bluuebunny/crossref_metadata_2025_split huggingface dataset:
The clinical value of IL-3, IL-4, IL-12p70, IL17A, IFN-γ, MIP-1β, NLR, P-selectin, and TNF-α in differentiating bloodstream infections caused by gram-negative, gram-positive bacteria and fungi in hospitalized patients
Authors: Li Xinjun , Yuan Xiaozhou , Wang Chengbin 
Published: October 2019

Abstract
Early differential diagnosis of bloodstream infections (BSIs) caused by different sources and species of bacteria in hospitalized patients is crucial for the timely targeted interventions including appropriate use of antibiotics. The aim of this study was to identify 9 biomarkers for the early differentiation of gram-negative-bloodstream infection (GN-BSI), gram-positive (GP)-BSI, and fungal-BSI.
A prospective study was conducted for a total of 390 inpatients who underwent blood culture in the Chinese PLA General Hospital from September 2015 to March 2018. Patients with positive culture of a single pathogen were divided into GN-BSI, GP-BSI, and Fungal-BSI groups, and a culture-negative disease control group was also established. The serum levels of macrophage inflammatory protein 1β (MIP-1β), tumor necrosis factor α (TNF-α), interleukin (IL)-3, interferon (IFN)-γ, IL-17A, IL-4, IL-12p70, and P-selectin were detected and the NLR was calculated from routine blood test. Receiver-operating characteristic analysis was used to determine the efficacy of various indicators in the differential diagnosis of BSIs. Prediction and validation experiments on clinical patient samples (263 cases) were also performed.
The level of IL-3 in the GP-BSI group was significantly higher than those in the other 3 groups. The level of IFN-γ in the fungal-BSI group was significantly higher than those in the other 3 groups. NLR, MIP-1β, TNF-α, IL-17A, and IL3 exhibited some efficacy when distinguishing between GN-BSI and GP-BSI and NLR had the largest area under curve (AUC) (0.728), followed by MIP-1β with an AUC of 0.679. IFN-γ and IL-3 exhibited some value in differential diagnosis between GN-BSI and Fungal-BSI. IL-3, MIP-1β, TNF-α, IFN-γ, NLR, IL-17A, and IL-4 exhibited some value in distinguishing fungal-BSI and GP-BSI, with IL-3 had the largest AUC (0.722), followed by MIP-1β with an AUC of 0.703.
NLR and MIP-1β may be valuable in differentiating GN-BSI from GP-BSI in hospitalized patients. IFN-γ and IL-3 may be helpful in differential diagnosis GN-BSI and fungal-BSI. IL-3 and MIP-1β exhibited some diagnostic efficacy in distinguishing fungal-BSI and GP-BSI. Additionally, IL-3 with high serum level may be a marker for GP-BSI and IFN-γ with high serum level may be a valuable marker for the prediction of Fungal-BSI. The utility of these biomarkers to predict BSIs owing to different pathogens in hospitalized patients needs to be assessed in further studies.
Comparative Early Hemodynamic Profiles in Patients Presenting to the Emergency Department with Septic and Nonseptic Acute Circulatory Failure Using Focused Echocardiography
Authors: Lafon Thomas , Appert Alexandra , Hadj Mathilde , Bigrat Vincent , Legarcon Vincent , Claveries Paul , Goudelin Marine , Evrard Bruno , Padilla Ana Catalina Hernandez , Baisse Arthur , Vignon Philippe 
Published: October 2019

ABSTRACT

Study Objective:
We evaluated the early hemodynamic profile of patients presenting with acute circulatory failure to the Emergency Department (ED) using focused echocardiography performed by emergency physicians after a dedicated training program.

Methods:
Patients presenting to the ED with an acute circulatory failure of any origin were successively examined by a recently trained emergency physician and by an expert in critical care echocardiography. Operators independently performed and interpreted online echocardiographic examinations to determine the leading mechanism of acute circulatory failure.

