bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue-Specific Enrichment Analysis (TSEA) to decode tissue specificity
Authors: Pei Guangsheng , Dai Yulin , Zhao Zhongming , Jia Peilin
Published: November 2018

Motivation

Diseases and traits are under dynamic tissue-specific regulation. However, heterogeneous tissues are often collected in biomedical studies, which reduce the power in the identification of disease-associated variants and gene expression profiles.

Results

We present TSEA, an R package to conduct Tissue-Specific Enrichment Analysis (TSEA) with two built-in reference panels. Statistical methods are developed and implemented for detecting tissue-specific genes and for enrichment test of different forms of query data. Our applications using multi-trait genome-wide association data and cancer expression data showed that TSEA could effectively identify the most relevant tissues for each query trait or sample, providing insights for future studies.

Availability

https://github.com/bsml320/TSEA

Contact

peilin.jia@uth.tmc.edu or zhongming.zhao@uth.tmc.edu
PhenotypeXpression: sub-classification of disease states using public gene expression data and literature
Authors: Wang Lucy Lu , Lin Huaiying , Bao Xiaojun , Sengupta Subhajit , Busby Ben , Butler Robert R
Published: November 2018

The success of personalized medicine relies on proper disease classification and subtyping. Differential gene expression among disease subtypes can have a significant impact on treatment effect. This complicates the role of clinicians seeking more tailored diagnoses in cases where granular disease subtypes are not well defined. PhenotypeXpression (PhenoX) is a tool for rapid disease subtyping using publicly available gene expression data and literature. PhenoX aggregates and clusters gene expression data to determine potential disease subtypes, and develops a phenotypic profile for each subtype using term co-occurrences in published literature. Although the availability of public gene expression data is limited, we are able to observe clearly defined subtypes for several conditions.
Modeling the relative role of human mobility, land-use and climate factors on dengue outbreak emergence in Sri Lanka
Authors: Zhang Ying , Riera Jefferson , Ostrow Kayla , Siddiqui Sauleh , de Silva Harendra , Sarkar Sahotra , Fernando Lakkumar , Gardner Lauren
Published: November 2018

Background

More than 80,000 dengue cases including 215 deaths were reported nationally in less than seven months between 2016-2017, a fourfold increase in the number of reported cases compared to the average number over 2010-2016. The region of Negombo, located in the Western province, experienced the greatest number of dengue cases in the country and is the focus area of our study, where we aim to capture the spatial-temporal dynamics of dengue transmission.

Methods

We present a statistical modeling framework to evaluate the spatial-temporal dynamics of the 2016-2017 dengue outbreak in the Negombo region of Sri Lanka as a function of human mobility, land-use, and climate patterns. The analysis was conducted at a 1 km × 1 km spatial resolution and a weekly temporal resolution.

Results

Our results indicate human mobility to be a stronger indicator for local outbreak clusters than land-use or climate variables. The minimum daily temperature was identified as the most influential climate variable on dengue cases in the region; while among the set of land-use patterns considered, urban areas were found to be most prone to dengue outbreak, followed by areas with stagnant water and then coastal areas. The results are shown to be robust across spatial resolutions.

Conclusions

Our study highlights the potential value of using travel data to target vector control within a region. In addition to illustrating the relative relationship between various potential risk factors for dengue outbreaks, the results of our study can be used to inform where and when new cases of dengue are likely to occur within a region, and thus help more effectively and innovatively, plan for disease surveillance and vector control.
Proprioceptive neurons of larvalDrosophila melanogastershow direction selective activity requiring the mechanosensory channel TMC
Authors: He Liping , Gulyanon Sarun , Skanata Mirna Mihovilovic , Karagyozov Doycho , Heckscher Ellie , Krieg Michael , Tsechpenakis Gavriil , Gershow Marc , Tracey W. Daniel
Published: November 2018

