bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expert-validated estimation of diagnostic uncertainty for deep neural networks in diabetic retinopathy detection
Authors: Ayhan Murat Seçkin , Kühlewein Laura , Aliyeva Gulnar , Inhoffen Werner , Ziemssen Focke , Berens Philipp 
Published: July 2019

ABSTRACTDeep learning-based systems can achieve a diagnostic performance comparable to physicians in a variety of medical use cases including the diagnosis of diabetic retinopathy. To be useful in clinical practise, it is necessary to have well calibrated measures of the uncertainty with which these systems report their decisions. However, deep neural networks (DNNs) are being often overconfident in their predictions, and are not amenable to a straightforward probabilistic treatment. Here, we describe an intuitive framework based on test-time data augmentation for quantifying the diagnostic uncertainty of a state-of-the-art DNN for diagnosing diabetic retinopathy. We show that the derived measure of uncertainty is well-calibrated and that experienced physicians likewise find cases with uncertain diagnosis difficult to evaluate. This paves the way for an integrated treatment of uncertainty in DNN-based diagnostic systems.
Population Structure Drives Differential Methicillin-resistantStaphylococcus aureusColonization Dynamics
Authors: Short Christopher T. , Samore Matthew , Lofgren Eric T. ,   for the CDC Modeling Infectious Diseases in Healthcare Program (MInD-Healthcare)
Published: July 2019

AbstractBackgroundUsing a model of methicillin-resistantStaphylococcus aureus(MRSA) within an intensive care unit (ICU), we explore how differing hospital population structures impact these infection dynamics.MethodsUsing a stochastic compartmental model of an 18-bed ICU, we compared the rates of MRSA acquisition across three potential population structures: a Single Staff Type (SST) model with nurses and physicians as a single staff type, a model with separate staff types for nurses and physicians (Nurse-MD model), and a Metapopulation model where each nurse was assigned a group of patients. By varying the proportion of time spent with the assigned patient group (γ) within the Metapopulation model, we explored whether simpler models may be acceptable approximations to more realistic patient-healthcare staff contact patterns.ResultsThe SST, Nurse-MD, and Metapopulation models had a mean annual number of cumulative MRSA acquisitions of 40.6, 32.2 and 19.6 respectively. All models were sensitive to the same parameters in the same direction, although the Metapopulation model was less sensitive. The number of acquisitions varied non-linearly by values of γ, with values below 0.40 resembling the Nurse-MD model, while values above that converged toward the metapopulation structure.DiscussionThe population structure of a modeled hospital has considerable impact on model results, with the SST model having more than double the acquisition rate of the more structured Metapopulation model. While the direction of parameter sensitivity remained the same, the magnitude of these differences varied, producing different infection rates across relatively similar populations. The non-linearity of the model’s response to differing values of γ suggests only a narrow space of relatively dispersed nursing assignments where simple model approximations are appropriate.ConclusionSimplifying assumptions around how a hospital population is modeled, especially assuming random mixing, may overestimate infection rates and the impact of interventions.
An atlas of infiltrated B-lymphocytes in breast cancer revealed by paired single-cell RNA-sequencing and antigen receptor profiling
Authors: Hu Qingtao , Hong Yu , Qi Pan , Lu Guangqing , Mai Xueying , Xu Sheng , He Xiaoying , Guo Yu , Gao Linlin , Jing Zhiyi , Wang Jiawen , Cai Tao , Zhang Yu 
Published: July 2019

