bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for miniscalpel-needle/needle knife in the management of chronic pain related conditions
Authors: Zhang Di , Cheng Ying , Xu Guixing , Yin Zihan , Chen Jiao , Liang Fanrong
Published: July 2019

Objective:

The aim of this systematic review with meta-analysis is to determine the effect of miniscalpel-needle/needle-knife in treatment of chronic pain symptoms.

Methods:

The following electronic databases will be searched by 2 independent reviewers: PubMed, Cochrane Library, EMBASE, Springer, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature Database (CBM). All randomized controlled trials on miniscalpel-needle/need-knife for chronic pain published in electronic databases from inception to August 1, 2019 with language restricted in Chinses and English will be included in the study.

Methodologic quality is assessed by 2 blinded reviewers independently screen and score the articles using the Physiotherapy Evidence Database (PEDro) scale and the Cochrane Collaboration risk of bias tool. A meta-analysis was performed when there is sufficient clinical homogeneity in at least 2 studies. The Grading of Recommendations Assessment, Development and Evaluation approach is used to rate the body of evidence in each meta-analysis. When the quantitive evaluation is not available, a qualitative description of the results of single study is provided.

Results:

A high-quality synthesis of current evidence of miniscapel-needle/needle-knife treating chronic pain will be illustrated using subjective reports and objective measures of performance. The primary outcomes consisted of pain intensity improvement rate clinically meaningful improvements in pain and disability are also noted. Secondary outcomes involve the short form of McGill Pain Questionnaire score (SF-MPQ) and the side effects.

Conclusion:

This protocol will present the evidence of whether miniscalpel-needle/needle-knife is an effective intervention for chronic pain.

PROSPERO registration number:

CRD42019129076
Effects of Conventional Milk Versus Milk Containing Only A2 β‐Casein on Digestion in Chinese Children
Authors: Sheng Xiaoyang , Li Zailing , Ni Jiayi , Yelland Greg
Published: July 2019

Objectives:

In this study, we hypothesized that replacing conventional milk, which contains A1 and A2 β‐casein proteins, with milk that contains only A2 β‐casein in the diet of dairy or milk‐intolerant preschoolers (age 5 to 6 years) would result in reduced gastrointestinal symptoms associated with milk intolerance, and that this would correspond with cognitive improvements.

Methods:

This randomized, double‐blind, crossover study aimed to compare the effects of 5 days’ consumption of conventional milk versus milk containing only A2 β‐casein on gastrointestinal symptoms, as assessed via visual analog scales, average stool frequency and consistency, and serum inflammatory and immune biomarkers in healthy preschoolers with mild‐to‐moderate milk intolerance. The study also aimed to compare changes in the cognitive behavior of preschoolers, based on Subtle Cognitive Impairment Test scores.

Results:

Subjects who consumed milk containing only A2 β‐casein had significantly less severe gastrointestinal symptoms as measured by visual analog scales, reduced stool frequency, and improvements in stool consistency, compared with subjects consuming conventional milk. There were significant increases from baseline in serum interleukin‐4, immunoglobulins G, E, and G1, and beta‐casomorphin‐7 coupled to lower glutathione levels, in subjects consuming conventional milk compared with milk containing only A2 β‐casein. Subtle Cognitive Impairment Test analysis showed significant improvements in test accuracy after consumption of milk containing only A2 β‐casein. There were no severe adverse events related to consumption of either milk product.

Conclusions:

Replacing conventional milk with milk containing only A2 β‐casein reduced gastrointestinal symptoms associated with milk intolerance in Chinese preschool children, with corresponding improvements in aspects of cognitive performance.
Creutzfeldt-Jakob Disease Mimicking Neurosyphilis
Authors: Mittenzwei Rhonda , Dibernardo Louis , Hulette Christine , Harrison William T.
Published: July 2019

Creutzfeldt-Jakob disease (CJD) is a complex and rapidly fatal prion infection of the central nervous system with characteristic clinical and pathological findings. Herein, we present the case of an 80-year-old man with a 2-month history of rapid cognitive decline and ataxic gait. He was found to have a positive rapid plasma reagin and fluorescent treponemal antibody absorption (FTA-ABS) upon clinical testing and was presumed to have neurosyphilis. His neurological status precipitously declined during his hospitalization and he died. A complete autopsy was performed, which revealed diffuse spongiform change throughout the cerebrum. Brain tissue was sent to the National Prion Disease Surveillance Center, where immunostaining for prion protein (3F4) showed granular deposits, confirming the diagnosis of CJD. There have been rare cases reported in which CJD was clinically suspected but neurosyphilis was confirmed at autopsy. To our knowledge, this is the first case to be published in which the clinical findings strongly favored neurosyphilis, but spongiform encephalopathy was identified at autopsy. We review the clinical, radiographic, electrophysiological, laboratory, and histopathological features of both diseases and discuss the overlapping findings and inherent diagnostic difficulties. We also review the recommended protocols for safely handling suspected prion-infected autopsy tissue. A heightened awareness of the features of CJD and other prion diseases is needed among forensic pathologists, neuropathologists, and general autopsy pathologists to understand how to safely handle the tissue to get definite diagnoses for the decedent's family members and clinical care team.
A One Health approach to prevention, treatment, and control of campylobacteriosis
Authors: Schiaffino Francesca , Platts-Mills James , Kosek Margaret N.
Published: July 2019

Purpose of review

To review recent findings regarding the control and treatment of campylobacteriosis.

