bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of fatal adverse prognosis in patients with fever-related diseases based on machine learning: A retrospective study
Authors: Zhao Chun-Hong , Wu Hui-Tao , Che He-Bin , Song Ya-Nan , Zhao Yu-Zhuo , Li Kai-Yuan , Xiao Hong-Ju , Zhai Yong-Zhi , Liu Xin , Lu Hong-Xi , Li Tan-Shi
Published: February 2020

Background

Fever is the most common chief complaint of emergency patients. Early identification of patients at an increasing risk of death may avert adverse outcomes. The aim of this study was to establish an early prediction model of fatal adverse prognosis of fever patients by extracting key indicators using big data technology.

Methods

A retrospective study of patients’ data was conducted using the Emergency Rescue Database of Chinese People's Liberation Army General Hospital. Patients were divided into the fatal adverse prognosis group and the good prognosis group. The commonly used clinical indicators were compared. Recursive feature elimination (RFE) method was used to determine the optimal number of the included variables. In the training model, logistic regression, random forest, adaboost and bagging were selected. We also collected the emergency room data from December 2018 to December 2019 with the same inclusion and exclusion criterion. The performance of the model was evaluated by accuracy, F1-score, precision, sensitivity and the areas under receiver operator characteristic curves (ROC-AUC).

Results

The accuracy of logistic regression, decision tree, adaboost and bagging was 0.951, 0.928, 0.924, and 0.924, F1-scores were 0.938, 0.933, 0.930, and 0.930, the precision was 0.943, 0.938, 0.937, and 0.937, ROC-AUC were 0.808, 0.738, 0.736, and 0.885, respectively. ROC-AUC of ten-fold cross-validation in logistic and bagging models were 0.80 and 0.87, respectively. The top six coefficients and odds ratio (OR) values of the variables in the Logistic regression were cardiac troponin T (CTnT) (coefficient=0.346, OR = 1.413), temperature (T) (coefficient=0.235, OR = 1.265), respiratory rate (RR) (coefficient= –0.206,OR = 0.814), serum kalium (K) (coefficient=0.137, OR = 1.146), pulse oxygen saturation (SPO2) (coefficient= –0.101, OR = 0.904), and albumin (ALB) (coefficient= –0.043, OR = 0.958). The weights of the top six variables in the bagging model were: CTnT, RR, lactate dehydrogenase, serum amylase, heartrate, and systolic blood pressure.

Conclusions

The main clinical indicators of concern included CTnT, RR, SPO2, T, ALB and K. The bagging model and logistic regression model had better diagnostic performance comprehesively. Those may be conducive to the early identification of critical patients with fever by physicians.
Neuroprotective effect of chronic administration of cannabidiol during the abstinence period on methamphetamine-induced impairment of recognition memory in the rats
Authors: Razavi Yasaman , Shabani Ronak , Mehdizadeh Mehdi , Haghparast Abbas
Published: February 2020

Neuropsychiatric disorders, such as addiction, are associated with cognitive impairment, including learning and memory deficits. Previous research has demonstrated that the chronic use of methamphetamine (METH) induces long-term cognitive impairment and cannabidiol (CBD), as a neuroprotectant, can reverse spatial memory deficits induced by drug abuse. The study aimed to evaluate the effect of CBD on METH-induced memory impairment in rats chronically exposed to METH (CEM). For the induction of CEM, animals received METH (2 mg/kg, twice/day) for 10 days. Thereafter, the effect of intracerebroventricular (ICV) administration of CBD (32 and 160 nmol) during the (10 days) abstinence period on spatial memory was evaluated using the Y-Maze test, while recognition memory was examined using the novel object recognition (NOR) test. The results revealed a significant increase in the motor activity of METH-treated animals compared with the control group and, after the 10-day abstinence period, motor activity returned to baseline. Notably, the chronic administration of METH had impairing effects on spontaneous alternation performance and recognition memory, which was clearly observed in the NOR test. Additionally, although the ICV administration of CBD (160 nmol) could reverse long-term memory, a lower dose (32 nmol) did not result in any significant increase in exploring the novel object during short-term memory testing. These novel findings suggest that the chronic administration of METH induces memory impairment and presents interesting implications for the potential use of CBD in treating impairment deficits after chronic exposure to psychostimulant drugs such as METH.
The Cerebrospinal Fluid Interleukin-6/Interleukin-10 Ratio Differentiates Pediatric Tick-borne Infections
Authors: Ygberg Sofia , Fowler Åsa , Bogdanovic Gordana , Wickström Ronny
Published: February 2020

Background:

Borrelia burgdorferi and tick-borne encephalitis (TBE) virus are 2 types of tick-borne pathogens that can cause central nervous system infection. Routine diagnostics have so far included analysis of cerebrospinal fluid (CSF) cell numbers, CSF serology for Borrelia burgdorferi and serum serology for TBE virus. However, early diagnosis may be difficult based on antibody detection which takes time to analyze, and with the possibility of false negative results, thus delaying treatment. Cytokine analyses are becoming increasingly available in clinical routine care and may offer important information.