AbstractWhile it has been well-recognized that T-cell mediated adaptive cellular immunity plays important roles in cancer immune response and tumor control, the roles of B lymphocytes in tumor development and therapy have only been proposed until recently, and are still mostly controversial. To gain mechanistic insights into the origin and dynamics of tumor infiltrated immune cells, especially B lymphocytes, we combine single-cell RNA-sequencing and antigen receptor lineage analysis to characterize a large number of triple-negative breast cancer (TNBC) infiltrated immune cells and present a comprehensive atlas of infiltrated B-lymphocytes in TNBC, the most aggressive breast cancer subtype. We demonstrate that TNBC infiltrated B cells showed more mature and memory B cell characteristics, as well as high clonality and extensive IgH class switching recombination and somatic hypermutations. The B cell signatures based on single-cell RNA-seq results are significantly associated with improved survival for TNBC patients and provide better prognostication than classic single B cell markers (CD19 or CD20). Further dissection of the mechanisms regulating the functions and dynamic distribution of tumor infiltrated B cell populations will provide new clues for tumor immunotherapy.
Chirp analyzer for estimating amplitude and latency of steady-state auditory envelope following responses
Authors: Martínez-Montes Eduardo , García-Puente Yalina , Zañartu Matías , Prado-Gutiérrez Pavel 
Published: July 2019

AbstractThe envelope following response (EFR) is a scalp-recorded evoked potential elicited by carrier tones or noise, modulated in amplitude with a continuous sweep of modulation frequencies. This non-stationary response reflects the phase-locked neural activity of the auditory pathway to the temporal envelope of sounds and has been commonly assessed by fixed-frequency methods based on the discrete Fourier transform, such as the Fourier Analyzer (FA). In this work, we study the estimation of the EFR with the use of explicit time-frequency methods, which offer more information about the energy distribution of the recorded signal, such as the Short-Term Fourier Transform (STFT) and the Morlet Continuous Wavelet Transform (CWT). We further introduce the Chirp Analyzer (CA), which is similar to FA, but using as basis function the same linear chirp that amplitude-modulates the carrier stimulus. In a direct comparison using controlled simulated responses, the CA showed to be able to estimate the correct EFR amplitudes, without the typical bias offered by the estimation using STFT (equivalent to FA) and more robust to noise than the CWT method, although with higher sensitivity to the presence of a delay in the response with respect to the stimulus. For addressing the latter issue, we also propose here a novel methodology for estimating the apparent latency of the response. This method proved to be reliable when using the STFT and the CA methods, as assessed using simulated responses. The estimation of the EFR amplitude with any of the methods, but especially with CA, should be corrected by using the estimated delay when possible. An illustrative application of these methods to small datasets of a rat and a human newborn, suggested that all time-frequency methods can be used to study the EFR amplitudes in a wide range of modulation frequencies, but they should be interpreted in the light of the limitations shown in the simulation studies.
Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy
Authors: Bai Peng , Li Yongzheng , Zhou Qiuping , Xia Jiaqi , Wei Peng-Cheng , Deng Hexiang , Wu Min , Chan Sanny K. , Kappler John W. , Zhou Yu , Tran Eric , Marrack Philippa , Yin Lei 
Published: July 2019

AbstractGenetic mutations lead to the production of mutated proteins from which peptides are presented to T cells as cancer neoantigens. Evidence suggests that T cells that target neoantigens are the main mediators of effective cancer immunotherapies. Although algorithms have been used to predict neoantigens, only a minority are immunogenic. The factors that influence neoantigen immunogenicity are not completely understood. Here, we classified human neoantigen/neopeptide data into three categories based on their TCR-pMHC binding events. We observed a conservative mutant orientation of the anchor residue from immunogenic neoantigens which we termed the “NP” rule. By integrating this rule with an existing prediction algorithm, we found improved performance in neoantigen prioritization. To better understand this rule, we solved several neoantigen/MHC structures. These structures showed that neoantigens that follow this rule not only increase peptide-MHC binding affinity but also create new TCR-binding features. These molecular insights highlight the value of immune-based classification in neoantigen studies and may enable the design of more effective cancer immunotherapies.
Rhizosphere bacterial communities of wheat vary across the growing season and among dryland farming systems
Authors: Ishaq Suzanne L. , Seipel Tim , Yeoman Carl J. , Menalled Fabian D. 
Published: July 2019

