bluuebunny/crossref_metadata_2025 huggingface dataset:
A Pilot Study of a Screening Tool for Pediatric Minimal Hepatic Encephalopathy
Authors: Ohnemus Daniella , Neighbors Katie , Sorensen Lisa G. , Lai Jin‐Shei , Alonso Estella M.
Published: September 2019

Objectives:

Despite the need for monitoring cognition for minimal hepatic encephalopathy (MHE) in children with portal hypertension, few screening methods exist. The Patient‐Reported Outcomes Measurement Information System (PROMIS) Pediatric Perceived Cognitive Function (PedsPCF) item bank, a 43‐item parent‐ and self‐report questionnaire, could be a useful screening tool. This study aimed to evaluate the PedsPCF item bank as a screening tool and explore its correlation with other neurocognitive measures and clinical indicators of portal hypertension.

Methods:

Pediatric patients with portal hypertension were recruited at Lurie Children's Liver Clinic. A short battery of neuropsychological tests tapping attention, executive functioning, and fine motor speed was administered along with surveys of cognitive functioning (PedsPCF, Behavior Rating Inventory of Executive Function; BRIEF) and quality of life (PROMIS Pediatric‐25 Profile).

Results:

Eighteen patients participated (ages 8––17). The PedsPCF correlated well with the BRIEF but did not correlate with neurocognitive testing. Qualitative heatmap analysis of the relationship between z‐scores and clinical signs of portal hypertension suggests the PedsPCF is less sensitive than the BRIEF. The fine motor task (Grooved Pegboard) appears to offer the highest sensitivity of the tests administered and is also relatively quick and easy to administer.

Conclusions:

Elements of the battery show promise in this small pilot sample. The BRIEF and the Grooved Pegboard may hold the most potential for screening in the clinical setting. Further study is necessary to examine this question in a larger multicenter sample.
Mental Health Literacy Among Chinese Rural Residents
Authors: Li Fenglan , Li Shengnan , Zhou Chunxiao , Wang Fei
Published: September 2019

A survey was carried among 412 participants to examine mental health literacy in rural China. Two vignettes depicting schizophrenia and depression were presented, and participants were asked to reflect on their recognition and the beliefs about the causes, consequences, and the treatments of the conditions described. Results show that the recognition rates for schizophrenia and depression were 76.9% and 67.7%, respectively. Participants believed work stress, life stress, and encountered frustration were the most important reasons for mental illnesses. Participants believed that mental illnesses could cause many severe consequences to patients, such as emotional pain, bringing pain to the family, deterioration of interpersonal relationships, and destroying the individual's life. The participants were more likely to recommend nonmedical treatment for the patients in the two vignettes. Participants having a higher educational level were more likely to be aware of the consequences of the mental illnesses, and they also had a more positive attitude toward seeking professional help.
Long-Term Health Consequences Among Wenchuan Earthquake Adult Survivors
Authors: Fu Mingqi , Guo Jing , Qu Zhiyong , Han Ziqiang , Wang Shuizhen , He Huan
Published: September 2019

The objective of this study was to examine the longitudinal health consequences of the Wenchuan earthquake. Based on descriptive analyses of national-level data and multivariate analyses on a six-wave repeated cross-sectional survey, the findings suggested that after 8 years health risks remained high among earthquake-affected survivors; however, a process of recovery existed. To conceptualize these findings, in this study, we proposed a three-stage recovery model in which the postdisaster health status was divided into three stages: acute, stagnant, and adaptive. At each stage, the health risk varied, and over time, associations between health outcomes and protective factors varied. The three-stage recovery model identified the trends of long-term health consequences among adult earthquake survivors and provided guidance for postdisaster reconstruction in China on the basis of protective factors analyses.
Exposure to Parental Threatening Behaviors and Internalizing Psychopathology in a Trauma-Exposed Inpatient Adolescent Sample
Authors: Trent Erika S. , Viana Andres G. , Raines Elizabeth M. , Woodward Emma C. , Zvolensky Michael J. , Candelari Abigail E.
Published: September 2019

Parental threatening behaviors have emerged as a subset of negative parental behaviors strongly related to internalizing symptoms among youth, yet the underlying mechanisms in this association have remained unexplored. The current investigation examined the role of difficulties engaging in goal-directed behavior while emotionally distressed in the association between exposure to maternal threatening behaviors and internalizing symptoms among trauma-exposed inpatient psychiatric youth. Participants (N = 50; mean [SD] age, 15.1 [0.51] years; age range, 12–17 years) completed measures of emotion dysregulation, exposure to maternal threatening behaviors, depression, anxiety, and posttraumatic stress disorder symptoms, as well as trauma-related functional impairment. Results revealed that inability to engage in goal-directed behavior while distressed significantly explained associations between exposure to maternal threatening behaviors and each of the three symptom classes, but not the association between exposure to maternal threatening behaviors and trauma-related functional impairment. These novel findings underscore the need for interventions that target the capacity for goal-directed behavior in the context of emotional distress, especially among trauma-exposed youth who have experienced parental threatening behaviors.
Molecular Pathology of Colorectal Cancer
Authors: Harada Shuko , Morlote Diana
Published: September 2019