DrosophilaTransmembrane channel-like (Tmc) is a protein that functions in larval proprioception. The closely related TMC1 protein is required for mammalian hearing, and is a pore forming subunit of the hair cell mechanotransduction channel. In hair cells, TMC1 is gated by small deflections of microvilli that produce tension on extracellular tip-links that connect adjacent villi. How Tmc might be gated in larval proprioceptors, which are neurons having a morphology that is completely distinct from hair cells, is unknown. Here, we have used high-speed confocal microscopy to both measure displacements of proprioceptive sensory dendrites during larval movement, and to optically measure neural activity of the moving proprioceptors. Unexpectedly, the pattern of dendrite deformation for distinct neurons was unique and differed depending on the direction of locomotion: ddaE neuron dendrites were strongly curved by forward locomotion while the dendrites of ddaD were more strongly deformed by backward locomotion. Furthermore, GCaMP6f calcium signals recorded in the proprioceptive neurons during locomotion indicated tuning to the direction of movement. ddaE showed strong activation during forward locomotion while ddaD showed responses that were strongest during backwards locomotion. Peripheral proprioceptive neurons in animals mutant forTmcshowed a near complete loss of movement related calcium signals. As the strength of the responses of wild type animals was correlated with dendrite curvature, we propose that Tmc channels may be activated by membrane curvature in dendrites that are exposed to strain. Our findings begin to explain how distinct cellular systems rely on a common molecular pathway for mechanosensory responses.
Perceptron learning and classification in a modeled cortical pyramidal cell
Authors: Moldwin Toviah , Segev Idan
Published: November 2018

The perceptron learning algorithm and its multiple-layer extension, the backpropagation algorithm, are the foundations of the present-day machine learning revolution. However, these algorithms utilize a highly simplified mathematical abstraction of a neuron; it is not clear to what extent real biophysical neurons with morphologically-extended nonlinear dendritic trees and conductance-based synapses could realize perceptron-like learning. Here we implemented the perceptron learning algorithm in a realistic biophysical model of a layer 5 cortical pyramidal cell. We tested this biophysical perceptron (BP) on a memorization task, where it needs to correctly binarily classify 100, 1000, or 2000 patterns, and a generalization task, where it should discriminate between two “noisy” patterns. We show that the BP performs these tasks with an accuracy comparable to that of the original perceptron, though the memorization capacity of the apical tuft is somewhat limited. We concluded that cortical pyramidal neurons can act as powerful classification devices.
Profiles of circulating histidine-rich glycoprotein associate with chronological age and risk of all-cause mortality
Authors: Hong Mun-Gwan , Dodig-Crnković Tea , Chen Xu , Drobin Kimi , Lee Woojoo , Wang Yunzhang , Edfors Fredrik , Kotol David , Thomas Cecilia Engel , Sjöberg Ronald , Odeberg Jacob , Hamsten Anders , Silveira Angela , Hall Per , Nilsson Peter , Pawitan Yudi , Hägg Sara , Uhlén Mathias , Pedersen Nancy L. , Magnusson Patrik K. E. , Schwenk Jochen M.
Published: November 2018

1.

Despite recognizing aging as risk factor of human diseases, little is still known about the molecular traits of biological age and mortality risk. To identify age-associated proteins circulating human blood, we screened 156 subjects aged 50-92 years using an exploratory and multiplexed affinity proteomics approach. We corroborated the top age-associated protein profile (adjusted P < 0.001) in eight additional study sets (N = 4,044 individuals), and confirmed a consistent age-associated increase (P = 6.61 × 10-6) by meta-analysis. Applying antibody validation determined circulating histidine-rich glycoprotein (HRG) as the target, and we observed that sequence variants influenced the antibodies ability to bind to the protein. Profiles of circulating HRG were associated to several clinical traits and predicted the risk of mortality during a follow-up period of 8.5 years (IQR = 7.7-9.3 years) after blood sampling (HR = 1.25 per SD; 95% CI = 1.12-1.39; P = 7.41 × 10-5). In conclusion, our affinity proteomics analysis found associations between the molecular traits of circulating HRG with age and all-cause mortality. This suggests that the profiles of multi-purpose protein HRG could serve as an accessible indicator of physiological processes related to aging.
A Double-Blind Pilot Dosing Study of Low Field Magnetic Stimulation (LFMS) for Treatment-Resistant Depression (TRD)
Authors: Dubin Marc J. , Ilieva Irena , Deng Zhi-De , Thomas Jeena , Cochran Ashly , Kravets Kamilla , Brody Benjamin D. , Christos Paul J. , Kocsis James H. , Liston Conor , Gunning Faith M.
Published: November 2018