Methods:

Fifteen cytokines and chemokines were measured in the CSF from the diagnostic lumbar puncture of 37 children with TBE, 34 children with neuroborreliosis and 19 children without evidence of central nervous system infection, using Luminex technology.

Results:

Significantly higher levels of proinflammatory interleukin-6 were detected in the samples from TBE-infected children, when compared with neuroborreliosis or controls. In comparison, children with neuroborreliosis had significantly higher levels of interleukin-7, interleukin-8, interleukin-10, and interleukin-13 when compared with TBE infected or controls. Furthermore, the ratio between interleukin-6 and interleukin-10 was significantly different between the 2 types of tick-borne infections.

Conclusions:

The interleukin-6/interleukin-10 ratio can be used as a rapid diagnostic cue upon suspected tick-borne infection, enabling fast and correct treatment. Also, in serology-negative results, such information may strengthen a clinical suspicion.
The Correlation Between Fall Prevention Knowledge and Behavior in Stroke Outpatients
Authors: Huang Yanxia , Wu Chanchan , Peng Huiping , Chen Qiaogen , Fan Xiujun , Xiao Lilan , Song Baiyan , Wan Lihong
Published: February 2020

BACKGROUND: Stroke outpatients have a high risk of falling. However, fall prevention measures in the community are insufficient to effectively reduce the fall rate among outpatients with stroke. We aimed to determine the correlation between fall prevention knowledge and behavior among outpatients with stroke and provide new strategies for community fall prevention. METHODS: We recruited 124 patients with stroke who were followed up in the outpatient department of a tertiary hospital in Zhuhai, China. Patients were assessed using a general information questionnaire, a fall prevention knowledge questionnaire for patients with stroke, and the Stroke Fall Prevention Behavior Scale. IBM SPSS 22.0 software was used for statistical analysis. RESULTS: The median fall prevention knowledge was 82.76 (68.97, 93.10) points, out of 100. The mean (SD) score for fall prevention behavior was 2.90 (0.52; range, 1–4) points. Fall prevention knowledge scores were positively related to those fall prevention behavior (Spearman r = 0.454, P < .01). CONCLUSION: Levels of fall prevention knowledge among outpatients with stroke were adequate, and this population had medium to high levels of fall prevention behavior. Better knowledge was accompanied with better prevention of falls. However, whether enriching the knowledge could lead to improvement of fall prevention is still undetermined.
Hospitalized Adult Patient Characteristics Associated With Participation in a Volunteer-Assisted Mobility Program
Authors: Dermody Gordana , Odom-Maryon Tamara , Zimmerman Jennifer , Glass Courtney
Published: February 2020

Background:

Physical inactivity during hospitalization commonly results in functional decline. Structured multidisciplinary programs/approaches may be useful to promote mobility in hospitalized adults.

Purpose:

The purpose was to determine whether a volunteer-assisted mobility program was feasible to improve the ambulation of hospitalized patients, and examine the characteristics of patients associated with willingness to participate in the program.

Methods:

A prospective descriptive correlation study was conducted in 2 acute care units. A volunteer-staffed program was implemented with the aim of improving the ambulation of hospitalized patients.

Results:

Hospitalized patients (N = 490) were approached, with 39.2% (n = 192) agreeing to ambulate an average of 109.7 m (interquartile range = 51.45-172.2 m). Patients with a low clinical frailty score, high body mass index, or physical therapy order were more likely to participate in the volunteer-assisted mobility program.

Conclusions:

The findings suggest that a volunteer-assisted interdisciplinary program is a feasible way to promote the ambulation of some patients.
Clinical Characteristics, Major Morbidity, and Mortality in Trauma-Related Pediatric Acute Respiratory Distress Syndrome*
Authors: Nair Alison B. , Cohen Mitchell J. , Flori Heidi R.
Published: February 2020

Objectives:

To determine the presence, central characteristics, and impact on major morbidity and mortality of trauma-related pediatric acute respiratory distress syndrome.

Design:

Retrospective review of a prospective trauma database.

Setting:

American College of Surgeons verified level 1 trauma center in an urban setting.

Patients:

Trauma patients age 0 to 18 years old inclusive.

Interventions:

None.

Measurements and Main Results:

Of the 7,382 patients presenting within the 10-year study period, 646 met study criteria for inclusion in the analysis. Trauma-related pediatric acute respiratory distress syndrome was present in 9% of the analyzed cohort. On univariate analysis and compared with those without, trauma-related pediatric acute respiratory distress syndrome occurred more commonly among those with traumatic brain injury (77.2% vs 45.5%; p < 0.001), non-accidental trauma (28.8% vs 10.2%; p < 0.001), and an injury severity score greater than 30 (27.1% vs 3.8%; p 0.001). New or progressive multiple organ dysfunction syndrome was significantly higher in trauma-related pediatric acute respiratory distress syndrome patients (86.7% vs 10.4%; p < 0.001) as was mortality (18.3% vs 3.1%; p < 0.001) than in those without. The presence of trauma-related pediatric acute respiratory distress syndrome (odds ratio, 6.98; 95% CI, 2.95–16.5; p < 0.001), younger age (odds ratio, 0.93; 95% CI, 0.87–0.99; p = 0.038), and worse injury severity (odds ratio, 1.19; 95% CI, 1.14–1.24; p < 0.001) were all independent statistical predictors of new or progressive multiple organ dysfunction syndrome in this retrospective cohort. Mortality in patients without trauma-related pediatric acute respiratory distress syndrome increased with increasing injury severity, whereas mortality in patients with trauma-related pediatric acute respiratory distress syndrome was the same regardless of injury severity. On multivariable regression analysis, while age and injury severity were independent statistical predictors of mortality, trauma-related pediatric acute respiratory distress syndrome was not (odds ratio, 2.35; 95% CI, 0.88–6.28; p = 0.087).

