bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma
Authors: Chung Katherine Minjee , Singh Jaffarguriqbal , Lawres Lauren , Dorans Kimberly Judith , Garcia Cathy , Burkhardt Daniel B. , Robbins Rebecca , Bhutkar Arjun , Cardone Rebecca , Zhao Xiaojian , Babic Ana , Vayrynen Sara A. , Costa Andressa Dias , Nowak Jonathan A. , Chang Daniel T. , Dunne Richard F. , Hezel Aram F. , Koong Albert C. , Wilhelm Joshua J. , Bellin Melena D. , Nylander Vibe , Gloyn Anna L. , McCarthy Mark I. , Kibbey Richard G. , Krishnaswamy Smita , Wolpin Brian M. , Jacks Tyler , Fuchs Charles S. , Muzumdar Mandar Deepak 
Published: June 2019

SUMMARYObesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant islet beta cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, beta cell CCK expression promotes oncogenicKras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression.
Targeting the Autonomic Nervous System Balance in Patients with Chronic Low Back Pain using Transcranial Alternating Current Stimulation: A Randomized, Crossover, Double-Blind, Placebo-Controlled Pilot Study
Authors: Prim Julianna H. , Ahn Sangtae , Davila Maria I. , Alexander Morgan L. , McCulloch Karen L. , Fröhlich Flavio 
Published: June 2019

AbstractBackgroundChronic low back pain (CLBP) is characterized by an alteration in pain processing by the central nervous system that may affect autonomic nervous system (ANS) balance. Heart rate variability (HRV) reflects the balance of parasympathetic and sympathetic ANS activation. In particular, respiratory sinus arrhythmia (RSA) solely reflects parasympathetic input and is reduced in CLBP patients. Yet, it remains unknown if non-invasive brain stimulation can alter ANS balance in CLBP patients.ObjectiveTo evaluate if non-invasive brain stimulation modulates the ANS, we analyzed HRV metrics collected in a previously published study of transcranial alternating current stimulation (tACS) for the modulation of CLBP through enhancing alpha oscillations. We hypothesized that tACS would increase RSA.MethodsA randomized, crossover, double-blind, sham-controlled pilot study was conducted to investigate the effects of 10Hz-tACS on metrics of ANS balance calculated from electrocardiogram (ECG). ECG data were collected for 2 minutes before and after 40 minutes of 10Hz-tACS or sham stimulation.ResultsThere were no significant changes in RSA or other frequency-domain HRV components from 10Hz-tACS. However, exploratory time-domain HRV analysis revealed a significant increase in the standard deviation of normal RR intervals (SDNN) for 10Hz-tACS relative to sham.Conclusion(s)Although tACS did not significantly increase RSA, we found in an exploratory analysis that tACS modulated an integrated HRV measure of both ANS branches. These findings support the further study of how the ANS and alpha oscillations interact and are modulated by tACS.
Functional connectivity changes with rapid remission from moderate-to-severe major depressive disorder
Authors: Xiao Xiaoqian , Bentzley Brandon S. , Cole Eleanor J. , Tischler Claudia , Stimpson Katy H. , Duvio Dalton , Bishop James H. , DeSouza Danielle D. , Schatzberg Alan , Keller Corey , Sudheimer Keith D. , Williams Nolan R. 
Published: June 2019

AbstractMajor depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited by insufficient understanding of the neurological changes associated with disease remission. In turn, efforts to elucidate these changes have been challenging due to disease heterogeneity as well as limited effectiveness, delayed onset, and significant off-target effects of treatments. We developed a form of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (lDLPFC) that in an open-label study was associated with remission from MDD in 90% of individuals in 1-5 days (Stanford Accelerated Intelligent Neuromodulation Therapy, SAINT). This provides a tool to begin exploring the functional connectivity (FC) changes associated with MDD remission. Resting-state fMRI scans were performed before and after SAINT in 18 participants with moderate-to-severe, treatment-resistant MDD. FC was determined between regions of interest defined a priori by well-described roles in emotion regulation. Following SAINT, FC was significantly decreased between subgenual cingulate cortex (sgACC) and 3 of 4 default mode network (DMN) nodes. Significant reductions in FC were also observed between the following: DLPFC-striatum, DLPFC-amygdala, DMN-amygdala, DMN-striatum, and amygdala-striatum. Greater clinical improvements were correlated with larger decreases in FC between DLPFC-amygdala and DLPFC-insula, as well as smaller decreases in FC between sgACC-DMN. Greater clinical improvements were correlated with lower baseline FC between DMN-DLPFC, DMN-striatum, and DMN-ventrolateral prefrontal cortex. The multiple, significant reductions in FC we observed following SAINT and remission from depression support the hypothesis that MDD is a state of hyper-connectivity within these networks, and rapid decoupling of network nodes may lead to rapid remission from depression.Significance statementMajor depressive disorder is common and debilitating. It has been difficult to study the brain changes associated with recovery from depression, because treatments take weeks-to-months to become effective, and symptoms fail to resolve in many people. We recently developed a type of magnetic brain stimulation called SAINT. SAINT leads to full remission from depression in 90% of people within 5 days. We used SAINT and functional magnetic resonance imaging to determine how the brain changes with rapid remission from depression. We found changes in areas of the brain associated with emotion regulation. This provides a significantly clearer picture of how the non-depressed brain differs from the depressed brain, which can be used to develop rapid and effective treatments for depression.
Probabilistic Cause-of-disease Assignment using Case-control Diagnostic Tests: A Latent Variable Regression Approach
Authors: Wu Zhenke , Chen Irena 
Published: June 2019