Low Field Magnetic Stimulation is a potentially rapid-acting treatment for depression with mood-enhancing effects in as little as one 20-minute session. The most convincing data for LFMS has come from treating bipolar depression. We examined whether LFMS also has rapid mood-enhancing effects in treatment-resistant major depressive disorder, and whether these effects are dose-dependent. We hypothesized that a single 20-min session of LFMS would reduce depressive symptom severity and that the magnitude of this change would be greater after three 20-min sessions than after a single 20-min session. In a double-blind randomized controlled trial, 30 participants (age 21–65) with treatment-resistant depression were randomized to three 20-minute active or sham LFMS treatments with 48 hours between treatments. Response was assessed immediately following LFMS treatment using the 6-item Hamilton Depression Rating Scale (HAMD-6), the Positive and Negative Affect Scale (PANAS) and the Visual Analog Scale. Following the third session of LFMS, the effect of LFMS on VAS and HAMD-6 was superior to sham (F(1, 24) = 7.45, p = 0.03, Holm-Bonferroni corrected; F(1,22) = 6.92, p = 0.03, Holm-Bonferroni corrected, respectively). There were no differences between sham and LFMS following the initial or second session with the effect not becoming significant until after the third session. Three 20-minute LFMS sessions were required for active LFMS to have a mood-enhancing effect for individuals with treatment-resistant depression. As this effect may be transient, future work should address dosing schedules of longer treatment course as well as biomarker-based targeting of LFMS to optimize patient selection and treatment outcomes.
Prawn aquaculture as a method for schistosomiasis control and poverty alleviation: a win-win approach to address a critical infectious disease of poverty
Authors: Hoover Christopher M. , Sokolow Susanne H. , Kemp Jonas , Sanchirico James N. , Lund Andrea J. , Jones Isabel , Higginson Tyler , Riveau Gilles , Savaya-Alkalay Amit , Coyle Shawn , Wood Chelsea L. , Micheli Fiorenza , Casagrandi Renato , Mari Lorenzo , Gatto Marino , Rinaldo Andrea , Perez-Saez Javier , Rohr Jason R. , Sagi Amir , Remais Justin V. , Leo Giulio A. De
Published: November 2018

Recent evidence suggests crustacean snail predators may aid schistosomiasis control programs by targeting the environmental component of the parasite’s life cycle through predation of the snail species that serve as intermediate hosts of the parasite. We evaluate costs, benefits, and potential synergies between schistosomiasis control and aquaculture of giant prawns using an integrated bio-economic-epidemiologic model. We identified combinations of stocking density and aquaculture cycle length that maximize profit and offer disease control benefits for sustainable schistosomiasis control. We consider two prawn species in sub-Saharan Africa: the endemic, non-domesticatedMacrobrachium vollenhovenii, and the non-native, domesticatedMacrobrachium rosenbergii. We find that, at profit-optimal densities, bothM. rosenbergiiandM. vollenhoveniican complement conventional control approaches (mass drug treatment of people) and lead to sustainable schistosomiasis control. We conclude that integrated aquaculture strategies can be a win-win strategy in terms of health and sustainable development in schistosomiasis endemic regions of the world.
The DeepTune framework for modeling and characterizing neurons in visual cortex area V4
Authors: Abbasi-Asl Reza , Chen Yuansi , Bloniarz Adam , Oliver Michael , Willmore Ben D.B. , Gallant Jack L. , Yu Bin
Published: November 2018