Conclusions:

Pediatric acute respiratory distress syndrome is present in the pediatric trauma population. Trauma-related pediatric acute respiratory distress syndrome is associated with eight times the organ dysfunction and five times the mortality compared with patients without trauma-related pediatric acute respiratory distress syndrome, yet research in this area is lacking. Further prospective, mechanistic evaluations are essential to understand why these patients are at risk and how to effectively intervene to improve outcomes.
In-Hospital Cost Comparison of Triple-Rule-Out Computed Tomography Angiography Versus Standard of Care in Patients With Acute Chest Pain
Authors: Takx Richard A.P. , Wichmann Julian L. , Otani Katharina , De Cecco Carlo N. , Tesche Christian , Baumann Stefan , Mastrodicasa Domenico , Litwin Sheldon E. , Bayer Richard R. , Nance John W. , Suranyi Pal , Jacobs Brian E. , Duguay Taylor M. , Vogl Thomas J. , Carr Christine M. , Schoepf U. Joseph
Published: February 2020

Purpose:

The purpose of this study was to evaluate the utilization of invasive and noninvasive tests and compare cost in patients presenting with chest pain to the emergency department (ED) who underwent either triple-rule-out computed tomography angiography (TRO-CTA) or standard of care.

Materials and Methods:

We performed a retrospective single-center analysis of 2156 ED patients who presented with acute chest pain with a negative initial troponin and electrocardiogram for myocardial injury. Patient cohorts matched by patient characteristics who had undergone TRO-CTA as a primary imaging test (n=1139) or standard of care without initial CTA imaging (n=1017) were included in the study. ED visits, utilization of tests, and costs during the initial episode of hospital care were compared.

Results:

No significant differences in the diagnosis of coronary artery disease, pulmonary embolism, or aortic dissection were observed. Median ED waiting time (4.5 vs. 7.0 h, P<0.001), median total length of hospital stay (5.0 vs. 32.0 h, P<0.001), hospital admission rate (12.6% vs. 54.2%, P<0.001), and ED return rate to our hospital within 30 days (3.5% vs. 14.6%, P<0.001) were significantly lower in the TRO-CTA group. Moreover, reduced rates of additional testing and invasive coronary angiography (4.9% vs. 22.7%, P<0.001), and ultimately lower total cost per patient (11,783$ vs. 19,073$, P<0.001) were observed in the TRO-CTA group.

Conclusions:

TRO-CTA as an initial imaging test in ED patients presenting with acute chest pain was associated with shorter ED and hospital length of stay, fewer return visits within 30 days, and ultimately lower ED and hospitalization costs.
Pneumothorax Rate and Diagnostic Adequacy of Computed Tomography–guided Lung Nodule Biopsies Performed With 18 G Versus 20 G Needles
Authors: Kolderman Nathan C. , Cheti Dev R. , Hasbrook Connor D. , Forsyth Andrew J. , Coffey Mary P. , Nair Girish B. , Al-Katib Sayf A.
Published: February 2020

Purpose:

Conflicting data exist with regard to the effect of needle gauge on outcomes of computed tomography (CT)-guided lung nodule biopsies. The purpose of this study was to compare the complication and diagnostic adequacy rates between 2 needle sizes: 18 G and 20 G in CT-guided lung nodule biopsies.

Materials and Methods:

This retrospective cohort study examined CT-guided lung biopsies performed between March 2014 and August 2016 with a total of 550 patients between the ages of 30 and 94. Biopsies were performed using an 18-G or a 20-G needle. Procedure-associated pneumothorax and other complication rates were compared between the 2 groups. Univariate and multiple logistic regression analyses were performed.

Results:

There was no significant difference in pneumothorax rate between 18 G (n=125) versus 20 G (n=425) (rates: 25.6% vs. 28.7%; P=0.50; odds ratio [OR]=0.86; 95% confidence interval [CI]=0.54-1.35), chest tube insertion rate (4.8% vs. 5.6%; P=0.71; OR=0.84; 95% CI=0.34-2.11), or diagnostic adequacy (95% vs. 93%; P=0.36; OR=1.51; 95% CI=0.61-3.72). Multiple logistic regression analysis demonstrated emphysema along the biopsy path (OR=3.12; 95% CI=1.63-5.98) and nodule distance from the pleural surface ≥4 cm (OR=1.85; 95% CI=1.05-3.28) to be independent risk factors for pneumothorax.