Results:
Focused echocardiography could be performed in 100 of 114 screened patients (55 with sepsis/septic shock and 45 with shock of other origin) after a median fluid loading of 500 mL (interquartile range: 187–1,500 mL). A hypovolemic profile was predominantly observed whether the acute circulatory failure was of septic origin or not (33/55 [60%] vs. 23/45 [51%]: P = 0.37). Although a vasoplegic profile associated with a hyperkinetic left ventricle was most frequently identified in septic patients when compared with their counterparts (17/55 [31%] vs. 5/45 [11%]: P = 0.02), early left or right ventricular failure was observed in 31% of them. Hemodynamic profiles were adequately appraised by recently trained emergency physicians, as reflected by a good-to-excellent agreement with the expert's assessment (Κ: 0.61–0.85).

Conclusions:
Hypovolemia was predominantly identified in patients presenting to the ED with acute circulatory failure. Although vasoplegia was more frequently associated with sepsis, early ventricular dysfunction was also depicted in septic patients. Focused echocardiography seemed reliable when performed by recently trained emergency physicians without previous experience in ultrasound.
Investigating Gut Microbiota-Host Interactions in a Microaerobic Environment
Authors: McGrath Conor , Bell Andrew , McGrath Emmanuelle , Juge Nathalie , Schüller Stephanie 
Published: October 2019

The gut microbiota has an important role in maintaining intestinal health and protecting against enteric infections (colonisation resistance). Nevertheless the majority of these interactions haven't been explored, largely due to a lack of experimental model systems that can culture oxygen-sensitive commensals alongside intestinal cells. In this project, we have established a novel in vitro model system of the human intestinal epithelium (Vertical Diffusion Chamber, VDC) which also supports growth of strictly anaerobic bacteria. We have applied this system to investigate the interactions of gut symbiont Ruminococcus gnavus with a functioning mucus-producing epithelium, established using T84 and goblet-like LS174T cell lines, and its effect on infection with foodborne pathogen enteropathogenic E. coli (EPEC).
Initial work focused on identifying a culture medium that supports R. gnavus and EPEC growth whilst maintaining epithelial integrity and barrier function. This has been achieved by establishing bacterial growth curves in different media and assessing epithelial barrier function by transepithelial electrical resistance and immunofluorescence staining (IFS) of tight-junction protein occludin. Further IFS demonstrated that introduction of LS174T cells to the epithelium causes mucin secretion and facilitates colonisation by R. gnavus. Co-culture of EPEC with R. gnavus reduces numbers of viable and adherent EPEC, but only when LS174T are present.
These data indicate potential colonisation resistance activity by R. gnavus, discovered by utilising a model system that supports anaerobic culture and a functioning epithelium side-by-side. Future work will investigate colonisation resistance activity for a panel of R. gnavus strains and attempt to elucidate mechanisms behind this activity.
The anaerobic skin colonizer Staphylococcus saccharolyticus, a possible agent of prosthetic joint infections, exhibits excessive genome decay
Authors: Brüggemann Holger , Söderquist Bo 
Published: October 2019

Human skin-colonizing bacteria can have double ‘personalities’, which muddles the distinction between commensals and pathogens. Coagulase-negative staphylococci (CoNS) are part of the normal skin microbiota, but some CoNS species can act as opportunistic pathogens.
The anaerobic CoNS species Staphylococcus saccharolyticus has not received much attention, although it is a frequent colonizer of human skin and associated with prosthetic joint infections. Therefore, we determined the frequencies of S. saccharolyticus on human skin and analyzed clinical and skin-derived S. saccharolyticus strains by genome sequencing and biochemical tests.
Analysis of skin samples from volunteers identified S. saccharolyticus on the forehead and in the elbow pit in approx. 20% of the samples. Genome sequencing revealed an unexpected feature of S. saccharolyticus: extensive genome decay, with over 300 pseudogenes, indicating ongoing reductive evolution. Many genes of the core metabolism are not functional, rendering the species auxotrophic for several amino acids, which could explain its slow growth, and the need for fastidious growth conditions.
In an attempt to evaluate the virulence potential of S. saccharolyticus, we determined abundantly secreted proteins: these included stress response proteins such as heat shock- and oxidative stress-related factors, as well as immunodominant staphylococcal surface antigens. The strains secrete lipases and a hyaluronic acid lyase; hyaluronidase as well as urease activities were detected with biochemical assays.
Our study revealed that S. saccharolyticus has adapted its genome, possibly due to a recent change of habitat; moreover, the data imply that the species has tissue-invasive potential and might cause prosthetic joint infections.
Survival strategies of Clostridium difficile to fluctuating concentrations of oxygen
Authors: Martins Maria Carlos , Salgueiro Bruno , Carlos Filipe , Romão Célia , Frazão Carlos , Teixeira Miguel 
Published: October 2019