AbstractOptimal prevention and treatment strategies for a disease of multiple causes, such as pneumonia, must be informed by the population distribution of causes among cases, or cause-specific case fractions (CSCFs). CSCFs may further depend on additional explanatory variables. Existing methodological literature in disease etiology research does not fully address the regression problem, particularly under a case-control design. Based on multivariate binary non-gold-standard diagnostic data and additional covariate information, this paper proposes a novel and unified regression modeling framework for estimating covariate-dependent CSCF functions in case-control disease etiology studies. The model leverages critical control data for valid probabilistic cause assignment for cases.We derive an efficient Markov chain Monte Carlo algorithm for flexible posterior inference. We illustrate the inference of CSCF functions using extensive simulations and show that the proposed model produces less biased estimates and more valid inference of the overall CSCFs than analyses that omit covariates. A regression analysis of pediatric pneumonia data reveals the dependence of CSCFs upon season, age, HIV status and disease severity. The paper concludes with a brief discussion on model extensions that may further enhance the utility of the regression model in disease etiology research.
Class of antiretroviral drugs and anemia risk in the current treatment era
Authors: Harding B.N. , Whitney B.M. , Nance R.M. , Crane H.M. , Burkholder G. , Moore R.D. , Mathews W.C. , Eron J.J. , Hunt P.W. , Volberding P. , Rodriguez B. , Mayer K.H. , Saag M.S. , Kitahata M.M. , Heckbert S.R. , Delaney J.A.C. 
Published: June 2019

AbstractOBJECTIVESAnemia is common among people living with HIV (PLWH) and has been associated with certain, often older, antiretroviral medications. Information on current antiretroviral therapy (ART) and anemia is limited. The objectives were to compare associations between anemia incidence or hemoglobin change with core ART classes in the current ART era.DESIGNRetrospective cohort study.SETTINGU.S.-based prospective clinical cohort of PLWH aged 18 and above receiving care at 8 sites between 1/2010-3/2018.PARTICIPANTS16,505 PLWH were included in this study.MAIN OUTCOME MEASURESAnemia risk and hemoglobin change were measured for person-time on a protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI), relative to a non-nucleoside reverse transcriptase inhibitor (NNRTI) reference. We also examined PLWH on multiple core classes. Cox proportional hazards regression analyses were conducted to measure associations between time-updated ART classes and incident anemia or severe anemia. Linear mixed effects models were used to examine relationships between ART classes and hemoglobin change.RESULTSDuring a median of 4.9 years of follow-up, 1,040 developed anemia and 488 developed severe anemia during. Compared to NNRTI use, INSTI-based regimens were associated with an increased risk of anemia (adjusted hazard ratio [aHR] 1.17, 95% confidence interval [CI] 0.94-1.47) and severe anemia (aHR1.55 95%CI 1.11-2.17), and a decrease in hemoglobin level. Time on multiple core classes was also associated with increased anemia risk (aHR 1.30, 95%CI 1.06-1.60) and severe anemia risk (aHR 1.35, 95%CI 0.99-1.85), while no associations were found for PI use.CONCLUSIONThese findings suggest INSTI use may increase the risk of anemia. If confirmed, screening for anemia development in users of INSTIs may be beneficial. Further research into underlying mechanisms is warranted.Strengths and limitations of this studyThis study utilized a large and geographically diverse population of PLWH in care across the U.S.This study leveraged comprehensive clinical data, including information on diagnoses, medication use, laboratory test results, demographic information, and medical history.This study investigated associations between specific types of ART core regimens and anemia risk.This observational study is subject to residual confounding.This study focused on anemia assessed from hemoglobin lab values taken at regular medical care visits without excluding participants with conditions strongly associated with hemoglobin level through non-traditional HIV mechanisms.
Multiple Drug Resistance in the canine hookwormAncylostoma caninum: an Emerging Threat
Authors: Jimenez Castro Pablo D. , Howell Sue , Schaefer John. J. , Avramenko Russell. W. , Gilleard John. S. , Kaplan Ray M. 
Published: June 2019