Colorectal cancer (CRC) is the third most commonly diagnosed cancer. This review gives an overview of the current knowledge of molecular mechanisms of colorectal carcinogenesis and the role of molecular testing in the management of CRC. The majority of CRCs arise from precursor lesions such as adenoma, transforming to adenocarcinoma. Three molecular carcinogenesis pathways have been identified; (1) chromosomal instability, (2) microsatellite instability (MSI), and (3) CpG island methylator phenotype, each account for ~85%, 15%, and 17%, respectively. Evaluation of MSI status, extended RAS mutation analysis, and BRAF mutation analysis are recommended by the guideline published by joint effort from professional societies. MSI testing is important for identification of Lynch syndrome patients and prognostic and predictive markers. Extended RAS testing is an important predictive marker for antiepidermal growth factor receptor therapy. BRAF p.V600 mutation status can be used as prognostic marker, but not predictive marker for antiepidermal growth factor receptor therapies. Emerging technologies utilizing high throughput sequencing have introduced novel biomarkers and testing strategies. Tumor mutation burden predicts immunotherapy response in addition to MSI status. Liquid biopsy can be utilized when adequate tissue sample is not available or for monitoring therapy response. However, assay standardization and guidelines and recommendations for utilization of these assay will be needed. The advancement in CRC research and technologies will allow better prognostication and therapy stratification for the management of patients with CRCs.
Custom-Made Eyeglass-Holding Hook on a Snapback Cap to Prevent Nose-Pads From Directly Resting Upon the Nose
Authors: Hwang Kun , Kim Dae Joong
Published: September 2019

The authors innovated a simple device that hooks the bridge of eyeglasses to a snapback cap (EHS) so that the nose-pads of glasses do not rest upon the nose.

A snapback cap with 2 eyelets on the front panel is prepared. A fishing line or IV tubing is introduced through 2 eyelets and a loop is made inside of the cap. A paper clip is bent to make a J-shaped hook that holds the bridge of the glasses. A loop of line is connected through the J-hook and the length is adjusted to prevent the nose-pads of glasses from directly resting on the nose.

The eyeglass-holding hook on a snapback cap pulls the eyeglasses, and the direction of the vector can be adjusted through the eyelets on the front panel and the strap on the back.

Our EHS is simple and cheap. It is considered that patients themselves can produce this device.
Orbital Emphysema After Repair of Orbital Fracture
Authors: Wang Hang , An Jingang
Published: September 2019

Orbital emphysema is a rare postoperative complication that can cause diplopia and even visual loss. Therefore, immediate diagnosis and treatment are crucial. In this study, a healthy male patient sustained left facial trauma caused by a fall 2 months ago; orbit emphysema occurred when the patient sneezed on the 5th day after surgery. The patient was treated conservatively with oral antibiotics and oral dexamethasone. Sixth-month follow-up showed no residual lesion.
Orbital Observation Chart: Significant in Orbital Fractures or Not?
Authors: Ghosh Rajarshi , Joshi Abhijit , Anehosur Venkatesh
Published: September 2019

Purpose:

The study was conducted to assess the efficacy of orbital chart in detecting postoperative complications of orbital fractures.

Materials and Methods:

A retrospective study was conducted in the Department of OMFS, SDM College of Dental Sciences, Dharwad from January 2011 to December 2016. It included all the patients with orbital fractures who underwent surgical intervention for reduction of the fracture in the study. We recorded data for the type of fracture, type of intervention, and orbital and ocular changes. Orbital changes measured and charted for 5 parameters which were: pain, proptosis, visual acuity, size of the pupil, and pupillary reaction to direct light reflex.

Results:

Two hundred thirty-six patients with orbital fractures underwent surgical intervention during these 5 years. The prevailing type of fracture for which they required orbital intervention remains zygomatic complex fractures (69%). The treatment protocol depended on the pattern and displacement of fracture and age of the patient. Pain was the most common symptom among these parameters (15.7%).

