilibrium fluctuations, rendering them rather susceptible to perturbations. These results were based on a novel diagrammatic approach to the ensemble partition function.
A hydraulic instability drives the cell death decision in the nematode germline
Authors: Chartier N. T. , Mukherjee A. , Pfanzelter J. , Fürthauer S. , Larson B. T. , Fritsch A.W. , Kreysing M. , Jülicher F. , Grill S. W. 
Published: May 2020

AbstractOocytes are large and resourceful. During oogenesis some germ cells grow, typically at the expense of others that undergo apoptosis. How germ cells are selected to live or die out of a homogeneous population remains unclear. Here we show that this cell fate decision inC. elegansis mechanical and related to tissue hydraulics. Germ cells become inflated when the pressure inside them is lower than in the common cytoplasmic pool. This condition triggers a hydraulic instability which amplifies volume differences and causes some germ cells to grow and others to shrink. Shrinking germ cells are extruded and die, as we demonstrate by reducing germ cell volumes via thermoviscous pumping. Together, this reveals a robust mechanism of mechanochemical cell fate decision making in the germline.
Impact assessment of accreditation in primary and secondary public Healthcare Institutions in the State of Kerala, India
Authors: Joseph Sindhu 
Published: June 2020

AbstractObjectivesThis study examines the impact of accreditation on the quality of public healthcare delivery in primary and secondary healthcare facilities in Kerala, India.Study DesignA cross-sectional study.SettingKerala State, IndiaParticipantsParticipants are the in-patients (621) who are admitted in medical wards at accredited (312) and non-accredited (309) public healthcare facilities.Main Outcome MeasuresTen constructs used in the study, overarching the quality healthcare delivery, adapting previous studies, SERVQUAL, and Donabedian’s SPO models, are Physical Facility, Admission Services, Patient centeredness, Accessibility of Medical Care, Financial Factors, Professionalism, Staff Services, Medical Quality, Diagnostic Services, and Patient Satisfaction.MethodsThe study employed a positivist approach using a survey questionnaire. The study was conducted from July 2017 to July 2018, using stratified random sampling consists of the four strata; GHs, W&C hospitals, THQHs/THs and CHCs.ResultsAccreditation has a positive impact on patient satisfaction and other quality dimensions, overarching structural and procedural quality in primary healthcare facilities under the public sector in Kerala. Conversely, accreditation has not improved the quality dimensions in secondary healthcare facilities and thereby, the satisfaction of patients.ConclusionsIt cannot be assumed that accreditation is always associated with quality care in primary healthcare facilities. The implementation process must be systematic and must be regularly monitored to make it useful. Mere structural transformation through accreditation alone cannot guarantee patient satisfaction. Secondary healthcare facilities must be transformed into quality care centres through rhetoric action of the authorities concerned through organized efforts.
Emotional distress and associated sociodemographic risk factors during the COVID-19 outbreak in Spain
Authors: Muñoz-Navarro Roger , Cano Vindel Antonio , Schmitz Florian , Cabello Rosario , Fernández-Berrocal Pablo 
Published: May 2020

AbstractBackgroundSpain is one of the countries that has been most affected by COVID-19 disease. However, the emotional distress on the Spanish population remains poorly understood. The aim of this study was to determine the presence of emotional disorders and related symptoms and to assess the influence of sociodemographic characteristics on this population.MethodsWe conducted a cross-sectional survey using an online platform. Participation was completely voluntary. Sociodemographic variables were collected and symptoms of anxiety, depression, and panic were assessed through three questionnaires: Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and the Patient Health Questionnaire-Panic Disorder (PHQ-PD). Chi-squared statistics were applied to determine the influence of sociodemographic variables on symptom severity and diagnosis.ResultsMost respondents (n = 1753) were female (76.8%), with a mean (SD) age of 40.4 (12.9) years; 39.1% were married and 39.5% held a high school degree. Severe and moderate symptoms of anxiety and depression were high (6.5% and 14.3%; 9.9% and 12.9%, respectively) and more than one in four participants (25.7%) experienced a panic attack. A high proportion of participants met diagnostic criteria for emotional disorders: 15.3% for GAD; 12.2% for MDD; and 17.2% for PD. Significant risk factors were as follows: female, young adult, single, unemployed, and low income.ConclusionDue to limitations related to the study design (convenience sample), the findings of these study may not be applicable to the general population. Nonetheless, the high prevalence of emotional symptoms and disorders in this sample suggests that mental health interventions are urgently needed in Spain.