AbstractIn the past few years, diagnoses by veterinarians of recurrent canine hookworm infections have dramatically increased, suggesting that anthelmintic resistance (AR) may have evolved in the parasiteAncylostoma caninum. To investigate this, we established three “suspected-resistant” and two susceptibleA. caninumisolates in research dogs for further study. The egg hatch assay (EHA) and the larval development assay (LDA) were used for detecting resistance to benzimidazoles, and macrocyclic lactones, respectively. Resistance ratios ranged from 6.0 to >100 and 5.5-69.8 for the EHA and LDA, respectively. Following treatments with fenbendazole, pyrantel and milbemycin oxime, reduction in faecal egg counts ranged from 64–86%, 0–72% and 58–92%, respectively. Deep amplicon sequencing of the isotype-1 β tubulin gene identified a high frequency of resistance-associated single nucleotide polymorphisms at codon 167 in the resistant isolates and clinical cases.. These data conclusively demonstrate multiple anthelmintic resistance inA. caninum, and provide pivotal evidence that this is an emerging problem in the United States. Consequently, these findings should provide some concern to the global health community, as the scale-up of mass drug administration for soil-transmitted helminths (STH) is now placing similar selection pressures for benzimidazole resistance in human hookworms.
De novoDNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands
Authors: Ali Masalmeh Roza H. , Rubio-Ramon Cristina , Taglini Francesca , Higham Jonathan , Davidson-Smith Hazel , Clark Richard , Wills Jimi , Finch Andrew J. , Murphy Lee , Sproul Duncan 
Published: June 2019

AbstractThe aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such asMLH1. Current models propose that these CGIs are targeted byde novoDNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels ofde novoDNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that insteadde novoDNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting thatde novoDNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.
hunchbackPromoters Can Readout Morphogenetic Positional Information in Less Than a Minute
Authors: Desponds Jonathan , Vergassola Massimo , Walczak Aleksandra M. 
Published: June 2019

ABSTRACTThe first cell fate decisions in the developing fly embryo are made very rapidly:hunchbackgenes decide in a few minutes whether a given nucleus follows the anterior or the posterior developmental blueprint by reading out the positional information encoded in the Bicoid morphogen. This developmental system constitutes a prototypical instance of the broad spectrum of regulatory decision processes that combine speed and accuracy. Traditional arguments based on fixed-time sampling of Bicoid concentration indicate that an accurate readout is not possible within the short times observed experimentally. This raises the general issue of how speed-accuracy tradeoffs are achieved. Here, we compare fixed-time sampling strategies to decisions made on-the-fly, which are based on updating and comparing the likelihoods of being at an anterior or a posterior location. We found that these more efficient schemes can complete reliable cell fate decisions even within the very short embryological timescales. We discuss the influence of promoter architectures on the mean decision time and decision error rate and present concrete promoter architectures that allow for the fast readout of the morphogen. Lastly, we formulate explicit predictions for new experiments involving Bicoid mutants.
Mycobacterial OtsA structures unveil substrate preference mechanism and allosteric regulation by 2-oxoglutarate and 2-phosphoglycerate
Authors: Mendes Vítor , Acebrón-García-de-Eulate Marta , Verma Nupur , Blaszczyk Michal , Dias Márcio V. B. , Blundell Tom L. 
Published: June 2019

AbstractTrehalose is an essential disaccharide for mycobacteria and a key constituent of several cell wall glycolipids with fundamental roles in pathogenesis. Mycobacteria possess two pathways for trehalose biosynthesis. However, only the OtsAB pathway was found to be essential inM. tuberculosis, with marked growth and virulence defects of OtsA mutants and strict essentiality of OtsB2. Herein, we report the first mycobacterial OtsA structures fromM. thermoresistibilein both apo and ligand-bound forms. Structural information reveals three key residues in the mechanism of substrate preference that were further confirmed by site-directed mutagenesis. Additionally, we identify 2-oxoglutarate and 2-phosphoglycerate as allosteric regulators of OtsA. The structural analysis in this work strongly contributed to define the mechanisms for feedback inhibition, show different conformational states of the enzyme and map a new allosteric site.
Quantifying eco-evolutionary contributions to trait divergence in spatially structured systems
Authors: Govaert Lynn , Pantel Jelena H. , De Meester Luc 
Published: June 2019