Conclusion:

No statistically significant difference in pneumothorax rate or diagnostic adequacy was found between 18-G versus 20-G core biopsy needles. Independent risk factors for pneumothorax include emphysema along the biopsy path and nodule distance from the pleural surface.
Humoral Alloreactivity in VCA Recipients: Should We Learn From Our Experience?
Authors: Sicard Antoine , Kanitakis Jean , Dubois Valérie , Morelon Emmanuel , Thaunat Olivier
Published: February 2020

Initially overlooked in favor of T cell–mediated rejection, the importance of the humoral alloimmune response has progressively emerged. As a result, antibody-mediated rejection is now widely recognized as the main cause of late allograft loss in most (if not all) types of solid-organ transplantation. Over the last 2 decades, vascularized composite allotransplantation (VCA) has appeared for replacing tissue defects in patients for whom no other satisfactory reconstructive options were available. Although it is now clear that VCA recipients can develop donor-specific antibodies, conclusions made in solid organ transplantation regarding antibody-mediated rejection may not systematically apply to VCA. Here, we propose to use the experience gained in organ transplantation to shed light on the path that shall be followed to evaluate and manage humoral alloreactivity in VCA recipients.
Cortical abnormalities and identification for first-episode schizophrenia via high-resolution magnetic resonance imaging
Authors: Liu Lin , Cui Long-Biao , Wu Xu-Sha , Fei Ning-Bo , Xu Zi-Liang , Wu Di , Xi Yi-Bin , Huang Peng , von Deneen Karen M. , Qi Shun , Zhang Ya-Hong , Wang Hua-Ning , Yin Hong , Qin Wei
Published: February 2020

Intro

Evidence from neuroimaging has implicated abnormal cerebral cortical patterns in schizophrenia. Application of machine learning techniques is required for identifying structural signature reflecting neurobiological substrates of schizophrenia at the individual level. We aimed to detect and develop a method for potential marker to identify schizophrenia via the features of cerebral cortex using high-resolution magnetic resonance imaging (MRI).

Method

In this study, cortical features were measured, including volumetric (cortical thickness, surface area, and gray matter volume) and geometric (mean curvature, metric distortion, and sulcal depth) features. Patients with first-episode schizophrenia (n = 52) and healthy controls (n = 66) were included from the Department of Psychiatry at Xijing Hospital. Multivariate computation was used to examine the abnormalities of cortical features in schizophrenia. Features were selected by least absolute shrinkage and selection operator (LASSO) method. The diagnostic capacity of multi-dimensional neuroanatomical patterns-based classification was evaluated based on diagnostic tests.

Results

Mean curvature (left insula and left inferior frontal gyrus), cortical thickness (left fusiform gyrus), and metric distortion (left cuneus and right superior temporal gyrus) revealed both group differences and diagnostic capacity. Area under receiver operating characteristic curve was 0.88, and the sensitivity, specificity, and accuracy of were 94%, 82%, and 88%, respectively. Confirming these findings, similar results were observed in the independent validation. There was a positive association between index score derived from the multi-dimensional patterns and the severity of symptoms (r = 0.40, P < .01) for patients.

Discussion

Our findings demonstrate a view of cortical differences with capacity to discriminate between patients with schizophrenia and healthy population. Structural neuroimaging-based measurements hold great promise of paving the road for their clinical utility in schizophrenia.
Trait-similarity and trait-hierarchy jointly determine co-occurrences of resident and invasive ant species
Authors: Wong Mark K. L. , Tsang Toby P. N. , Lewis Owen T. , Guénard Benoit
Published: February 2020

Interspecific competition, a dominant process structuring ecological communities, acts on species’ phenotypic differences. Species with similar traits should compete intensely (trait-similarity), while those with traits that confer competitive ability should outcompete others (trait-hierarchy). Either or both of these mechanisms may drive competitive exclusion within a community, but their relative importance and interacting effects are rarely studied. We show empirically that spatial associations (pairwise co-occurrences) between an invasive antSolenopsis invictaand 28 other ant species across a relatively homogenous landscape are explained largely by an interaction of trait-similarity and trait-hierarchy in one morphological trait. We find that increasing trait-hierarchy leads to more negative associations; however these effects are counteracted when species are sufficiently dissimilar (by 37-95%) in their trait ranges. We also show that a model of species co-occurrences integrating trait-similarity and trait-hierarchy consolidates predictions of different theoretical assembly rules. This highlights the explanatory potential of the trait-based co-occurrence approach.
The multiplicity of infection does not affect interactions betweenCryptococcus neoformansand macrophages
Authors: Pline Katherine , Johnston Simon
Published: February 2020