Conclusion:

Orbital chart monitoring represents a straightforward and effective method to detect any complications after surgical management of orbital fractures.
Treatment of Traumatic Depressed Compound Skull Fractures
Authors: Shao Xuefei , Wang Qifu , Shen Jun , Liu Jiaqiang , Chen Sansong , Jiang Xiaochun
Published: September 2019

Background:

A skull fracture widely occurs in patients with traumatic brain injury, leading to intracranial hematoma, brain contusion, and intracranial infection. It also influences the prognosis and death of patients. This study aimed to discuss cases of patients with comminuted skull fractures.

Methods:

From October 2015 to December 2018, 38 patients with comminuted skull fractures were admitted to the hospital. All patients underwent three-dimensional reconstruction of computed tomography scan images. Digital subtraction angiography or magnetic resonance venography was performed to find out the venous sinus. The clinical findings of the patients were significant regarding gender, age, injury mechanism, location, admission Glasgow Coma Scale (GCS), combined epidural, subdural, cerebral contusion, intracranial pneumatosis, maximum depth of depression, admission to surgery, dural tear, post-operative cerebrospinal fluid leakage, post-operative infection, and Glasgow Outcome Scale (GOS) 3 months after surgery.

Results:

The incidence of traffic accidents, fall from a height, railway accidents, fall of an object, and chop injury was 60.5%, 18.4%, 13.2%, 5.3%, and 2.6%, respectively. Intra-operative dural trar negatively correlated with epidural hematoma, cerebral contusion, and subdural hematoma. Also, post-operative infection negatively correlated with intracranial pneumatosis, depth of fracture depression, and pre-operative cerebrospinal fluid leakage. No correlation was found between contusion, subdural hematoma, intracranial pneumatosis, depth of fracture depression, and post-operative infection. The GOS score positively correlated with age, pre-operative cerebrospinal fluid leakage, and admission GCS score.

Conclusions:

A perfect pre-operative examination is a key to successful surgery. Further studies should be conducted to find out more effective treatments for traumatic comminuted skull fractures.
White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans
Authors: Sbierski-Kind Julia , Mai Knut , Kath Jonas , Jurisch Anke , Streitz Mathias , Kuchenbecker Leon , Jürchott Karsten , Spranger Leonard , von Schwartzenberg Reiner Jumpertz , Decker Anne-Marie , Krüger Ulrike , Volk Hans-Dieter , Spranger Joachim
Published: September 2019

Obesity is a growing global health problem due to its association with chronic low-grade inflammation contributing to metabolic complications. Multiple studies indicate that white adipose tissue (WAT) inflammation can promote type 2 diabetes. However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal obese women who either underwent CR for three months followed by a 4 weeks phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and subcutaneous WAT (SAT) (n=21). The T cell receptor repertoire was analyzed by next generation sequencing (n=20) and cytokine levels were determined in SAT (n=22). Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp and then correlated to immune cell subsets. We found that insulin resistance (IR) correlates significantly with a shift towards the memory T cell compartment in SAT. Among various T cell subsets, predominantly CD8+ effector memory T cells were associated with obesity-related IR. Interestingly, T cell receptor analysis revealed a diverse repertoire in SAT arguing against an antigen-driven intra-SAT expansion of effector memory T cells. Surprisingly, neither inflammatory cytokine levels nor leucocyte subpopulations were significantly altered upon CR. Our findings demonstrate the accumulation of effector memory T cells in obese SAT contributing to chronic inflammation. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR induced weight loss.
Bathymetric and geographical trends in growth of golden redfish (Sebastes norvegicus)
Authors: Monferrer Natalia Llopis , Planque Benjamin
Published: September 2019

Golden redfish (Sebastes norvegicus) are a long-living (>50 years), late maturing (>10 years) species of commercial interest, distributed along the coast, shelves and continental slope of Norway, down to approximately 400 m depth in the water column. In recent years, analyses of size-at-age data have revealed variable growth trajectories for this species. Whilst some individuals appear to grow slowly after sexual maturity (37cm at ~ 15 years), others continue to grow throughout their lifetime up to 100 cm or more. To investigate how depth and latitude affect golden redfish growth patterns, we developed non-linear mixed effects statistical models. Alongside this, small scale experiments were also conducted to assess the quality of age-determination. The results showed that individuals found in deeper, northern waters present a higher growth potential, even when uncertainty in age determination and species identification were considered. The proximal causes for variations in the growth potential of S. norvegicus are still unresolved and the existence of a possible cryptic species remains a fundamental issue that will need to be addressed, in order to understand the causes behind observed growth variations.
Inhibition of IL-1β secretion and mitochondria respiration by arsenite which acts on myocardial ischemia-reperfusion injury
Authors: Li Min , Mei Yingwu , Liu Jingeng , Fan Kaikai , Gu Xinyue , Xu Jitian , Li Yuebai , Mi Yang
Published: September 2019