AbstractDespite knowledge that seasonality and plant phenology impact soil microbiota, farming system effects on soil microbiota are not often evaluated across the growing season. We assessed the bacterial diversity in wheat rhizosphere soil through the spring and summer of 2016 in winter wheat (Triticum aestiviumL.) in Montana, USA, from three contrasting farming systems: a chemically-managed no-tillage system, and two USDA-certified organic systems in their fourth year, one including tillage and one where sheep grazing partially offsets tillage frequency. Bacterial richness (range 605 – 1174 OTUs) and evenness (range 0.80 – 0.92) peaked in early June and dropped by late July (range 92 – 1190, 0.62-0.92, respectively), but was not different by farming systems. Organic tilled plots contained more putative nitrogen-fixing bacterial genera than the other two systems. Bacterial community similarities were significantly altered by sampling date, minimum and maximum temperature at sampling, bacterial abundance at date of sampling, total weed richness, and coverage ofTaraxacum officinale,Lamium ampleuxicaule,andThlaspi arvense. This study highlights that weed diversity, season, and farming management system all influence rhizosphere soil microbial communities. Local environmental conditions will strongly affect any practical applications aimed at improving soil diversity and functionality, especially in semi-arid regions where abiotic stress and seasonal variability in temperature and water availability drive primary production.
Maternal antioxidant treatment prevents behavioural and neural changes in offspring exposed to prenatal social stress
Authors: Scott H , Phillips TJ , Sze Y , Alfieri A , Rogers MF , Case CP , Brunton PJ 
Published: July 2019

AbstractMaternal exposure to social stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. However, the mechanism through which the effects of maternal stress are transmitted to the foetus is unclear. Using a rat model, we explored the mechanisms by which maternal social stress is conveyed to the foetus and the potential for targeted treatment to prevent disease in the offspring. Maternal stress increased circulating corticosterone in the mother, but not the foetuses. Maternal stress also induced oxidative stress in the placenta, but not in the foetal brain, and this was prevented by administration of a nanoparticle-bound antioxidant. Moreover, antioxidant treatment prevented prenatal stress-induced anxiety-like behaviour in the adult male offspring, along with several stress-induced neuroanatomical, neurochemical and gene expression changes in the offspring brain. Importantly, many of these neural effects were mimicked in neuronal cultures by application of placental-conditioned medium or foetal plasma from stressed pregnancies. Both placental-conditioned medium and foetal plasma contained differentially abundant extracellular microRNAs following prenatal stress. The present study highlights the crucial role of the placenta, and the molecules it secretes, in foetal brain development and provides evidence of the potential for treatment that can prevent maternal stress-induced foetal programming of neurological disease.
Cell Type-Specific Modulation of Layer 6A Excitatory Microcircuits by Acetylcholine in Rat Barrel Cortex
Authors: Yang Danqing , Günter Robert , Qi Guanxiao , Radnikow Gabriele , Feldmeyer Dirk 
Published: July 2019

AbstractAcetylcholine (ACh) is known to regulate cortical activity during different behavioral states, e.g. wakefulness and attention. Here we show a differential expression of muscarinic ACh receptors (mAChRs) and nicotinic AChRs (nAChRs) in different layer 6A (L6A) pyramidal cell (PC) types of somatosensory cortex. At low concentrations, ACh induced a persistent hyperpolarization in corticocortical (CC) but a depolarization in corticothalamic (CT) L6A PCs via M4 and M1 mAChRs, respectively. At ∼1 mM ACh depolarized exclusively CT PCs via α4β2 subunit-containing nAChRs without affecting CC PCs. Miniature EPSC frequency in CC PCs was decreased by ACh but increased in CT PCs. In synaptic connections with a presynaptic CC PC, glutamate release was suppressed via M4 mAChR activation but enhanced by nAChRs via α4β2 nAChRs when the presynaptic neuron was a CT PC. Thus, in layer 6A the interaction of mAChRs and nAChRs results in an altered excitability and synaptic release, effectively strengthening corticothalamic output while weakening corticocortical synaptic signaling.
Characterisation of cefotaxime-resistant urinary Escherichia coli from primary care in South-West England 2017-2018
Authors: Findlay Jacqueline , Gould Virginia C. , North Paul , Bowker Karen E. , Williams O. Martin , MacGowan Alasdair P. , Avison Matthew B. 
Published: July 2019