Major determinants of the outcome of infection include growth of the pathogen and response of immune cells such as macrophages.Cryptococcus neoformansis a fungal pathogen which may grow within the extracellular environment, or may exploit host macrophages as a niche for replication and dissemination. The clinical outcome of cryptococcal infection varies widely between individuals even when key host and pathogen molecular factors are the same. For a broad range of infections altering pathogen density is known to influence progression and outcome of infection by affecting immune response and pathogen biology (e.g. via innate immune signalling or microbial quorum sensing). Here, using time lapse imaging of murine cell line and human primary macrophagesin vitro, we examined the effect of altering pathogen density on the interactions of macrophages with cryptococci. We find that increasing fungal burden over several orders of magnitude did not increase or decrease phagocytosis by murine J774 macrophage-like cells or human monocyte-derived macrophages, illustrating neither dose-dependent immune activation nor dampening of the phagocytic response. Furthermore, increasing fungal density alone was not sufficient to alter the ability of cryptococci to grow intracellularly and has no significant effect on fungal doubling time for cryptococci that were intracellular or extracellular. This suggested that individual macrophage-Cryptococcusinteractions were not affected by even large changes in fungal density, an important finding in understanding what determines the outcome of cryptococcal infection.
A Versatile Vector System for the Fast Generation of Knock-in Cell Lines with CRISPR
Authors: Perez-Leal Oscar , Nixon-Abell Jonathon , Barrero Carlos A. , Gordon John , Rico Mario C.
Published: February 2020

Until recent advancements in genome editing via CRISPR/Cas9 technology, understanding protein function typically involved artificially overexpressing proteins of interest. Despite that CRISPR/Cas9 has ushered in a new era of possibilities for modifying endogenous genes with labeling tags (knock-in) to more accurately study proteins under physiological conditions, the technique is largely underutilized due to its tedious, multi-step process. Here we outline a homologous recombination system (FAST-HDR) to be used in combination with CRISPR/Cas9 that significantly simplifies and accelerates this process while introducing multiplexing to allow live-cell studies of 3 endogenous proteins within the same cell line. Furthermore, the recombination vectors are assembled in a single reaction that is enhanced for eliminating false positives and reduces the overall creation time for the knockin cell line from~8 weeks to <15 days. Finally, the system utilizes a modular construction to allow for seamlessly swapping labeling tags to ensure flexibility according to the area under study. We validated this new methodology by developing advanced cell lines with 3 fluorescent-labeled endogenous proteins that support high-content phenotypic drug screening without using antibodies or exogenous staining. Therefore, Fast-HDR cell lines provide a robust alternative for studying multiple proteins of interest in live cells without artificially overexpressing labeled proteins.
Next generation cytogenetics: comprehensive assessment of 48 leukemia genomes by genome imaging
Authors: Neveling Kornelia , Mantere Tuomo , Vermeulen Susan , Oorsprong Michiel , van Beek Ronald , Kater-Baats Ellen , Pauper Marc , van der Zande Guillaume , Smeets Dominique , Weghuis Daniel Olde , Stevens-Kroef Marian J , Hoischen Alexander
Published: February 2020

Somatic structural variants are important for cancer development and progression. In a diagnostic set-up, especially for hematological malignancies, the comprehensive analysis of all cytogenetic aberrations in a given sample still requires a combination of techniques, such as karyotyping, fluorescencein situhybridization and CNV-microarrays. We hypothesize that the combination of these classical approaches could be replaced by high-resolution genome imaging.

Bone marrow aspirates or blood samples derived from 48 patients with leukemia, who received a clinical diagnoses of different types of hematological malignancies, were processed for genome imaging with the Bionano Genomics Saphyr system. In all cases cytogenetic abnormalities had previously been identified using standard of care workflows. Based on these diagnostic results, the samples were divided into two categories: simple cases (<5 aberrations, n=37) and complex cases (≥5 aberrations or an unspecified marker chromosome, n=11). By imaging the labelled ultra-long gDNA molecules (average N50 >250kb), we generated on average ∼280-fold mapped genome coverage per sample. Chromosomal aberrations were called by Bionano Genomics Rare variant pipeline (RVP) specialized for the detections of somatic variants.

Per sample, on average a total of 1,454 high confidence SVs were called, and on average 44 (range: 14-130) of those were rarei.e. not present in the population control database. Importantly, for the simple cases, all clinically reported aberrations with variant allele frequencies higher than 10% were detected by genome imaging. This held true for deletions, insertions, inversions, aneuploidies and translocations. The results for the complex cases were also largely concordant between the standard of care workflow and optical mapping, and in several cases, optical mapping revealed higher complexity than previously known. SV and CNV calls detected by optical mapping were more complete than any other previous single test and likely delivered the most accurate and complete underlying genomic architecture. Even complex chromothripsis structures were resolved. Finally, optical mapping also identified multiple novel events, including balanced translocations that lead to potential novel fusion-genes, opening the potential to discover new prognostic and diagnostic biomarkers.

The full concordance with diagnostic standard assays for simple cases and the overall great concordance with (previously likely incompletely understood) complex cases demonstrates the potential to replace classical cytogenetic tests with genome imaging. In addition, this holds the potential to rapidly map new fusion genes and identify novel SVs and CNVs as novel potential leukemia drivers.
Hydrogen sulfide exposure reduces thermal set point in zebrafish
Authors: Skandalis Dimitri A. , Dobell Cheryl D. , Shaw Joshua C. , Tattersall Glenn J.
Published: February 2020