Recent findings

The application of improved diagnostics has led to an upward shift in the attributable burden of Campylobacter infections, in both the United States and Europe as well as in resource-poor settings. Increased focus has brought a fundamental feature of campylobacteriosis -- the ability to cause relapsing disease back into focus, and expanding data on antimicrobial resistance has lead from a switch in first-line therapy for severe diarrhea from quinolones to azithromycin in most contexts, even as evidence of expanding macrolide resistance emerges.

Campylobacter spp. infection is a common infection worldwide. Antibiotic-resistant Campylobacter spp. has become an emerging threat with the increase in industrial poultry production, as well as the broad use of antibiotics in both animals and humans.
Zika circulation, congenital syndrome, and current guidelines: making sense of it all for the traveller
Authors: Chen Lin H. , Wilson Mary E.
Published: July 2019

Purpose of review

Zika virus (ZIKV) swept through the Americas and led to recognition of its neurotropism. Zika circulation elsewhere in the world, nonvector transmission including maternal–fetal/sexual/transfusion routes, and additional reports on congenital Zika syndrome (CZS) and Guillain–Barré syndrome (GBS) have been published.

Recent findings

In 2018–2019, ZIKV transmission occurred in Cuba, India, and is suspected to appear sporadically in other countries. Maternal–fetal ZIKV transmission appears to occur in about 26% of ZIKV-infected pregnant women. The US ZIKV Pregnancy and Infant Registry identified 6% of live births to have at least one ZIKV-associated birth defect; 9% had at least one neurodevelopmental abnormality; 1% had both. Infectious virus was rarely isolated from semen of ZIKV-infected male patients beyond day 38 after symptom onset. Brazilian blood donations had low ZIKV prevalence in 2015–2016; in the United States, screening donations was cost-effective only in the high mosquito season in Puerto Rico.

ZIKV transmission continues; many countries with competent mosquitoes are at risk. Transmission can occur without detection where surveillance is poor and laboratory capacity limited. Travelers are important sentinels. Variations exist among ZIKV strains and Aedes mosquitoes that influence competence for transmission. Maternal–fetal transmission results in significant rates of abnormality. Identification of infectious virus in semen clarifies sexual transmission risk, with updated recommendations for preconception planning. ZIKV neurotropism requires further research and long-term follow-up.
Laparoscopic Distal Pancreatectomy With Peritoneal Staple-line Reinforcement: A Novel Technique (With Video)
Authors: Bruno Marco A. , Mandojana Facundo , Liaño Jilián , Doniquian Alejandro M. , Alvarez Fernando A.
Published: July 2019

Introduction:

Postoperative pancreatic fistula (PPF) is still the major source of morbidity in distal pancreatectomy (DP). Despite the many surgical techniques and technology devices developed for the closure of the pancreatic stump, the PPF rate remains high, and there is no consensus with regard to the most appropriate stump closure technique. We herein present, for the first time, an innovative approach for staple-line reinforcement in DP using an autologous peritoneal patch.

Materials and Methods:

The results of 2 consecutive patients who underwent laparoscopic DP due to mucinous cystic neoplasms were included in this report. The pancreas was transected with a reinforced stapler using a peritoneal patch obtained from the anterolateral wall of the abdomen, divided into 2 pieces, and sutured around each stapler jaw. The embedded video (Supplemental Digital Content 1, http://links.lww.com/SLE/A209) reports our standardized technique.

Results:

Both patients had a favorable recovery without PPF or any complication and were discharged fully recovered 4 and 5 days after surgery without drains. Currently, both patients are alive and free of disease 1 year and 8 months after the procedure.

Conclusions:

The use of an autologous parietal peritoneal patch for staple-line reinforcement in DP was feasible and safe in experienced hands. Further studies are needed to confirm our findings and elucidate whether this readily available, inexpensive, rapid, and versatile alternative could reduce the PPF rate.
Identifying an Optimal Cutoff of the Montreal Cognitive Assessment to Predict Amyloid-PET Positivity in a Referral Memory Clinic
Authors: Nair Anil K. , Ramaswamy Srinath , Kan Krystal , Nair Shreya
Published: July 2019

Background:

Brain amyloid- positron emission tomography (PET) imaging is highly sensitive for identifying Alzheimer disease. Currently, there is a lack of insight on the association between amyloid-PET status and the widely used Montreal cognitive assessment (MoCA). Studying this relationship may optimize the clinical use of amyloid-PET imaging.

Objectives:

To evaluate the relationship between amyloid-PET status and MoCA scores and to identify a MoCA score cutoff that translates to amyloid-PET positivity.

Methods:

Using retrospective chart review, patients from 2010 to 2017 with amyloid-PET scans (positive or negative) and MoCA test scores were included. We studied the relationship between amyloid-PET status and MoCA scores and the influence of age, sex, education, and race. A MoCA score cutoff for amyloid-PET positivity was estimated.