AbstractObjectivesThird-generation cephalosporin-resistant Escherichia coli from community-acquired urinary tract infections (UTI) have been increasingly reported worldwide. In this study we sought to determine and characterise the mechanisms of cefotaxime-resistance (CTX-R) employed by urinary E. coli obtained from primary care over a 12-month period, in Bristol and surrounding counties in the South West of England.MethodsCephalexin resistant (Ceph-R) E. coli isolates were identified directly from general practice (GP) referred urine samples using disc susceptibility testing as per standard diagnostic procedures. CTX-R was determined by subsequent plating onto MIC breakpoint plates. β-Lactamase genes were detected by PCR. Whole Genome Sequencing (WGS) was performed on 225 urinary isolates and analyses were performed using the Centre for Genomic Epidemiology platform. Patient information provided by the referring GPs was reviewed.ResultsDuring the study period, Ceph-R E. coli (n=900) were obtained directly from urines from 146 GPs. Seventy-percent (626/900) of isolates were CTX-R. WGS of 225 non-duplicate isolates identified that the most common mechanism of CTX-R was blaCTX-M carriage (185/225; 82.2%), predominantly blaCTX-M-15 (114/185; 61.6%), followed by carriage of plasmid mediated AmpCs (pAmpCs) (17/225; 7.6%), ESBL blaSHV variants (6/225; 2.7%), AmpC hyperproduction (13/225; 5.8%), or a combination of both blaCTX-M and pAmpC carriage (4/225; 1.8%). Forty-four sequence types (STs) were identified with ST131 representing 101/225 (45.0%) of sequenced isolates, within which the blaCTX-M-15-positive clade C2 was dominant (54/101; 53.5%). Ciprofloxacin-resistance (CIP-R) was observed in 128/225 (56.9%) of sequenced CTX-R isolates – predominantly associated with fluoroquinolone-resistant clones ST131 and ST1193.ConclusionsMost Ceph-R urinary E. colis were CTX-R, predominantly caused by blaCTX-M carriage. There was a clear correlation between CTX-R and CIP-R, largely attributable to the dominance of the high-risk pandemic clones, ST131 and ST1193 in this study. This localised epidemiological data provides greater resolution than regional data and can be valuable for informing treatment choices in the primary care setting.
Genetic rescue without genomic swamping in wild populations
Authors: Fitzpatrick Sarah W. , Bradburd Gideon S. , Kremer Colin T. , Salerno Patricia E. , Angeloni Lisa M. , Funk W. Chris 
Published: July 2019

AbstractGene flow is an enigmatic evolutionary force because it can limit adaptation but can also help populations escape inbreeding depression. Manipulating gene flow for conservation purposes is a controversial, but potentially powerful management strategy. We use multigenerational pedigrees and genomics to test demographic and evolutionary consequences of manipulating gene flow in two isolated wild Trinidadian guppy populations. We found that on average, hybrids lived longer and reproduced more. Despite overall genome-wide homogenization, alleles potentially associated with local adaptation were not entirely swamped by gene flow. Our results suggest that combining new genomic variation from immigrants with potentially adaptive variation from the recipient population resulted in highly fit hybrids and subsequent increases in population size. Contrary to the prevailing view that gene flow constrains adaptation, our study shows that immigration can produce long-term fitness benefits in small populations without swamping locally adaptive variation.
An atomistic perspective on ADCC quenching by core-fucosylation of IgG1 Fc N-glycans from enhanced sampling molecular dynamics
Authors: Harbison Aoife , Fadda Elisa 
Published: July 2019