Arsenite (NaAsO2) is a potent toxin that significantly contributes to human pathogenesis. Chronic exposure to arsenite results in various diseases. The physiologically important biological target(s) of arsenite exposure is largely unknown. Here we found that transient sodium arsenite treatment (1) blocks nigericin or Rotenone induced IL-1β secretion; (2) inhibits mitochondrial respiration with complex I–linked substrate; (3) induces Heme oxygenase-1 (HO-1) in myocardial tissue. (4) attenuates the myocardial ischemia-reperfusion injury in an in vivo model of rats. The causal relationship among these activities needs further investigation.
Using nano zero valent iron supported on diatomite to remove acid blue dye: synthesis, characterization and toxicology test
Authors: Justo-Cabrera Erick , Flores-Rojas Ernesto , Schnabel Denhi , Poggi-Varaldo Héctor , Solorza-Feria Omar , Breton-Deval Luz
Published: September 2019

The aim of this work was to synthesize and characterize nanoscale zero-valent iron (NZVI) supported on diatomaceous earth (DE) at two different molar concentration 3 M and 4M (nZVI-DE-1 nZVI-DE-2), to test the decolorization treatment of acid blue dye (AB) and perform a toxicological test using zebrafish. The synthesis of the nanoparticles was obtained using the chemical reduction method and the material was characterized by X-ray diffraction, Scanning Electron Microscopy (SEM), Energy-Dispersive X-Ray (EDX), and transmission electron microscopy and Specific Surface Area (BET). The results showed spherical forms in clusters between 20 to 40 nm of zero valent iron supported on diatomaceous earth. The removal of 1 g/l of AB from water treated with NZVI-DE-1 and NZVI-DE-2 reached the decolorization of 90% and 98% of all dye. While controls like NZVI and DE-1 and DE-2 achieved the removal of 40, 37 and 24 % of the dye. Toxicological analysis using zebrafish showed that AB causes a severe defect in development and embryos die after exposure. However, the water samples treated with NZVI-DE-1 and NZVI-DE-2 are not harmful for the zebrafish embryos during the first 24 hours. We conclude that the use of NZVI-DE-1 and NZVI-DE-2 is a promising treatment for dye pollution.
A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding
Authors: Akbar Rahmad , Robert Philippe A. , Pavlović Milena , Jeliazkov Jeliazko R. , Snapkov Igor , Slabodkin Andrei , Weber Cédric R. , Scheffer Lonneke , Miho Enkelejda , Haff Ingrid Hobæk , Haug Dag Trygve Tryslew , Lund-Johansen Fridtjof , Safonova Yana , Sandve Geir K. , Greiff Victor
Published: September 2019

Antibody-antigen binding relies on the specific interaction of amino acids at the paratope-epitope interface. The predictability of antibody-antigen binding is a prerequisite for de novo antibody and (neo-)epitope design. A fundamental premise for the predictability of antibody-antigen binding is the existence of paratope-epitope interaction motifs that are universally shared among antibody-antigen structures. In the largest set of non-redundant antibody-antigen structures, we identified structural interaction motifs, which together compose a commonly shared structure-based vocabulary of paratope-epitope interactions. We show that this vocabulary enables the machine learnability of antibody-antigen binding on the paratope-epitope level using generative machine learning. The vocabulary (i) is compact, less than 104motifs, (ii) distinct from non-immune protein-protein interactions, and (iii) mediates specific oligo- and polyreactive interactions between paratope-epitope pairs. Our work successfully leveraged combined structure- and sequence-based learning showing that machine-learning-driven predictive paratope and epitope engineering is feasible.
A computational observer model of spatial contrast sensitivity: Effects of photocurrent encoding, fixational eye movements and inference engine
Authors: Cottaris Nicolas P. , Wandell Brian A. , Rieke Fred , Brainard David H.
Published: September 2019