Behavioural flexibility allows ectotherms to exploit the environment to govern their metabolic physiology, including in response to environmental stress. Hydrogen sulfide (H2S) is a widespread environmental toxin that can lethally inhibit metabolism. However, H2S can also alter behaviour and physiology, including a hypothesised induction of hibernation-like states characterised by downward shifts of the innate thermal setpoint (anapyrexia). Support for this hypothesis has proved controversial because it is difficult to isolate active and passive components of thermoregulation, especially in animals with high resting metabolic heat production. Here, we directly test this hypothesis by leveraging the natural behavioural thermoregulatory drive of fish to move between environments of different temperatures in accordance with their current physiological state and thermal preference. We observed a decrease in adult zebrafish (Danio rerio) preferred body temperature with exposure to 0.02% H2S, which we interpret as a shift in thermal setpoint. Individuals exhibited consistent differences in shuttling behaviour and preferred temperatures, which were reduced by a constant temperature magnitude during H2S exposure. Seeking lower temperatures alleviated H2S-induced metabolic stress, as measured by reduced rates of aquatic surface respiration rate. Our findings highlight the interactions between individual variation and sublethal impacts of environmental toxins on behaviour.
Comparative analysis of CPI-motif regulation of biochemical functions of actin capping protein
Authors: McConnell Patrick , Mekel Marlene , Kozlov Alexander G. , Mooren Olivia L. , Lohman Timothy M. , Cooper John A.
Published: February 2020

The heterodimeric actin capping protein (CP) is regulated by a set of proteins that contain CP-interacting (CPI) motifs. Outside of the CPI motif, the sequences of these proteins are unrelated and distinct. The CPI motif and surrounding sequences are conserved within a given protein family, when compared to those of other CPI-motif protein families. Using biochemical assays with purified proteins, we compared the ability of CPI-motif-containing peptides from different protein families to a) bind to CP, b) allosterically inhibit barbed-end capping by CP, and c) allosterically inhibit interaction of CP with V-1, another regulator of CP. We found large differences in potency among the different CPI-motif-containing peptides, and the different functional assays showed different orders of potency. These biochemical differences among the CPI-motif peptides presumably reflect interactions between CP and CPI-motif peptides involving amino-acid residues that are conserved but are not part of the strictly defined consensus, as it was originally identified in comparisons of sequences of CPI motifs(1, 2) across all protein families (1, 2). These biochemical differences may be important for conserved distinct functions of CPI-motif protein families in cells with respect to the regulation of CP activity and actin assembly near membranes.
Recombinant human MG53 protein preserves mitochondria integrity in cardiomyocytes during ischemia reperfusion-induced oxidative stress
Authors: Gumpper Kristyn , Ma Hanley , Krishnamurthy Karthikeyan , Zhou Xinyu , Park Ki Ho , Sermersheim Matthew , Zhou Jingsong , Tan Tao , Lin Pei-Hui , Li Lei , Liu Jianxun , Zhu Hua , Ma Jianjie
Published: February 2020

Ischemic injury to the heart causes a loss of mitochondria function due to an increase in oxidative stress. MG53, also known as TRIM72, is highly expressed in striated muscle and is essential to repair damage to plasma membrane. We have shown thatmg53-/-mice are more susceptible to ischemia-reperfusion injury, whereas treatment with exogenous recombinant human MG53 (rhMG53) reduces both infarct damage and restores cardiac function. This study assesses whether MG53 protects and repairs mitochondria injury after oxidative stress associated with myocardial infarction. We hypothesize that in addition to known cell membrane repair function, MG53 acts as a myokine to protect cardiomyocytes by maintaining mitochondrial function. A combination ofin vivoandin vitroischemia/reperfusion models were used to assess MG53’s effect on mitochondria using biochemical assays and confocal microscopic imaging. Treatment with rhMG53 allowed cells to maintain a healthy mitochondrial membrane potential, reduced release of mitochondrial reactive oxygen species, and mitigated mitophagy. Mitochondrial localization of rhMG53 is mediated by exposure of and interaction with cardiolipin on the mitochondrial membrane. Our data demonstrates that rhMG53 protein preserves mitochondria integrity in cardiomyocytes during ischemia reperfusion-induced oxidative stress.
Predatory colponemids are the sister group to all other alveolates
Authors: Tikhonenkov Denis V. , Strassert Jürgen F. H. , Janouškovec Jan , Mylnikov Alexander P. , Aleoshin Vladimir V. , Burki Fabien , Keeling Patrick J.
Published: February 2020

Alveolates are a major supergroup of eukaryotes encompassing more than ten thousand free-living and parasitic species, including medically, ecologically, and economically important apicomplexans, dinoflagellates, and ciliates. These three groups are among the most widespread eukaryotes on Earth, and their environmental success can be linked to unique innovations that emerged early in each group. Understanding the emergence of these well-studied and diverse groups and their innovations has relied heavily on the discovery and characterization of early-branching relatives, which allow ancestral states to be inferred with much greater confidence. Here we report the phylogenomic analyses of 313 eukaryote protein-coding genes from transcriptomes of three members of one such group, the colponemids (Colponemidia), which unambiguously support their monophyly and position as the sister lineage to all other alveolates. Colponemid-related sequences from environmental surveys and our microscopical observations show that colponemids are not common in nature, but diverse and widespread in freshwater habitats around the world. Studied colponemids possess two types of extrusive organelles (trichocysts or toxicysts) for active hunting of other unicellular eukaryotes and potentially play an important role in microbial food webs. Colponemids have generally plesiomorphic morphology and illustrate the ancestral state of Alveolata. We further discuss their importance in understanding the evolution of alveolates as well as origin of myzocytosis and plastids.