Oxygen and reactive oxygen species (ROS) can react with multiple cellular components, leading to the inactivation of a plethora of metabolic pathways. Therefore, organismshave systems to sense and eliminate O2 and ROS, contributing to their survival in the adverse host environment.
Clostridium difficileP28 is an anaerobic pathogenic bacterium that contains in its genome a flavodiiron protein (FDP) and a rubrerythrin (Rbr),that are putatively involved in the detoxification pathways used by this organism.
Flavodiiron proteins are widespread in all life domains, with a crucial role in O2detoxification, through its reduction directly to water. FDPs are cytoplasmic enzymes with a minimal structural unit composed by two main domains, a metallo-β-lactamase domain, containing the catalytic diiron site, and a flavodoxin domain having a flavin mononucleotide. Rubrerythrins are generally considered to act as NADH-linked hydrogen peroxide reductases, thus eliminating this ROS, and are composed by two iron sites:a diiron center and a rubredoxin-like FeCys4 center.
In this work with characterized biochemically, spectroscopically, structurally and kinetically the FDP and Rbr and their twoputative redox partners, a High Molecular Weight Rubredoxin (HRb) and a Rubredoxin (Rd). We confirmed theexistence of direct electron transfer betweenHRb, Rd and FDP and also between HRb, Rd and Rbr. In addition, we alsoestablished the reaction rates for the reduction, by FDP, of O2(0.43s-1) and H2O2 (0.06s-1) and for the reduction of H2O2by Rbr (1.53s-1). The enzymatic activity of Rbr towards O2 was also investigated.
Romão, C.V., et al, 2016.JBIC., 21:39-52.
Martins, M.C., et al., 2019. FRBM, in press.
The role of metalloenzymes for the survival of the anaerobe Clostridium difficile during infection
Authors: Folgosa Filipe , Alves Catarina , Martins Maria C. , Teixeira Miguel 
Published: October 2019

Clostridium difficile is the most prevalent pathogen among all healthcare-associated infections. This anaerobic bacterium can colonize the human gut, typically following agents that disrupt the normal gut microbiota, like antibiotics. In the gut, C. difficile is subjected to oxygen, which it has to eliminate for survival. Its genome encodes for two flavodiiron proteins, capable to reduceoxygen to water. Besides, some FDPs also reduce NO to N2O, an important feature as a resistance mechanism towards the human innate immune system[1,2]. Flavodiiron enzymes are constituted by a minimal core of two domains: a metallo-β-lactamase-like one, harboring the catalytic center, followed by a short-chain flavodoxin[1,2]. More complex FDPs exist, with multiple extra domains and redox centers[1,2]. C. difficile contains a ‘classical’ FDP, and a very complex one, with an extra short-type rubredoxin domain followed by an NADH:rubredoxin oxidoreductase-like one[3]. The biochemical, redox and spectroscopic studies demonstrated that this enzyme receives electrons directly from NADH, reducing its substrates, precluding the need for extra partners. This FDP is selective for O2 (16s-1), almost 10x higher than with NO. The reactivity towards hydrogen peroxide, as an H2O2 reductase with formation of water, with a non-negligible turnover (2s-1) is a novelty in the field of FDPs. Site directed mutants revealed that the rubredoxin-like center is essential for electron transfer from NADH to the catalytic center.
[1] Martins et al, Free Rad. Biol. Med., in press, 2019.
[2] Romão et al, J. Biol.Inorg. Chem., 21,39-52, 2016.
[3] Folgosa et al, Sci.Rep., 8, 10164, 2018.
Reptile-like physiology in Early Jurassic stem-mammals
Authors: Newham Elis , Gill Pamela G. , Brewer Philippa , Benton Michael J. , Fernandez Vincent , Gostling Neil J. , Haberthür David , Jernvall Jukka , Kankanpää Tuomas , Kallonen Aki , Navarro Charles , Pacureanu Alexandra , Zeller-Plumhoff Berit , Richards Kelly , Robson-Brown Kate , Schneider Philipp , Suhonen Heikki , Tafforeau Paul , Williams Katherine , Corfe Ian J. 
Published: October 2019