We have recently shown that using the information carried by the mosaic of cone excitations of a stationary retina, the relative spatial contrast sensitivity function (CSF) of a computational observer has the same shape as a typical human subject. Absolute human sensitivity, however, is lower than the computational observer by a factor of 5 to 10. Here we model how additional known features of early vision affect spatial contrast sensitivity: fixational eye movements and the conversion of cone photopigment excitations to cone photocurrent responses. For a computational observer that uses a linear classifier applied to the responses of a stimulus-matched linear filter, fixational eye movements substantially change the shape of the spatial CSF, primarily by reducing sensitivity at spatial frequencies above 10 c/deg. For a computational observer that uses a translation-invariant calculation, in which decisions are based on the squared response of a quadrature-pair of linear filters, the CSF shape is little changed by eye movements, but there is a two-fold reduction in sensitivity. The noise and response dynamics of conversion of cone excitations into photocurrent introduce an additional two-fold sensitivity decrease. Hence, the combined effects of fixational eye movements and phototransduction bring the absolute sensitivity of the translation-invariant computational observer CSF to within a factor of 1 to 2 of the human CSF. We note that the human CSF depends on processing of the initial representation by many thalamic and cortical neurons, which are individually quite noisy. Our computational modeling suggests that the net effect of this noise on contrast-detection performance, when considered at the neural population level and behavioral level, is quite small: the inference mechanisms that determine the CSF, presumably in cortex, make efficient use of the information available from the cone photocurrents of the fixating eye.
A Novel and Direct Metamobilome Approach improves the Detection of Larger-sized Circular Elements across Kingdoms
Authors: Alanin Katrine Skov , Jørgensen Tue Sparholt , Browne Patrick , Petersen Bent , Riber Leise , Kot Witold , Hansen Lars Hestbjerg
Published: September 2019

Mobile genetic elements (MGEs) are instrumental in natural prokaryotic genome editing, permitting genome plasticity and allowing microbes to accumulate immense genetic diversity. MGEs include DNA elements such as plasmids, transposons and Insertion Sequences (IS-elements), as well as bacteriophages (phages), and they serve as a vast communal gene pool. These mobile DNA elements represent a human health risk as they can add new traits, such as antibiotic resistance or virulence, to a bacterial strain. Sequencing libraries targeting circular MGEs, referred to as mobilomes, allows the expansion of our current understanding of the mechanisms behind the mobility, prevalence and content of these elements. However, metamobilomes from bacterial communities are not studied to the same extent as metagenomics, partly because of methodological biases arising from multiple displacement amplification (MDA), often used in previous metamobilome publications. In this study, we show that MDA is detrimental to the detection of larger-sized plasmids if small plasmids are present by comparing the abundances of reads mapping to plasmids in a wastewater sample spiked with a mock community of selected plasmids with and without MDA. Furthermore, we show that it is possible to produce samples consisting almost exclusively of circular MGEs and obtain a catalog of larger, complete, circular MGEs from complex samples without the use of MDA.

Importance

Mobile genetic elements (MGEs) can transport genetic information between genomes in different bacterial species, adding new traits, potentially generating dangerous multidrug-resistant pathogens. In fact, plasmids and circular MGEs can encode bacterial genetic specializations such as virulence, resistance to metals, antimicrobial compounds, and bacteriophages, as well as the degradation of xenobiotics. For this reason, circular MGEs are crucial to investigate, but they are often missed in metagenomics and ecological studies. In this study, we present, for the first time, an improved method, which reduces the bias towards small MGEs and we demonstrate that this method can unveil larger, complete circular MGEs from complex samples without the use of multiple displacement amplification. This method may result in the detection of larger-sized plasmids that have hitherto remained unnoticed and therefore has the potential to reveal novel accessory genes, acting as possible targets in the development of preventive strategies directed at pathogens.
Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens
Authors: Hunt Allison L. , Bateman Nicholas W. , Barakat Waleed , Makohon-Moore Sasha , Hood Brian L. , Conrads Kelly A. , Zhou Ming , Calvert Valerie , Pierobon Mariaelena , Loffredo Jeremy , Litzi Tracy J. , Oliver Julie , Mitchell Dave , Gist Glenn , Rojas Christine , Blanton Brian , Robinson Emma L. , Odunsi Kunle , Sood Anil K. , Casablanca Yovanni , Darcy Kathleen M. , Shriver Craig D. , Petricoin Emanuel F. , Rao Uma N. M. , Maxwell G. Larry , Conrads Thomas P.
Published: September 2019

Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten primary high-grade serous ovarian tumors and analyzed using proteomics (mass spectrometry and reverse phase protein microarray) and RNA-sequencing analyses. Comparative analyses of transcript and protein abundances revealed independent clustering of enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering between purified collections, driven by overall tumor purity. Comparison of historic prognostic molecular subtypes for HGSOC revealed protein and transcript expression from tumor epithelium correlated most strongly with the differentiated molecular subtype, whereas stromal proteins and transcripts most strongly correlated with mesenchymal subtype. Protein and transcript abundance in tumor epithelium and stromal collections from neighboring sections exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial protein and transcript expression heterogeneity within the tumor microenvironment that directly bears on prognostic signatures and underscore the need to enrich cellular subpopulations for expression profiling.
Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)
Authors: Giusti-Rodríguez Paola , Xenakis James G. , Crowley James J. , Nonneman Randal J. , DeCristo Daniela M. , Ryan Allison , Quackenbush Corey R. , Miller Darla R. , Shaw Ginger D. , Zhabotynsky Vasyl , Sullivan Patrick F. , de Villena Fernando Pardo-Manuel , Zou Fei
Published: September 2019