Results:

Among the 684 clinic patients with dementia, 99 fulfilled inclusion criteria. Amyloid-PET positivity was associated significantly with lower MoCA scores (median=19, U=847, P=0.01). The MoCA score cutoff (25) used for minimal cognitive impairment (MCI) predicted amyloid-PET positivity suboptimally (sensitivity=94.6%, specificity=13.9%). A MoCA score cutoff of 20 patients had optimal sensitivity (64.2%) and specificity (67.4%).

Conclusions:

Amyloid-PET positivity is associated with lower MoCA scores. Clinical utility of amyloid-PET scan is likely to be suboptimal at the MoCA score cutoff for minimal cognitive impairment.
Detection of malaria parasites in dried human blood spots using mid-infrared spectroscopy and logistic regression analysis
Authors: Mwanga Emmanuel P. , Minja Elihaika G. , Mrimi Emmanuel , Jiménez Mario González , Swai Johnson K. , Abbasi Said , Ngowo Halfan S. , Siria Doreen J. , Mapua Salum , Stica Caleb , Maia Marta F. , Olotu Ally , Sikulu-Lord Maggy T. , Baldini Francesco , Ferguson Heather M. , Wynne Klaas , Selvaraj Prashanth , Babayan Simon A. , Okumu Fredros O.
Published: July 2019

Background

Epidemiological surveys of malaria currently rely on microscopy, polymerase chain reaction assays (PCR) or rapid diagnostic test kits for Plasmodium infections (RDTs). This study shows that mid-infrared (MIR) spectroscopy coupled with supervised machine learning could constitute an alternative method for rapid malaria screening, directly from dried human blood spots.

Methods

Filter papers containing dried blood spots (DBS) were obtained from a cross-sectional malaria survey in twelve wards in south-eastern Tanzania in 2018/19. The DBS were scanned using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectrometer to obtain high-resolution MIR spectra in the range, 4000 cm-1 to 500 cm−1. The spectra were cleaned to compensate for atmospheric water vapor and CO2 interference bands and used to train different classification algorithms to distinguish between malaria-positive and malaria-negative DBS papers based on PCR test results as reference. The analysis considered 296 individuals, including 123 PCR-confirmed malaria-positives and 173 negatives. Model training was done using 80% of the dataset, after which the best-fitting model was optimized by bootstrapping of 80/20 train/test stratified splits. The trained models were evaluated by predicting Plasmodium falciparum positivity in the 20% validation set of DBS.

Results

Logistic regression was the best-performing model. Considering PCR as reference, the models attained overall accuracies of 92% for predicting P. falciparum infections (specificity = 91.7%; sensitivity = 92.8%) and 85% for predicting mixed infections of P. falciparum and P. ovale (specificity = 85%, sensitivity = 85%) in the field-collected specimen.

Conclusion

These results demonstrate that mid-infrared spectroscopy coupled with supervised machine learning (MIR-ML) could be used to screen for malaria parasites in dried human blood spots. The approach could have potential for rapid and high-throughput screening of Plasmodium infections in both non-clinical settings (e.g. field surveys) and clinical settings (diagnosis to aid case management). However, full utility will require further advances in classification algorithms, field validation of this technology in other study sites and an in-depth evaluation of the biological basis of the observed test results. Training the models on larger datasets could also improve specificity and sensitivity of the technique. The MIR-ML spectroscopy system is robust, low-cost, and requires minimum maintenance.
Cardiac arrest outcomes after targeted temperature management with an esophageal cooling device
Authors: Anderson Cedar Morrow , Fisher Rick , Berry Donald , Diestelhorst J Brad , Wayne Marvin
Published: July 2019

Objective

To assess the efficacy of an esophageal device to provide TTM (Target Temperature Management) post Cardiac Arrest

Design

A chart review of all patients treated with ETTM, following cardiac arrest. Initial patient temperature, time to target, supplemental methods (water blankets, head wraps, or ice packs), and patient survival were extracted for analysis.

Setting

Community Medical Center Intensive Care Unit

Patients

All patients receiving TTM via an esophageal device post Cardiac Arrest from August 2016 to November 2018

Interventions

TTM both cooling and warming via an esophageal device

Measurements and Results

A total of 54 patients were treated from August 2016 to November 2018; 30 received ETM only, 22 received supplemental cooling, and 2 had treatment discontinued prior to reaching target due to recovery. Target temperatures ranged from 32 to 36 degrees. The median time to target temperature for the entire cohort was 219 minutes (IQR 81-415). For the cohorts without, and with, supplemental cooling modalities, the median time to attain target temperature was 128 minutes (IQR 71-334), and 285 minutes (IQR 204-660), respectively. Survival to ICU discharge was 51.9% for the entire cohort.