Highlights

Phylogenomics resolves Colponemidia as a sister group to all other alveolates

The ancestor of all alveolates was a biflagellate predator feeding by phagocytosis

Colponemids may illuminate the ancestral states of apicomplexans, dinoflagellates, and ciliates

Colponemids are geographically widespread in freshwater habitats
Intimate functional interactions between TGS1 and the Smn complex revealed by an analysis of the Drosophila eye development
Authors: Maccallini Paolo , Bavasso Francesca , Scatolini Livia , Bucciarelli Elisabetta , Noviello Gemma , Lisi Veronica , Palumbo Valeria , D’Angeli Simone , Cacchione Stefano , Cenci Giovanni , Ciapponi Laura , Wakefield James G. , Gatti Maurizio , Raffa Grazia Daniela
Published: February 2020

Trimethylguanosine synthase 1 (TGS1) is a conserved enzyme that mediates formation of the trimethylguanosine cap on several RNAs, including snRNAs and telomerase RNA. Previous studies have shown that TGS1 binds the Survival Motor Neuron (SMN) protein, whose deficiency causes spinal muscular atrophy (SMA). In addition, TGS1 depletion results in increased hTR levels and telomere elongation in human cells. Here, we analyzed the roles of theDrosophilaorthologs of the humanTGS1andSMNgenes. We show that theDrosophilaTGS1 protein (dTgs1) physically interacts with all subunits of theDrosophilaSmn complex (Smn, Gem2, Gem3, Gem4 and Gem5), and that a humanTGS1transgene rescues the mutant phenotype caused bydTgs1loss. We demonstrate that bothdTgs1andSmnare required for viability of retinal progenitor cells and that downregulation of these genes leads to a reduced eye size. Importantly, overexpression ofdTgs1partially rescues the eye defects caused by Smn depletion, and vice versa. These results suggest that theDrosophilaeye model can be exploited for screens aimed at the identification of genes and drugs that modify the phenotypes elicited by Tgs1 and Smn deficiency. These modifiers could help to devise new therapies for SMA and diseases caused by telomerase insufficiency.
Multi-Stage Feature Selection (MSFS) Algorithm for UWB-Based Early Breast Cancer Size Prediction
Authors: Vijayasarveswari V. , Andrew A.M. , Jusoh M. , Sabapathy T. , Raof R.A.A. , Yasin M.N.M. , Ahmad R.B. , Khatun S.
Published: February 2020

Breast cancer is the most common cancer among women and it is one of the main causes of death for women worldwide. To attain an optimum medical treatment for breast cancer, an early breast cancer detection is crucial. This paper proposes a multistage feature selection method that extracts statistically significant features for breast cancer size detection using proposed data normalization techniques. Ultra-wideband (UWB) signals, controlled using microcontroller are transmitted via an antenna from one end of the breast phantom and are received on the other end. These ultra-wideband analogue signals are represented in both time and frequency domain. The preprocessed digital data is passed to the proposed multi-stage feature selection algorithm. This algorithm has four selection stages. It comprises of data normalization methods, feature extraction, data dimensional reduction and feature fusion. The output data is fused together to form the proposed datasets, namely, 8-HybridFeature, 9-HybridFeature and 10-HybridFeature datasets. The classification performance of these datasets is tested using the Support Vector Machine, Probabilistic Neural Network and Naïve Bayes classifiers for breast cancer size classification. The research findings indicate that the 8-HybridFeature dataset performs better in comparison to the other two datasets. For the 8-HybridFeature dataset, the Naïve Bayes classifier (91.98%) outperformed the Support Vector Machine (90.44%) and Probabilistic Neural Network (80.05%) classifiers in terms of classification accuracy. The finalized method is tested and visualized in the MATLAB based 2D and 3D environment.
A genome-wide case-only test for the detection of digenic inheritance in human exomes
Authors: Kerner Gaspard , Bouaziz Matthieu , Cobat Aurélie , Bigio Benedetta , Timberlake Andrew T , Bustamante Jacinta , Lifton Richard P , Casanova Jean-Laurent , Abel Laurent
Published: February 2020

Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a novel two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene x gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment and bias of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we validated our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients.

Significance statement

Despite a growing number of reports of rare disorders not fully explained by monogenic lesions, digenic inheritance has been reported for only 54 diseases to date. The very few existing methods for detecting gene x gene interactions from next-generation sequencing data were generally studied in rare-variant association studies with limited simulation analyses for short genomic regions, under a case-control design. We describe the first case-only approach designed specifically to search for digenic inheritance, which avoids recruitment and bias related to controls. We show, through both extensive simulation studies on real WES datasets and application to a real example of craniosynostosis, that our method is robust and powerful for the genome-wide identification of digenic lesions.
The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome
Authors: Duran-Ferrer Martí , Clot Guillem , Nadeu Ferran , Beekman Renée , Baumann Tycho , Nordlund Jessica , Marincevic-Zuniga Yanara , Lönnerholm Gudmar , Rivas-Delgado Alfredo , Martin Silvia , Ordoñez Raquel , Castellano Giancarlo , Kulis Marta , Queirós Ana , Seung-Tae Lee , Wiemels Joseph , Royo Romina , Puiggrós Montserrat , Lu Junyan , Gine Eva , Beà Sílvia , Jares Pedro , Agirre Xabier , Prosper Felipe , López-Otín Carlos , Puente Xosé S. , Oakes Christopher C. , Zenz Thorsten , Delgado Julio , López-Guillermo Armando , Campo Elías , Martin-Subero José Ignacio
Published: February 2020