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.
Complex genetic admixture histories reconstructed with Approximate Bayesian Computations
Authors: Fortes-Lima Cesar A. , Laurent Romain , Thouzeau Valentin , Toupance Bruno , Verdu Paul
Published: September 2019

Admixture is a fundamental evolutionary process that has influenced genetic patterns in numerous species. Maximum-likelihood approaches based on allele frequencies and linkage-disequilibrium have been extensively used to infer admixture processes from dense genome-wide datasets mostly in human populations. Nevertheless, complex admixture histories, beyond one or two pulses of admixture, remain methodologically challenging to reconstruct, especially when large datasets are unavailable. We develop an Approximate Bayesian Computations (ABC) framework to reconstruct complex admixture histories from independent genetic markers. We built the software packageMetHisto simulate independent SNPs in a two-way admixed population for scenarios with multiple admixture pulses, or monotonically decreasing or increasing admixture at each generation; drawing model-parameter values from prior distributions set by the user. For each simulated dataset, we calculate 24 summary statistics describing genetic diversity and moments of individual admixture fraction. We coupledMetHiswith existing ABC algorithms and investigate the admixture history of an African American and a Barbadian population. Results show that Random-Forest ABC scenario-choice, followed by Neural-Network ABC posterior parameter estimation, can distinguish most complex admixture scenarios and provide accurate model-parameter estimations. For both admixed populations, we find that monotonically decreasing contributions over time, from the European and African sources, explain the observed data more accurately than multiple admixture pulses. Furthermore, we find contrasted trajectories of introgression decay from the European and African sources between the two admixed populations. This approach will allow for reconstructing detailed admixture histories in numerous populations and species, particularly when maximum-likelihood methods are intractable.
Complement component 4 genes contribute sex-specific vulnerability in diverse illnesses
Authors: Kamitaki Nolan , Sekar Aswin , Handsaker Robert E. , de Rivera Heather , Tooley Katherine , Morris David L. , Taylor Kimberly E. , Whelan Christopher W. , Tombleson Philip , Olde Loohuis Loes M. ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, Boehnke Michael , Kimberly Robert P. , Kaufman Kenneth M. , Harley John B. , Langefeld Carl D. , Seidman Christine E. , Pato Michele T. , Pato Carlos N. , Ophoff Roel A. , Graham Robert R. , Criswell Lindsey A. , Vyse Timothy J. , McCarroll Steven A.
Published: September 2019

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men1,2, whereas schizophrenia affects men more frequently and severely3–5. All three illnesses have their strongest common-genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise fromHLAalleles6–13. Here we show that the complement component 4 (C4) genes in the MHC locus, recently found to increase risk for schizophrenia14, generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61;p< 10−117in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59-30.89;p< 10−23in total), withC4Aprotecting more strongly thanC4Bin both illnesses. The same alleles that increase risk for schizophrenia, greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses,C4alleles acted more strongly in men than in women: common combinations ofC4AandC4Bgenerated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjögren’s syndrome in men (vs. 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid (p< 10−5for both C4 and C3) and plasma among adults ages 20-5015–17, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects ofC4alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
Identification of key determinants ofStaphylococcus aureusvaginal colonization
Authors: Deng Liwen , Schilcher Katrin , Burcham Lindsey R. , Kwiecinski Jakub M. , Johsnon Paige M. , Head Steven R. , Heinrichs David E. , Horswill Alexander R. , Doran Kelly S.
Published: September 2019

Staphylococcus aureusis an important pathogen responsible for nosocomial and community acquired infections in humans, and methicillin-resistantS. aureus(MRSA) infections have continued to increase despite wide-spread preventative measures.S. aureuscan colonize the female vaginal tract and reports have suggested an increase in MRSA infections in pregnant and postpartum women as well as outbreaks in newborn nurseries. Currently, little is known about specific factors that promote MRSA vaginal colonization and subsequent infection. To studyS. aureuscolonization of the female reproductive tract in a mammalian system, we developed a mouse model ofS. aureusvaginal carriage and demonstrated that both hospital-associated and community-associated MRSA isolates can colonize the murine vaginal tract. Immunohistochemical analysis revealed an increase in neutrophils in the vaginal lumen during MRSA colonization. Additionally, we observed that a mutant lacking fibrinogen binding adhesins exhibited decreased persistence within the mouse vagina. To further identify novel factors that promote vaginal colonization, we performed RNA-sequencing to determine the transcriptome of MRSA growingin vivoduring vaginal carriage at 5 hours, 1-day, and 3-days post-inoculation. Over 25% of bacterial genes were differentially regulated at all time points during colonization compared to laboratory cultures. The most highly induced genes were those involved in iron acquisition, including the Isd system and siderophore transport systems. Mutants deficient in these pathways did not persist as well duringin vivocolonization. These results reveal that fibrinogen binding as well as the capacity to overcome host nutritional limitation are important determinants of MRSA vaginal colonization.