Conclusions

ETM attains target temperature at a rate consistent with current guidelines and with similar performance to alternative modalities. This may provide a more cost-effective and approachable core cooling option to community hospitals that only use water blankets or other surface methods.
Comparison of Gene Expression During Early Phases of Limb Regeneration Between Regeneration-permissive Neotenic and Regeneration-deficient Metamorphic Axolotl
Authors: Sibai Mustafa , Altuntaş Ebru , Süzek Barış Ethem , Şahin Betül , Parlayan Cüneyd , Öztürk Gürkan , Baykal Ahmet Tarık , Demircan Turan
Published: July 2019

The axolotl (Ambystoma Mexicanum) salamander, an urodele amphibian, has an exceptional regenerative capacity to fully restore an amputated limb throughout the life-long lasting neoteny. By contrast, when axolotls are experimentally induced to metamorphosis, attenuation of the limb’s regenerative competence is noticeable. Here, we sought to discern the proteomic profiles of the early stages of blastema formation of neotenic and metamorphic axolotls after limb amputation by means of LC-MS/MS technology. We quantified a total of 714 proteins having an adjusted p < 0.01 with FC greater or equal to 2 between two conditions. Principal component analysis revealed a conspicuous clustering between neotenic and metamorphic samples at 7 days post-amputation. Different set of proteins was identified as differentially expressed at all of the time points (1, 4, and 7 days post-amputations against day0) for neotenic and metamorphic stages. Although functional enrichment analyses underline the presence of common pathways between regenerative and nonregenerative stages, cell proliferation and its regulation associated pathways, immune system related pathways and muscle tissue and ECM remodeling and degradation pathways were represented at different rate between both stages. To validate the proteomics results and provide evidence for the putative link between immune system activity and regenerative potential, qRT-PCR for selected genes was performed.
Linking light-dependent life history traits with population dynamics forProchlorococcusand cyanophage
Authors: Demory David , Liu Riyue , Chen Yue , Zhao Fangxin , Coenen Ashley , Zeng Qinglu , Weitz Joshua S.
Published: July 2019

Prochlorococcusgrow in diurnal rhythms driven by diel cycles. Their ecology depends on light, nutrients, and top-down mortality processes including lysis by viruses. Cyanophage, viruses that infect cyanobacteria, are also impacted by light. For example, extracellular viability and intra-cell infection kinetics of some cyanophage vary between light and dark conditions. Nonetheless, it remains unclear if light-dependent viral life history traits scale-up to influence population-level dynamics. Here we examined the impact of diel-forcing on both cellular- and population-scale dynamics in multipleProchlorococcus-phage systems. To do so, we developed a light-driven population model including both cellular growth and viral infection dynamics. We then tested the model against measurements of experimental infection dynamics with diel forcing to examine the extent to which population level changes in both viral and host abundances could be explained by light-dependent life history traits. Model-data integration reveals that light-dependent adsorption can improve fits to population dynamics for some virus-host pairs. However, light-dependent variation alone does not fully explain realized host and virus population dynamics. Instead, we show evidence of a previously unrecognized lysis saturation at relatively high virus to cell ratios. Altogether, our study represents a quantitative approach to integrate mechanistic models to reconcileProchlorococcus-virus dynamics spanning cellular to population scales.
Sub-nucleosomal organization in urine cell-free DNA
Authors: Markus Havell , Zhao Jun , Contente-Cuomo Tania , Raupach Elizabeth , Odenheimer-Bergman Ahuva , Connor Sydney , McDonald Bradon R. , Hutchins Elizabeth , McGilvery Marissa , de la Maza Michelina C. , Van Keuren-Jensen Kendall , Pirrotte Patrick , Goel Ajay , Becerra Carlos , Von Hoff Daniel D. , Celinski Scott A. , Hingorani Pooja , Murtaza Muhammed
Published: July 2019

Cell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented and whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we perform comprehensive characterization of fragmentation patterns in urine cfDNA. We show modal size and genome-wide distribution of urine cfDNA fragments are consistent with transient protection from degradation by stable intermediates of nucleosome disassembly. Genome-wide nucleosome occupancy and fragment sizes in urine cfDNA are informative of cell of origin and renal epithelial cells are amongst the highest contributors in urine. Compared to a nucleosome occupancy map based on control urine samples, we observe a higher fraction of fragments with aberrant ends in cancer patients, distinguishing cancer samples with an area under the curve of 0.89. Our results demonstrate sub-nucleosomal organization in urine cfDNA and are proof-of-principle that genome-wide fragmentation analysis of urine cfDNA can enable cancer diagnostics.
The fate of carbon in a mature forest under carbon dioxide enrichment
Authors: Jiang M. , Medlyn B.E. , Drake J.E. , Duursma R.A. , Anderson I.C. , Barton C.V.M. , Boer M.M. , Carrillo Y. , Castañeda-Gómez L. , Collins L. , Crous K.Y. , De Kauwe M.G. , Emmerson K.M. , Facey S.L. , Gherlenda A.N. , Gimeno T.E. , Hasegawa S. , Johnson S.N. , Macdonald C.A. , Mahmud K. , Moore B.D. , Nazaries L. , Nielsen U.N. , Noh N.J. , Ochoa-Hueso R. , Pathare V.S. , Pendall E. , Pineiro J. , Powell J.R. , Power S.A. , Reich P.B. , Renchon A.A. , Riegler M. , Rymer P. , Salomón R.L. , Singh B.K. , Smith B. , Tjoelker M.G. , Walker J.K.M. , Wujeska-Klause A. , Yang J. , Zaehle S. , Ellsworth D.S.
Published: July 2019