AbstractThere is uncertainty regarding the timing and fossil species in which mammalian endothermy arose, with few studies of stem-mammals on key aspects of endothermy such as basal or maximum metabolic rates, or placing them in the context of living vertebrate metabolic ranges. Synchrotron X-ray imaging of incremental tooth cementum shows two Early Jurassic stem-mammals,MorganucodonandKuehneotherium, had lifespans (a basal metabolic rate proxy) considerably longer than comparably sized living mammals, but similar to reptiles.Morganucodonalso had femoral blood flow rates (a maximum metabolic rate proxy) intermediate between living mammals and reptiles. This shows maximum metabolic rates increased evolutionarily before basal rates, and that contrary to previous suggestions of a Triassic origin, Early Jurassic stem-mammals lacked the endothermic metabolism of living mammals.One Sentence SummarySurprisingly long lifespans and low femoral blood flow suggest reptile-like physiology in key Early Jurassic stem-mammals.
pyCancerSig: subclassifying human cancer with comprehensive single nucleotide, structural and microsatellite mutational signature deconstruction from whole genome sequencing
Authors: Thutkawkorapin Jessada , Eisfeldt Jesper , Tham Emma , Nilsson Daniel 
Published: October 2019

AbstractBackgroundDNA damage accumulates over the course of cancer development. The often-substantial amount of somatic mutations in cancer poses a challenge to traditional methods to characterize tumors based on driver mutations. However, advances in machine learning technology can take advantage of this substantial amount of data.ResultsWe developed a command line interface python package, pyCancerSig, to perform sample profiling by integrating single nucleotide variation (SNV), structural variation (SV) and microsatellite instability (MSI) profiles into a unified profile. It also provides a command to decipher underlying cancer processes, employing an unsupervised learning technique, Non-negative Matrix Factorization, and a command to visualize the results. The package accepts common standard file formats (vcf, bam). The program was evaluated using a cohort of breast- and colorectal cancer from The Cancer Genome Atlas project (TCGA). The result showed that by integrating multiple mutations modes, the tool can correctly identify cases with known clear mutational signatures and can strengthen signatures in cases with unclear signal from an SNV-only profile.ConclusionspyCancerSig has demonstrated its capability in identifying known and unknown cancer processes, and at the same time, illuminates the association within and between the mutation modes.
High-speed quantitative optical imaging of absolute metabolism in the rat cortex
Authors: Wilson R. H. , Crouzet C. , Torabzadeh M. , Bazrafkan A. , Maki N. , Tromberg B. J. , Akbari Y. , Choi B. 
Published: October 2019

AbstractQuantitative measures of blood flow and metabolism are essential for improved assessment of brain health and response to ischemic injury. In this report, we demonstrate a multimodal technique for measuring the cerebral metabolic rate of oxygen (CMRO2) in the rodent brain on an absolute scale (μM O2 / min). We use laser speckle imaging (LSI) at 809 nm and spatial frequency domain imaging (SFDI) at 655 nm, 730 nm, and 850 nm to obtain spatiotemporal maps of cerebral blood flow (CBF), tissue absorption (μa), and tissue scattering (μs’). Knowledge of these three values enables calculation of a characteristic blood flow speed, which in turn is input to a mathematical model with a “zero-flow” boundary condition to calculate absolute CMRO2. We apply this method to a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation. With this model, the zero-flow condition occurs during entry into CA. The CMRO2 values calculated with our method are in good agreement with those measured with magnetic resonance (MR) and positron emission tomography (PET) by other groups. Our technique provides a quantitative metric of cerebral metabolism that can potentially be used for comparison between animals and longitudinal monitoring of a single animal over multiple days, to assess differences in baseline metabolism and track recovery of metabolism in survival studies following ischemia and reperfusion.
Functions for Cdc42p BEM Adaptors in Regulating a Differentiation-Type MAP Kinase Pathway
Authors: Basu Sukanya , González Beatriz , Li Boyang , Kimble Garrett , Kozminski Keith G. , Cullen Paul J. 
Published: October 2019