Deep neural network models have recently been shown to be effective in predicting single neuron responses in primate visual cortex areas V4. Despite their high predictive accuracy, these models are generally difficult to interpret. This limits their applicability in characterizing V4 neuron function. Here, we propose the DeepTune framework as a way to elicit interpretations of deep neural network-based models of single neurons in area V4. V4 is a midtier visual cortical area in the ventral visual pathway. Its functional role is not yet well understood. Using a dataset of recordings of 71 V4 neurons stimulated with thousands of static natural images, we build an ensemble of 18 neural network-based models per neuron that accurately predict its response given a stimulus image. To interpret and visualize these models, we use a stability criterion to form optimal stimuli (DeepTune images) by pooling the 18 models together. These DeepTune images not only confirm previous findings on the presence of diverse shape and texture tuning in area V4, but also provide rich, concrete and naturalistic characterization of receptive fields of individual V4 neurons. The population analysis of DeepTune images for 71 neurons reveals how different types of curvature tuning are distributed in V4. In addition, it also suggests strong suppressive tuning for nearly half of the V4 neurons. Though we focus exclusively on the area V4, the DeepTune framework could be applied more generally to enhance the understanding of other visual cortex areas.
Long-term exposure to PFE-360 in the AAV-α-synuclein rat model: findings and implications
Authors: Andersen Michael Aagaard , Sotty Florence , Jensen Poul Henning , Badolo Lassina , Jeggo Ross , Smith Garrick Paul , Christensen Kenneth Vielsted
Published: November 2018

Significance statement

Treatment of Parkinson’s disease is reliant on symptomatic treatments, without any option to slow or halt disease progression. Mutations in LRRK2 and α-synuclein are known risk factors for Parkinson’s disease. Presence of α-synuclein aggregates at autopsies in both idiopathic and most G2019S cases is suggestive of a common disease pathogenesis. LRRK2 and α-synuclein interaction is hypothesized to play a pivotal role in the pathological mechanisms and inhibitors of LRRK2 are investigated as novel disease modulatory treatments in the clinic. However, preclinical in vivo evidence of a beneficial effect of LRRK2 inhibition is mixed and limited. This study increases our understanding of LRRK2 as a mediator of neuronal dysfunction and the potential of LRRK2 as a promising target in PD.
Suppression and facilitation of motion perception in humans
Authors: Tzvetanov Tzvetomir
Published: November 2018

In a study that investigated the putative neuronal origin of suppression and facilitation in human motion perception Schallmo et al. (2018) used various techniques to investigate how motion perception is shaped by excitatory and inhibitory interactions within hMT+ or earlier areas. They further proposed that neuronal normalization is a sufficient account of the behavioural results, discounting accepted and precise neuronal mechanisms of excitation or inhibition. In this Research Advance, it is shown (1) that once the full computational model that predicts the psychophysical results is defined, it is not “divisive normalization” but actually excitatory and inhibitory processes that are the neuronal mechanisms shaping facilitation and suppression in the behavioural domain, then (2) that the experimental design they used allows a quantitative comparison and usage of such “contrast–size tuning” data.
A mutant bacteriophage evolved to infect resistant bacteria gained a broader host range
Authors: Habusha Michal , Tzipilevich Elhanan , Ben-Yehuda Sigal
Published: November 2018

Bacteriophages (phages) are the most abundant entities in nature, yet little is known about their capacity to acquire new hosts and invade new niches. By exploiting the Gram positive soil bacteriumBacillus subtilis(B. subtilis) and its lytic phage SPO1 as a model, we followed the co-evolution of bacteria and phages. After infection, phage resistant bacteria were readily isolated. These bacteria were defective in production of glycosylated wall teichoic acid (TA) polymers, served as SPO1 receptor. Subsequently, a SPO1 mutant phage that could infect the resistant bacteria evolved. The emerging phage contained mutations in two genes, encoding the baseplate and fibers required for host attachment. Remarkably, the mutant phage gained the capacity to infect non-hostBacillusspecies that are not infected by the wild type phage. We provide evidence that the evolved phage lost its dependency on the species specific glycosylation pattern of TA polymers. Instead, the mutant phage gained the capacity to directly adhere to the TA backbone, conserved among different species, thereby crossing the species barrier.
Shifts in microbial transcription patterns prior to onset of Necrotizing enterocolitis may indicate low oxygen levels in the gut
Authors: Sher Yonatan , Olm Matthew R. , Raveh-Sadka Tali , Brown Christopher , Sher Ruth , Firek Brian , Baker Robyn , Morowitz Michael , Banfield Jillian F.
Published: November 2018