Atmospheric carbon dioxide enrichment (eCO2) can enhance plant carbon uptake and growth1,2,3,4,5, thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2concentration6. While evidence gathered from young aggrading forests has generally indicated a strong CO2fertilization effect on biomass growth3,4,5, it is unclear whether mature forests respond to eCO2in a similar way. In mature trees and forest stands7,8,9,10, photosynthetic uptake has been found to increase under eCO2without any apparent accompanying growth response, leaving an open question about the fate of additional carbon fixed under eCO24, 5, 7,8,9,10,11. Here, using data from the first ecosystem-scale Free-Air CO2Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responds to four years of eCO2exposure. We show that, although the eCO2treatment of ambient +150 ppm (+38%) induced a 12% (+247 gCm-2yr-1) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone contributing ∼50% of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO2, and challenge the efficacy of climate mitigation strategies that rely on CO2fertilization as a driver of increased carbon sinks in standing forests and afforestation projects.
Machine-learning classification suggests that many alphaproteobacterial prophages may instead be gene transfer agents
Authors: Kogay Roman , Neely Taylor B. , Birnbaum Daniel P. , Hankel Camille R. , Shakya Migun , Zhaxybayeva Olga
Published: July 2019

Many of the sequenced bacterial and archaeal genomes encode regions of viral provenance. Yet, not all of these regions encode bona fide viruses. Gene transfer agents (GTAs) are thought to be former viruses that are now maintained in genomes of some bacteria and archaea and are hypothesized to enable exchange of DNA within bacterial populations. In Alphaproteobacteria, genes homologous to the ‘head-tail’ gene cluster that encodes structural components of the Rhodobacter capsulatus GTA (RcGTA) are found in many taxa, even if they are only distantly related to Rhodobacter capsulatus. Yet, in most genomes available in GenBank RcGTA-like genes have annotations of typical viral proteins, and therefore are not easily distinguished from their viral homologs without additional analyses. Here, we report a ‘support vector machine’ classifier that quickly and accurately distinguishes RcGTA-like genes from their viral homologs by capturing the differences in the amino acid composition of the encoded proteins. Our open-source classifier is implemented in Python and can be used to scan homologs of the RcGTA genes in newly sequenced genomes. The classifier can also be trained to identify other types of GTAs, or even to detect other elements of viral ancestry. Using the classifier trained on a manually curated set of homologous viruses and GTAs, we detected RcGTA-like ‘head-tail’ gene clusters in 57.5% of the 1,423 examined alphaproteobacterial genomes. We also demonstrated that more than half of the in silico prophage predictions are instead likely to be GTAs, suggesting that in many alphaproteobacterial genomes the RcGTA-like elements remain unrecognized.

Data deposition

Sequence alignments and phylogenetic trees are available in a FigShare repository at DOI 10.6084/m9.figshare.8796419. The Python source code of the described classifier and additional scripts used in the analyses are available via a GitHub repository at https://github.com/ecg-lab/GTA-Hunter-v1
Iterative Hard Thresholding in GWAS: Generalized Linear Models, Prior Weights, and Double Sparsity
Authors: Chu Benjamin B. , Keys Kevin L. , German Christopher A. , Zhou Hua , Zhou Jin J. , Sobel Eric , Sinsheimer Janet S. , Lange Kenneth
Published: July 2019

1

Background

Consecutive testing of single nucleotide polymorphisms (SNPs) is usually employed to identify genetic variants associated with complex traits. Ideally one should model all covariates in unison, but most existing analysis methods for genome-wide association studies (GWAS) perform only univariate regression.

Results

We extend and efficiently implement iterative hard thresholding (IHT) for multiple regression, treating all SNPs simultaneously. Our extensions accommodate generalized linear models (GLMs), prior information on genetic variants, and grouping of variants. In our simulations, IHT recovers up to 30% more true predictors than SNP-by-SNP association testing, and exhibits a 2 to 3 orders of magnitude decrease in false positive rates compared to lasso regression. We also test IHT on the UK Biobank hypertension phenotypes and the Northern Finland Birth Cohort of 1966 cardiovascular phenotypes. We find that IHT scales to the large datasets of contemporary human genetics and recovers the plausible genetic variants identified by previous studies.

Conclusions

Our real data analysis and simulation studies suggest that IHT can (a) recover highly correlated predictors, (b) avoid over-fitting, (c) deliver better true positive and false positive rates than either marginal testing or lasso regression, (d) recover unbiased regression coefficients, (e) exploit prior information and group-sparsity and (f) be used with biobank sized data sets. Although these advances are studied for GWAS inference, our extensions are pertinent to other regression problems with large numbers of predictors.
Critical Role for the Unique N-Terminus of Chlamydial MreB in Directing Its Membrane Association and Interaction with Elements of the Divisome
Authors: Lee Junghoon , Cox John V. , Ouellette Scot P.
Published: July 2019