ABSTRACTRho GTPases regulate cell polarity and signal transduction pathways to control morphogenetic responses in different settings. In yeast, the Rho GTPase Cdc42p regulates cell polarity, and through the p21-activated kinase Ste20p, Cdc42p also regulates mitogen-activated protein kinase (MAPK) pathways (mating, filamentous growth or fMAPK, and HOG). Although much is known about how Cdc42p regulates cell polarity and the mating pathway, how Cdc42p regulates the fMAPK pathway is not clear. To address this question, Cdc42p-dependent MAPK pathways were compared in the filamentous (∑1278b) strain background. Each MAPK pathway showed a unique activation profile, with the fMAPK pathway exhibiting slow activation kinetics compared to the mating and HOG pathways. A previously characterized version of Cdc42p, Cdc42pE100A, that is specifically defective for fMAPK pathway signaling, was defective for interaction with Bem4p, the pathway-specific adaptor for the fMAPK pathway. Corresponding residues in Bem4p were identified that were required for interaction with Cdc42p and fMAPK pathway signaling. The polarity adaptor Bem1p also regulated the fMAPK pathway. In the fMAPK pathway, Bem1p recruited Ste20p to the plasma membrane, cycled between an open and closed conformation, and interacted with the GEF for Cdc42, Cdc24p. Bem1p also regulated effector pathways in different ways, behaving as a multi-functional adaptor in some pathways and an inert scaffold in others. Genetic suppression tests showed that Bem4p and Bem1p regulate the fMAPK pathway in an ordered sequence. Collectively, the study demonstrates unique and sequential functions for Rho GTPase adaptors in regulating MAPK pathways.HIGHLIGHTSComparing Cdc42p-dependent MAPK pathways showed that the fMAPK pathway had slow activation kinetics compared to the mating and HOG pathways.A collection ofcdc42alleles was tested for MAPK pathway functions.§ Cdc42pE100A, previously characterized as being specifically defective for fMAPK signaling, showed reduced interaction with the fMAPK pathway adaptor Bem4p.§ Corresponding residues in Bem4p were identified that were required for interaction with Cdc42p and fMAPK signaling.The polarity adaptor Bem1p regulated the fMAPK pathway.§ Bem1p regulated the fMAPK pathway by recruiting Ste20p to the plasma membrane, cycling between an open and closed conformation, and interacting with the Cdc42p GEF, Cdc24p.Different domains of Bem1p had different roles in regulating effector pathways.§ Bem1p may function as a multi-functional adaptor in some pathways and an inert scaffold in others.Bem4p and Bem1p regulated the fMAPK pathway in an ordered sequence.§ The data support a model where Bem4p recruits Cdc24p to GDP-Cdc42p, and Bem1p directs GTP-Cdc42p to Ste20p at the plasma membrane.§ The bud-site GTPase Rsr1p regulates Cdc24p in the fMAPK pathway but does not initiate signaling.
Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms
Authors: Rao Junhua , Peng Lihua , Chen Fang , Jiang Hui , Geng Chunyu , Zhao Xia , Liu Xin , Liang Xinming , Mu Feng 
Published: October 2019

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.
Deep residual neural networks resolve quartet molecular phylogenies
Authors: Zou Zhengting , Zhang Hongjiu , Guan Yuanfang , Zhang Jianzhi 
Published: October 2019

ABSTRACTPhylogenetic inference is of fundamental importance to evolutionary as well as other fields of biology, and molecular sequences have emerged as the primary data for this task. Although many phylogenetic methods have been developed to explicitly take into account substitution models of sequence evolution, such methods could fail due to model misspecification and insufficiency, especially in the face of heterogeneities in substitution processes across sites and among lineages. In this study, we propose to infer topologies of four-taxon trees using deep residual neural networks, a machine learning approach needing no explicit modeling of the subject system and having a record of success in solving complex non-linear inference problems. We train residual networks on simulated protein sequence data with extensive amino acid substitution heterogeneities. We show that the well-trained residual network predictors can outperform existing state-of-the-art inference methods such as the maximum likelihood method on diverse simulated test data, especially under extensive substitution heterogeneities. Reassuringly, residual network predictors generally agree with existing methods in the trees inferred from real phylogenetic data with known or widely believed topologies. We conclude that deep learning represents a powerful new approach to phylogenetic reconstruction, especially when sequences evolve via heterogeneous substitution processes. We present our best trained predictor in a freely available program namedPhylogenetics byDeepLearning (PhyDL,https://gitlab.com/ztzou/phydl).