We report a systematic analysis of the biological and clinical implications of DNA methylation variability in five categories of B-cell tumors derived from B cells spanning the entire maturation spectrum. We used 2056 primary samples including training and validation series and show that 88% of the human DNA methylome is dynamically modulated under normal and neoplastic conditions. B-cell tumors display both epigenetic imprints of their cellular origin andde novo, disease-specific epigenetic alterations that in part are related to differential transcription factor binding. These differential methylation patterns were used by a machine-learning approach to create a diagnostic algorithm that accurately classifies 14 B-cell tumor entities and subtypes with different clinical management. Beyond this, we identified extensive patient-specific epigenetic variability targeting constitutively silenced chromatin regions, a phenomenon we could relate to the proliferative history of normal and neoplastic B cells. We observed that, depending on the maturation stage of the tumor cell of origin, mitotic activity leaves different imprints into the DNA methylome. Subsequently, we constructed a novel DNA methylation-based mitotic clock called epiCMIT (epigenetically-determinedCumulativeMIToses), whose lapse magnitude represents a strong independent prognostic variable within specific B-cell tumor subtypes and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracker of B-cell tumor developmental history, with implications in the differential diagnosis and prediction of the outcome of the patients.
A gatekeeping role of ESR2 to maintain the primordial follicle reserve
Authors: Chakravarthi V. Praveen , Ghosh Subhra , Roby Katherine F. , Wolfe Michael W. , Rumi M. A. Karim
Published: February 2020

Over the entire reproductive lifespan in mammals, a fixed number of primordial follicles serve as the source of mature oocytes. Uncontrolled and excessive activation of primordial follicles can lead to depletion of the ovarian reserve. We observed that disruption of ESR2-signaling results in increased activation of primordial follicles inEsr2-null (Esr2-/-) rats. However, follicle assembly was unaffected, and the total number of follicles remained comparable between neonatal wildtype andEsr2-/-ovaries. While the activated follicle counts were increased inEsr2-/-ovary, the number of primordial follicles were markedly decreased. Excessive recruitment of primordial follicles led to premature ovarian senescence inEsr2-/-rats and was associated with reduced levels of serum AMH and estradiol. Disruption of ESR2-signaling through administration of a selective antagonist (PHTPP) increased the number of activated follicles in wildtype rats, whereas a selective agonist (DPN) decreased follicle activation. In contrast, primordial follicle activation was not increased in the absence of ESR1 indicating that the regulation of primordial follicle activation is ESR2-specific. Follicle activation was also increased inEsr2-mutants lacking the DNA-binding domain, suggesting a role for the canonical transcriptional activation function. Both primordial and activated follicles express ESR2 suggesting a direct regulatory role for ESR2 within these follicles. We also detected that loss of ESR2 augmented the activation of AKT, ERK and mTOR pathways. Our results indicate that the lack of ESR2 upregulated both granulosa and oocyte factors, which can facilitate AKT and mTOR activation inEsr2-/-ovaries leading to increased activation of primordial follicles.
An efficient RNA-seq-based segregation analysis identifies the sex chromosomes of Cannabis sativa
Authors: Prentout Djivan , Razumova Olga , Rhoné Bénédicte , Badouin Hélène , Henri Hélène , Feng Cong , Käfer Jos , Karlov Gennady , Marais Gabriel A.B.
Published: February 2020

Cannabissativa–derived tetrahydrocannabinol (THC) production is increasing very fast worldwide. C. sativa is a dioecious plant with XY Chromosomes, and only females (XX) are useful for THC production. Identifying the sex chromosome sequence would improve early sexing and better management of this crop; however, the C. sativa genome projects have failed to do so. Moreover, as dioecy in the Cannabaceae family is ancestral, C. sativa sex chromosomes are potentially old and thus very interesting to study, as little is known about old plant sex chromosomes. Here, we RNA-sequenced a C. sativa family (two parents and 10 male and female offspring, 576 million reads) and performed a segregation analysis for all C. sativa genes using the probabilistic method SEX-DETector. We identified >500 sex-linked genes. Mapping of these sex-linked genes to a C. sativa genome assembly identified the largest chromosome pair being the sex chromosomes. We found that the X-specific region (not recombining between X and Y) is large compared to other plant systems. Further analysis of the sex-linked genes revealed that C. sativa has a strongly degenerated Y Chromosome and may represent the oldest plant sex chromosome system documented so far. Our study revealed that old plant sex chromosomes can have large, highly divergent nonrecombining regions, yet still be roughly homomorphic.