Chlamydiaelack the conserved central coordinator protein of cell division FtsZ, a tubulin-like homolog. Current evidence indicatesChlamydiauses the actin-like homolog, MreB, to substitute for the role of FtsZ. Interestingly, we observed MreB as a ring at the septum in dividing cells ofChlamydia. We hypothesize that MreB, to substitute for FtsZ inChlamydia, must possess unique properties compared to canonical MreB orthologs. Sequence differences between chlamydial MreB and orthologs in other bacteria revealed that chlamydial MreB possesses an extended N-terminal region and the conserved amphipathic helix found in other bacterial MreBs. The extended N-terminal region was sufficient to restore the localization of a truncatedE. coliMreB mutant lacking its amphipathic helix to the membrane and was crucial for interactions with cell division components RodZ and FtsK, though the region was not required for homotypic interactions. Importantly, the N-terminal region was sufficient to direct GFP to the membrane when expressed inChlamydia. A mutant N-terminal region with reduced amphipathicity was unable to perform these functions. From these data, the extended N-terminal region of chlamydial MreB is critical for localization and interactions of this protein. Our data provide mechanistic support for chlamydial MreB to serve as a substitute for FtsZ.

Importance

Chlamydia trachomatisis an obligate intracellular pathogen, causing sexual transmitted diseases and trachoma. Studying chlamydial physiology, especially its cell division mechanism, is important for developing novel therapeutic strategies for the treatment of these diseases. Since chlamydial cell division has unique features, including a polarized cell division process independent of FtsZ, a canonical cell division coordinator, studying the subject is helpful for understanding undefined aspects of chlamydial growth. In this study, we characterized MreB, a substitute for FtsZ, as a cell division coordinator. It forms a filamentous ring at the septum, like FtsZ inE. coli. We show that the localization of MreB is dependent upon the amphipathic nature of its extended N-terminus. Furthermore, this region is crucial for its interaction with other proteins involved in cell division. Given these results, chlamydial MreB may function as a scaffold for cell divisome proteins at the septum and regulate cell division in this organism.
Forced isoform switching of Neat1_1 to Neat1_2 leads to the loss of Neat1_1 and the hyperformation of paraspeckles but does not affect the development and growth of mice
Authors: Isobe Momo , Toya Hikaru , Mito Mari , Chiba Tomoki , Asahara Hiroshi , Hirose Tetsuro , Nakagawa Shinichi
Published: July 2019

Neat1 is a long noncoding RNA (lncRNA) that serves as an architectural component of the nuclear bodies known as paraspeckles. Two isoforms of Neat1, the short isoform Neat1_1 and the long isoform Neat1_2, are generated from the same gene locus by alternative 3’ processing. Neat1_1 is the most abundant and the best conserved isoform expressed in various cell types, whereas Neat1_2 is expressed in a small population of particular cell types, including the tip cells of the intestinal epithelium. To investigate the physiological significance of isoform switching, we created mutant mice that solely expressed Neat1_2 by deleting the upstream polyadenylation (poly-A) signal (PAS) required for the production of Neat1_1. We observed the loss of Neat1_1 and strong upregulation of Neat1_2 in various tissues and cells and the subsequent hyperformation of paraspeckles, especially in cells that normally express Neat1_2. However, the mutant mice were born at the expected Mendelian ratios and did not exhibit obvious external and histological abnormalities. These observations suggested that the hyperformation of paraspeckles does not interfere with the development and growth of these animals under normal laboratory conditions.
Species-specific differences in the susceptibility of fungi towards the antifungal protein AFP depend on C3 saturation of glycosylceramides
Authors: Paege Norman , Warnecke Dirk , Zäuner Simone , Hagen Silke , Rodrigues Ana , Baumann Birgit , Thiess Melanie , Jung Sascha , Meyer Vera
Published: July 2019

AFP is an antimicrobial peptide (AMP) produced by the filamentous fungusAspergillus giganteusand a very potent inhibitor of fungal growth without affecting the viability of bacteria, plant or mammalian cells. It targets chitin synthesis and causes plasma membrane permeabilization in many human and plant pathogenic fungi, but its exact mode of action is not known. We have recently proposed adoption of the “damage-response framework of microbial pathogenesis” put forward by Pirofksi and Casadevall in 1999 regarding the analysis of interactions between AMPs and microorganisms, thus, predicting that the cytotoxic capacity of a given AMP is relative and depends not only on the presence/absence of its target(s) in the host and the AMP concentration applied but also on other variables, such as microbial survival strategies. We show here using the examples of three filamentous fungi (Aspergillus niger, Aspergillus fumigatus, Fusarium graminearum) and two yeasts (Saccharomyces cerevisiae, Pichia pastoris) that the important parameters defining the AFP susceptibilities of these fungi are (i) the presence/absence of glycosylceramides, (ii) the presence/absence of Δ3(E)-desaturation of the fatty acid chain therein, and (iii) the (dis)ability of these fungi to respond to AFP inhibitory effects with the fortification of their cell walls via increased chitin and β-(1,3)-glucan synthesis. These observations support the adoption of the damage-response framework to holistically understand the outcome of AFP inhibitory effects.