AbstractThe immunoglobulin type G (IgG) Fc N-glycans are known to modulate the interaction with membrane-bound Fc γ receptors (FcγRs), fine-tuning the antibody’s effector function in a sequence-dependent manner. Particularly interesting in this respect are the roles of galactosylation, which levels are linked to autoimmune conditions and aging, of core fucosylation, which is known to reduce significantly the antibody-dependent cellular cytotoxicity (ADCC), and of sialylation, which also reduces ADCC but only in the context of core-fucosylation. In this work we provide an atomistic level perspective through enhanced sampling computer simulations, based on replica exchange molecular dynamics (REMD), to understand the molecular determinants linking the Fc N-glycans sequence to the observed IgG1 function. Our results indicate that the two symmetrically opposed N-glycans interact extensively through their core trimannose residues. At room temperature the terminal galactose on the α(1-6) arm is restrained to the protein through a network of interactions that keep the arm outstretched, meanwhile the α(1-3) arm extends towards the solvent where a terminal sialic acid remains fully accessible. We also find that the presence of core fucose interferes with the extended sialylated α(1-3) arm, altering its conformational propensity and as a consequence of steric hindrance, significantly enhancing the Fc dynamics. Furthermore, structural analysis shows that the core fucose position within the Fc core obstructs the access of N162 glycosylated FcγRs very much like a “door-stop”, potentially decreasing the IgG/FcγR binding free energy. All of these factors could represent important clues to understand at the molecular level the dramatic reduction of ADCC as a result of core fucosylation and provide an atomistic level-of-detail framework for the design of high potency IgG1 Fc N-glycoforms.
CASLFA: CRISPR/Cas9-mediated lateral flow nucleic acid assay
Authors: Wang Xusheng , Xiong Erhu , Tian Tian , Cheng Meng , Lin Wei , Sun Jian , Zhou Xiaoming 
Published: July 2019

AbstractThe lateral flow assay is one of the oldest and most convenient analytical techniques for analyzing the immune response, but its applicability to precise genetic analyses is limited by the tedious and inefficient hybridization steps. Here, we have introduced a new version of the lateral flow assay, termed Cas9-mediated lateral flow nucleic acids assay (CASLFA), to address such issues. In this study, CASLFA is utilized to identifyListeria monocytogenes, genetically modified organisms (GMOs), and African swine fever virus (ASFV) at a sensitivity of hundreds of copies of genome samples with high specificity within 1 h. CASLFA satisfies some of the characteristics of a next-generation molecular diagnostics tool due to its rapidity and accuracy, allowing for point-of-care use without the need for technical expertise and complex ancillary equipment. This method has great potential for analyzing genes in resource-poor or nonlaboratory environments.
Dinoflagellates with relic endosymbiont nuclei as novel models for elucidating organellogenesis
Authors: Sarai Chihiro , Tanifuji Goro , Nakayama Takuro , Kamikawa Ryoma , Takahashi Kazuya , Miyashita Hideaki , Ishida Ken-ichiro , Iwataki Mitsunori , Inagaki Yuji 
Published: July 2019

AbstractNucleomorphs are relic endosymbiont nuclei so far found only in two algal groups, cryptophytes and chlorarachniophytes, which have been studied to model the evolutionary process integrating an endosymbiont alga into be a host-governed plastid (organellogenesis). Nevertheless, past studies suggested that DNA transfer from the endosymbiont to host nuclei had already ceased in both cryptophytes and chlorarachniophytes, implying that the organellogenesis at the genetic level has been completed in the two systems. Moreover, we have yet to pinpoint the closest free-living relative of the endosymbiotic alga engulfed by the ancestral chlorarachniophyte or cryptophyte, making difficult to infer how organellogenesis altered the endosymbiont genome. To counter the above issues, we need novel nucleomorph-bearing algae, in which from-endosymbiont-to-host DNA transfer is on-going and of which endosymbiont/plastid origins can be inferred at a fine taxonomic scale. Here, we report two previously undescribed dinoflagellates, strains MGD and TGD, with green algal endosymbionts enclosing plastids as well as relic nuclei (nucleomorphs). We provide the evidence for the presence of DNA in the two nucleomorphs and transfer of endosymbiont genes to the host (dinoflagellate) genomes. Furthermore, DNA transfer between the host and endosymbiont nuclei was found to be in progress in both MGD and TGD systems. Phylogenetic analyses successfully resolved the origins of the endosymbionts at the genus level. Combined, we conclude that the host-endosymbiont integration in MGD/TGD is less advanced than that in cryptophytes/chrorarachniophytes, and propose the two dinoflagellates as new models for elucidating organellogenesis.