IMPORTANCE

Staphylococcus aureusis an opportunistic pathogen able to cause a wide variety of infections in humans. Recent reports have suggested an increasing prevalence of MRSA in pregnant and postpartum women, coinciding with the increased incidence of MRSA infections in the NICU and newborn nurseries. Vertical transmission from mothers to infants at delivery is a likely route of MRSA acquisition by the newborn, however, essentially nothing is known about host and bacterial factors that influence MRSA carriage in the vagina. Here, we established a mouse model of vaginal colonization and observed that multiple MRSA strains can persist in the vaginal tract. Additionally, we determined that MRSA interactions with fibrinogen as well as iron uptake can promote vaginal persistence. This study is the first to identify molecular mechanisms which govern vaginal colonization by MRSA, the critical initial step preceding infection and neonatal transmission.
Neuro-transcriptomic signatures for mood disorder morbidity and suicide mortality
Authors: Jabbi Mbemba , Arasappan Dhivya , Eickhoff Simon B. , Strakowski Stephen M. , Nemeroff Charles B. , Hofmann Hans A.
Published: September 2019

Suicidal behaviors are strongly linked with mood disorders, but the specific neurobiological and functional gene-expression correlates for this linkage remain elusive. We performed neuroimaging-guided RNA-sequencing in two studies to test the hypothesis that imaging-localized gray matter volume (GMV) loss in mood disorders, harbors gene-expression changes associated with disease morbidity and related suicide mortality in an independent postmortem cohort. To do so, first, we conducted study 1 using an anatomical likelihood estimation (ALE) MRI meta-analysis including a total of 47 voxel-based morphometry (VBM) publications (i.e. 26 control>major depressive disorder (MDD) studies, and 21 control>bipolar disorder (BD) studies) in 2387 (living) participants. Study 1 meta-analysis identified a selective anterior insula cortex (AIC) GMV loss in mood disorders. We then used this results to guide study 2postmortemtissue dissection and RNA-Sequencing of 100 independent donor brain samples with a life-time history of MDD (N=30), BD (N=37) and control (N=33). In study 2, exploratory factor-analysis identified a higher-order factor representing number of Axis-1 diagnoses (e.g. substance use disorders/psychosis/anxiety, etc.), referred to here asmorbidityand suicide-completion referred to asmortality. Comparisons of case-vs-control, and factor-analysis defined higher-order-factor contrast variables revealed that the imaging-identified AIC GMV loss sub-region harbors differential gene-expression changes in high morbidity-&-mortalityversuslow morbidity-&-mortality cohorts in immune, inflammasome, and neurodevelopmental pathways. Weighted gene co-expression network analysis further identified co-activated gene modules for psychiatric morbidity and mortality outcomes. These results provide evidence that AIC anatomical signature for mood disorders are possible correlates for gene-expression abnormalities in mood morbidity and suicide mortality.
Dynamic Price and Breeder’s equations for variable environments
Authors: Coulson Tim , Potter Tomos , Felmy Anja
Published: September 2019

The Breeder’s and Price equations are static models of evolution. Recent work has demonstrated how components of these equations, such as selection differentials and heritabilities, can be calculated for each time-step from dynamic, evolutionarily-explicit, structured population models. These dynamic models consist of functions that describe how environmental factors impact associations of genotypes and phenotypic traits with survival, reproduction, development, and non-genetic inheritance. Because evolutionarily explicit versions of these structured models can include feedbacks and can capture all the routes via which environmental variation can impact evolution, they i) provide a more powerful predictive tool for modelling eco-evolution in natural settings than existing approaches, and ii) reveal how key evolutionary parameters incorporated into static models change with time as evolution, or environmental change, proceeds.
Estimating a novel stochastic model for within-field disease dynamics of banana bunchy top virus via approximate Bayesian computation
Authors: Varghese Abhishek , Drovandi Christopher , Mengersen Kerrie , Mira Antonietta
Published: September 2019

The Banana Bunchy Top Virus (BBTV) is one of the most economically important vector-borne banana diseases throughout the Asia-Pacific Basin and presents a significant challenge to the agricultural sector. Current models of BBTV are largely deterministic, limited by an incomplete understanding of interactions in complex natural systems, and the appropriate identification of parameters. A stochastic network-based Susceptible-Infected model has been created which simulates the spread of BBTV across the subsections of a banana plantation, parameterising nodal recovery, neighbouring and distant infectivity across summer and winter. Findings from posterior results achieved through Markov Chain Monte Carlo approach to approximate Bayesian computation suggest seasonality in all parameters, which are influenced by correlated changes in inspection accuracy, temperatures and aphid activity. This paper demonstrates how the model may be used for monitoring and forecasting of various disease management strategies to support policy-level decision making.