Importance

Our data suggest a fundamental role of glycosylceramides in the susceptibility of fungi towards AFP. We discovered that only a minor structural difference in these molecules – the saturation level of their fatty acid chain, controlled by a 2-hydroxy fatty N-acyl-Δ3(E)-desaturase – is a key to understanding the inhibitory activity of AFP. As glycosylceramides are important components of fungal plasma membranes, we propose a model which links AFP-mediated inhibition of chitin synthesis in fungi with its potential to disturb plasma membrane integrity.
Separating Measured Genetic and Environmental Effects: Evidence Linking Parental Genotype and Adopted Child Outcomes
Authors: Domingue Benjamin W. , Fletcher Jason
Published: July 2019

There has been widespread adoption of genome wide summary scores (polygenic scores) as tools for studying the importance of genetics and associated lifecourse mechanisms across a range of demographic and socioeconomic outcomes. However, an often unacknowledged issue with these studies is that parental genetics impact both child environments and child genetics, leaving the effects of polygenic scores difficult to interpret. This paper uses multi-generational data containing polygenic scores for parents (n=7,193) and educational outcomes for adopted (n=855) and biological (n=20,939) children, many raised in the same families, which allows us to separate the influence of parental polygenic scores on children outcomes between environmental (adopted children) and environmental and genetic (biological children) effects. Our results complement recent work on “genetic nurture” by showing associations of parental polygenic scores with adopted children’s schooling, providing additional evidence that polygenic scores combine genetic and environmental influences and that research designs are needed to separate these estimated impacts.
Snake deltavirus utilizes envelope proteins of different viruses to generate infectious particles
Authors: Szirovicza Leonora , Hetzel Udo , Kipar Anja , Martinez-Sobrido Luis , Vapalahti Olli , Hepojoki Jussi
Published: July 2019

Hepatitis D virus (HDV) is the only known human satellite virus, and it requires hepatitis B virus (HBV) to form infectious particles. Until 2018 HDV was the sole representative of the genusDeltavirus. The subsequent identification of HDV-like agents in non-human hosts indicated a much longer evolutionary history of deltaviruses than previously hypothesized. Interestingly, none of the HDV-like agents were found in co-infection with an HBV-like agent suggesting that these viruses use different helper virus(es). Here we show, using snake deltavirus (SDeV), that HBV represents only a single example of helper viruses for deltaviruses. We cloned the SDeV genome into a mammalian expression plasmid, and by transfection could initiate SDeV replication in cultured snake and mammalian cells. By superinfecting SDeV infected cells with arenaviruses, or by transfecting different viral surface proteins, we could induce infectious SDeV particle production. Our findings indicate that deltaviruses can likely use a multitude of helper viruses or even viral glycoproteins to form infectious particles. Persistent and recurrent infections would be beneficial for the spread of deltaviruses. It seems plausible that new human and veterinary disease associations with deltavirus infections will be identified in the future.
Mutations in a novel cadherin gene associated with Bt resistance inHelicoverpa zea
Authors: Fritz Megan L. , Nunziata Schyler O. , Guo Rong , Tabashnik Bruce E. , Carrière Yves
Published: July 2019

Transgenic corn and cotton produce crystalline (Cry) proteins derived from the soil bacteriumBacillus thuringiensis(Bt) that are toxic to lepidopteran larvae.Helicoverpa zea,a key pest of corn and cotton in the U.S., has evolved widespread resistance to these proteins produced in Bt corn and cotton. While the genomic targets of Cry selection and the mutations that produce resistant phenotypes are known in other lepidopteran species, little is known about how Cry proteins shape the genome ofH. zea. We scanned the genomes of Cry1Ac-selected and unselectedH. zealines, and identified eleven genes on six scaffolds that showed evidence of selection by Cry1Ac, includingcadherin-86C(cad-86C), a gene from a family that is involved in Cry1A resistance in other lepidopterans. Although this gene was expressed in theH. zealarval midgut, the protein it encodes has only 17 to 22% identity with cadherin proteins from other species previously reported to be involved in Bt resistance. An analysis of midgut-expressed cDNAs showed significant between-line differences in the frequencies of putative nonsynonymous substitutions (both SNPs and indels). Our results indicate thatcad-86Cis a target of Cry1Ac selection inH. zea. Future work should investigate phenotypic effects of these nonsynonymous substitutions and their impact on phenotypic resistance in field populations.
Tree-weighting for multi-study ensemble learners
Authors: Ramchandran Maya , Patil Prasad , Parmigiani Giovanni
Published: July 2019

Multi-study learning uses multiple training studies, separately trains classifiers on individual studies, and then forms ensembles with weights rewarding members with better cross-study prediction ability. This article considers novel weighting approaches for constructing tree-based ensemble learners in this setting. Using Random Forests as a single-study learner, we perform a comparison of either weighting each forest to form the ensemble, or extracting the individual trees trained by each Random Forest and weighting them directly. We consider weighting approaches that reward cross-study replicability within the training set. We find that incorporating multiple layers of ensembling in the training process increases the robustness of the resulting predictor. Furthermore, we explore the mechanisms by which the ensembling weights correspond to the internal structure of trees to shed light on the important features in determining the relationship between the Random Forests algorithm and the true outcome model. Finally, we apply our approach to genomic datasets and show that our method improves upon the basic multi-study learning paradigm.
Increased Mistranslation ProtectsE. colifrom Protein Misfolding Stress due to Activation of a RpoS-dependent Heat Shock Response
Authors: Evans Christopher R. , Fan Yongqiang , Ling Jiqiang
Published: July 2019