AbstractEcological and evolutionary processes can occur at similar time scales, and hence influence one another. There has been much progress in the development of metrics that quantify contributions of ecological and evolutionary components to trait change over time. However, many empirical evolutionary ecology studies document genetic differentiation among populations structured in space. In both time and space, the observed differentiation in trait values among populations and communities can be the result of interactions between non-evolutionary (phenotypic plasticity, changes in the relative abundance of species) and evolutionary (genetic differentiation among populations) processes. However, the tools developed so far to quantify ecological and evolutionary contributions to trait change are implicitly addressing temporal dynamics because they require directionality of change from an ancestral to a derived state. Identifying directionality from one site to another in spatial studies of eco-evolutionary dynamics is not always possible and often not desired. We here suggest three modifications to existing metrics so they allow the partitioning of ecological and evolutionary contributions to changes in population and community trait values across landscapes. Applying these spatially modified metrics to published empirical examples shows how these metrics can be used to generate new empirical insights and to facilitate future comparative analyses. The possibility to apply eco-evolutionary partitioning metrics to populations and communities in real landscapes is critical as it will broaden our capacity to quantify eco-evolutionary interactions as they occur in nature.
Architecture and modular assembly ofSulfolobusS-layers revealed by electron cryo-tomography
Authors: Gambelli Lavinia , Meyer Benjamin , McLaren Mathew , Sanders Kelly , Quax Tessa E.F. , Gold Vicki , Albers Sonja-Verena , Daum Bertram 
Published: June 2019

AbstractSurface protein layers (S-layers) often form the only structural component of the archaeal cell wall and are therefore important for cell survival. S-layers have a plethora of cellular functions including maintenance of cell shape, osmotic and mechanical stability, the formation of a semi-permeable protective barrier around the cell, cell-cell interaction, as well as surface adhesion. Despite the central importance of the S-layer for archaeal life, their three-dimensional architecture is still poorly understood. Here we present the first detailed 3D electron cryo-microscopy maps of archaeal S-layers from three differentSulfolobusstrains. We were able to pinpoint the positions and determine the structure of the two subunits SlaA and SlaB. We also present a model describing the assembly of the mature S-layer.
Significance of trends in gait dynamics
Authors: Kozlowska Klaudia , Latka Miroslaw , West Bruce J. 
Published: June 2019

AbstractTrends in time series generated by physiological control systems are ubiquitous. Determining whether trends arise from intrinsic system dynamics or originate outside of the system is a fundamental problem of fractal series analysis. In the latter case, it is necessary to filter out the trends before attempting to quantify correlations in the noise (residuals). For over two decades, detrended fluctuation analysis (DFA) has been used to calculate scaling exponents of stride time (ST), stride length (SL), and stride speed (SS) of human gait. Herein, rather than relying on the very specific form of detrending characteristic of DFA, we adopt Multivariate Adaptive Regression Splines (MARS) to explicitly determine trends in spatio-temporal gait parameters during treadmill walking. Then, we use the madogram estimator to calculate the scaling exponent of the corresponding MARS residuals. The durations of ST and SL trends are determined to be independent of treadmill speed and have distributions with exponential tails. At all speeds considered, the trends of ST and SL are strongly correlated and are statistically independent of their corresponding residuals. The group-averaged values of scaling exponents of ST and ST MARS residuals are slightly smaller than 0.5, indicating weak anti-persistence. Thus, contrary to the interpretation prevalent in the literature, the statistical properties of ST and SL time series originate from the superposition of large scale trends and small scale fluctuations. We show that trends serve as the control manifolds about which ST and SL fluctuate. Moreover, the trend speed, defined as the ratio of instantaneous values of SL and ST trends, is tightly controlled about the treadmill speed. The strong coupling between the ST and SL trends ensures that the concomitant changes of their values correspond to movement along the constant speed goal equivalent manifold as postulated by Dingwell et al. doi:10.1371/journal.pcbi.1000856.Author summaryDuring treadmill walking, the subject’s stride time (ST) and stride length (SL) must yield a stride speed which can fluctuate over a narrow range centered on the treadmill belt’s speed. The fact that both ST and SL are persistent is an intriguing property of human gait. For persistent fluctuations any deviation from the mean value is likely to be followed by a deviation in the same direction. To trace the origin of such persistence, we used a novel approach to determine trends in spatio-temporal gait parameters. We find that the trends of ST and SL of a subject are strongly correlated and are statistically independent of their corresponding residuals. Moreover, the trend speed, defined as the ratio of instantaneous values of SL and ST trends, is tightly controlled about the treadmill speed. The persistence of gait parameters stems from superposition of large scale trends and small scale fluctuations.