Author summary

The Banana Bunchy Top Virus (BBTV) poses one of the greatest threats to the food security of developing nations and the banana industry throughout the Asia-Pacific Basin. Decision-makers face significant challenges in mitigating BBTV spread in banana plantations due to the vector-borne spread of this disease, which is significantly influenced by a vast array of external environmental factors that are unique to each plantation.

We propose a flexible network-based model that describes the spread of BBTV in a real banana plantation through a random process while accounting for individual plantation characteristics and utilise a principled methodology for estimating model parameters. Our findings quantify the effect of seasonal changes and plantation configuration on BBTV spread and predict for high-risk areas in this plantation. We believe that our model might be used by decision-makers to evaluate the effectiveness of current disease management strategies and explore opportunities for improvements.
Predicting neuropsychiatric symptoms of Parkinson’s disease with measures of striatal dopaminergic deficiency
Authors: Bishnoi Ram , Badir Marina C. , Surya Sandarsh , Youssef Nagy A.
Published: September 2019

The role of nigrostriatal dopaminergic neurons degeneration is well established in the pathophysiology of Parkinson’s disease. However, it is unclear if and how the degeneration of the dopamine pathways affects the manifestation of the neuropsychiatric symptoms (NPS) of Parkinson’s disease (PD). Dopamine transporter (DAT) imaging, a technique to measure the reduction in the dopamine transporters is increasingly used as a tool in the diagnosis of PD. In this study, we examine if the baseline dopamine transporter density in the striatum measured by striatal binding ratio (SBR) is associated with the longitudinal onset and/or progression of NPS in PD as measured by the part 1 of Movement Disorder Society - Unified Parkinson’s Disease Rating Scale, over four years. Data of patients with PD and an abnormal screening present on 123I-ioflupane single-proton emission computed tomography were obtained from Parkinson’s Progression Markers Initiative (PPMI) database. Latent Growth Modeling (LGM), a statistical technique that can model the change over time while considering the variability in rate of change at the individual level was used to examine the progression of NPS over time. The results indicate the SBR did not correlate with the baseline NPS but did correlate with the rate of change of NPS (p<0.001) over the next four years, even after eliminating age related variance which can be a significant confounding factor. In conclusion, this study showed gradual worsening in NPS in patients with Parkinson’s disease which inversely correlates with the density of the dopamine transporters as measured by SBR at baseline.
Repression of Viral Gene Expression and Replication by the Unfolded Protein Response Effector XBP1u
Authors: Hinte Florian , van Anken Eelco , Tirosh Boaz , Brune Wolfram
Published: September 2019

The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (XBP1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced XBP1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.
Single Volume Image Generator and Deep Learning-based ASD Classification
Authors: Ahmed Md Rishad , Zhang Yuan , Inan Omer T. , Liao Hongen
Published: September 2019

Autism spectrum disorder (ASD) is an intricate neuropsychiatric brain disorder characterized by social deficits and repetitive behaviors. Associated ASD biomarkers can be supportive of apprehending the underlying roots of the disease and lead the targeted diagnosis as well as treatment. Although deep learning approaches have been applied in functional magnetic resonance imaging (fMRI) based clinical or behavioral identification of ASD, most erstwhile models are inadequate in their capacity to exploit the data richness. Classification techniques often solely rely on region-based summary and/or functional connectivity analysis of one pipeline or unique site dataset. Besides these, biomedical data modeling to analyze big data related to ASD is still perplexing due to its complexity and heterogeneity. Single volume image consideration has not been previously investigated in classification purposes. By deeming these challenges, in this work, firstly, we design an image generator to generate single volume brain images from the whole-brain image of each subject. Secondly, the single volume images are analyzed by evaluating four deep learning approaches comprising one amended volume base Convolutional Neural Network framework to classify ASD and typical control participants. Thirdly, we propose a novel deep ensemble learning classifier using VGG16 as feature extractor to ensure further classification performance. Then, to evaluate the classifier performance across the inter sites, we apply the proposed method on each site individually and validate our findings by comparing literature reports. We showcase our approaches on large-scale multi-site brain imaging dataset (ABIDE) by considering four preprocessing pipelines, and the outcome demonstrates the state-of-the-art performance compared with the literature findings; hence, which are robust and consistent.