The misincorporation of an incorrect amino acid into a polypeptide during protein synthesis is considered a detrimental phenomenon. Mistranslated protein is often misfolded and degraded or non-functional and results in an increased cost to quality control machinery. Despite these costs, errors during protein synthesis are common in bacteria. Here we report that increased rates of mistranslation inEscherichia coliprovide protection from protein misfolding stress by increasing the level of the heat shock sigma factor, RpoH. Surprisingly, this increase in RpoH due to mistranslation is dependent on the presence of the general stress response sigma factor, RpoS. This report provides evidence for a protective function of mistranslation and suggests a novel regulatory role of RpoS on the RpoH-activated heat shock.
Metabolomics profiling reveals new aspects of dolichol biosynthesis inPlasmodium falciparum
Authors: Zimbres Flavia M. , Valenciano Ana Lisa , Merino Emilio F. , Florentin Anat , Holderman Nicole R. , He Guijuan , Gawarecka Katarzyna , Skorupinska-Tudek Karolina , Fernández-Murga Maria L. , Swiezewska Ewa , Wang Xiaofeng , Muralidharan Vasant , Cassera Maria Belen
Published: July 2019

Thecis-polyisoprenoid lipids namely polyprenols, dolichols and their derivatives are linear polymers of several isoprene units. In eukaryotes, polyprenols and dolichols are synthesized as a mixture of four or more homologues of different length with one or two predominant species with sizes varying among organisms. Polyprenols have been hardly detectable in eukaryotic cells under normal conditions with the exception of plants and sporulating yeast. Our metabolomics studies revealed thatcis-polyisoprenoids are more prevalent and diverse in the parasitePlasmodium falciparumthan previously postulated as we uncovered activede novobiosynthesis and substantial levels of accumulation of polyprenols and dolichols of 15 to 19 isoprene units. A distinctive polyprenol and dolichol profile both within the intraerythrocytic asexual cycle and between asexual and gametocyte stages was also observed suggesting thatcis-polyisoprenoid biosynthesis changes throughout parasite’s development. In addition, we confirmed the presence of an activecis-prenyltransferase (PfCPT) and that dolichol biosynthesis occurs via reduction of the polyprenol to dolichol by an active polyprenol reductase (PfPPRD) in the malaria parasite. Isotopic labeling and metabolomic analyses of a conditional mutant of PfCPT or PfPPRD suggest that polyprenols may be able to substitute dolichols in their biological functions when dolichol synthesis is impaired inPlasmodium.
CoGAPS 3: Bayesian non-negative matrix factorization for single-cell analysis with asynchronous updates and sparse data structures
Authors: Sherman Thomas D. , Gao Tiger , Fertig Elana J.
Published: July 2019

Motivation

Bayesian factorization methods, including Coordinated Gene Activity in Pattern Sets (CoGAPS), are emerging as powerful analysis tools for single cell data. However, these methods have greater computational costs than their gradient-based counterparts. These costs are often prohibitive for analysis of large single-cell datasets. Many such methods can be run in parallel which enables this limitation to be overcome by running on more powerful hardware. However, the constraints imposed by the prior distributions in CoGAPS limit the applicability of parallelization methods to enhance computational efficiency for single-cell analysis.

Results

We upgraded CoGAPS in Version 3 to overcome the computational limitations of Bayesian matrix factorization for single cell data analysis. This software includes a new parallelization framework that is designed around the sequential updating steps of the algorithm to enhance computational efficiency. These algorithmic advances were coupled with new software architecture and sparse data structures to reduce the memory overhead for single-cell data. Altogether, these updates to CoGAPS enhance the efficiency of the algorithm so that it can analyze 1000 times more cells, enabling factorization of large single-cell data sets.

Availability

CoGAPS is available as a Bioconductor package and the source code is provided at github.com/FertigLab/CoGAPS. All efficiency updates to enable single-cell analysis available as of version 3.2.

Contact

ejfertig@jhmi.edu
LRRK2 regulates innate immune responses and neuroinflammation during Mycobacterium tuberculosis infection
Authors: Weindel C.G. , Bell S.L. , Huntington T.E. , Vail K.J. , Srinivasan R. , Patrick K.L. , Watson R.O.
Published: July 2019

Despite many connections between mutations in leucine-rich repeat kinase 2 (LRRK2) and susceptibility to mycobacterial infection, we know little about its function outside of the brain, where it is studied in the context of Parkinson’s Disease (PD). Here, we report that LRRK2 controls peripheral macrophages and brain-resident glial cells’ ability to respond to and express inflammatory molecules. LRRK2 KO macrophages express elevated basal levels of type I interferons, resulting from defective purine metabolism, mitochondrial damage, and engagement of mitochondrial DNA with the cGAS DNA sensing pathway. While LRRK2 KO mice can control Mycobacterium tuberculosis (Mtb) infection, they exhibit exacerbated lung inflammation and altered activation of glial cells in PD-relevant regions of the brain. These results directly implicate LRRK2 in peripheral immunity and support the “multiple-hit hypothesis” of neurodegenerative disease, whereby infection coupled with genetic defects in LRRK2 create an immune milieu that alters activation of glial cells and may trigger PD.