Premature infants are at risk for developing necrotizing enterocolitis (NEC), an inflammatory disease that can progress to necrosis of gut tissue. Previous attempts have failed to identify any consistent predictor of NEC. We hypothesized that prior to the appearance of NEC symptoms, the gut microbiome shifts in its transcriptional profile. To test this hypothesis we integrated genome-resolved metagenomic and metatranscriptomic data from multiple time-points in the first month of life of four preterm infants, two of whom later developed NEC. Gut microbiomes of NEC infants showed increased transcription of high oxygen affinity cytochrome oxidases and lower transcription of genes to detoxify nitric oxide, an antimicrobial compound released by host cells. These results, and high transcription of H2 production genes, suggest low O2 conditions prior to NEC onset, and are consistent with hypoxic conditions in diseased gut tissue. The findings motivate further testing of transcript data as a predictor of NEC.

Highlights

Transcription of high oxygen affinity microbial cytochrome oxidase may predict necrotizing enterocolitis (NEC) development.

Lower transcription of microbial genes to detoxify nitric oxide (NO) may also predict NEC development.

Higher transcription of H2 production genes by Escherichia sp. was found in the gut of premature infants that develop NEC.
Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment
Authors: Galstyan Anna , Chiechi Antonella , Korman Alan J. , Sun Tao , Israel Liron L. , Braubach Oliver , Patil Rameshwar , Shatalova Ekaterina , Ljubimov Vladimir A. , Markman Janet , Grodzinski Zachary , Black Keith L. , Penichet Manuel L. , Holler Eggehard , Ljubimov Alexander V. , Ding Hui , Ljubimova Julia Y.
Published: November 2018

Treatment of brain gliomas with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross the blood-brain barrier (BBB). We describe a new generation of nano immunoconjugates (NICs) developed on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 and/or a-PD-1 for delivery across the BBB and activation of local brain anti-tumor immune response in glioma-bearing mice. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) resulted in an increase of CD8+ T-cells with a decrease of T regulatory cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with combination of NICs was significantly longer compared to animals treated by single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of nanopolymer-conjugated checkpoint inhibitors as an effective treatment of GBM via activation of both systemic and local brain tumor immune response.
Michigan Neural Distinctiveness (MiND) project: Investigating the scope, causes, and consequences of age-related neural dedifferentiation
Authors: Gagnon Holly , Simmonite Molly , Cassady Kaitlin , Chamberlain Jordan D. , Freiburger Erin , Lalwani Poortata , Kelley Shannon , Foerster Bradley , Park Denise C. , Petrou Myria , Seidler Rachael D. , Taylor Stephan F. , Weissman Daniel H. , Polk Thad A.
Published: November 2018

Background

Aging is often associated with behavioral impairments, but some people age more gracefully than others. Why? One factor that may play a role is individual differences in the distinctiveness of neural representations. Previous research has found that neural activation patterns in visual cortex in response to different visual stimuli are often more similar (i.e., less distinctive) in older vs. young participants, a phenomenon referred to as age-related neural dedifferentiation. Furthermore, older people whose neural representations are less distinctive tend to perform worse on a wide range of behavioral tasks. The Michigan Neural Distinctiveness (MiND) project aims to investigate the scope of neural dedifferentiation (e.g., does it also occur in auditory, motor, and somatosensory cortex?), one potential cause (age-related reductions in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)), and the behavioral consequences of neural dedifferentiation. This protocol paper describes the study rationale and methods being used in complete detail, but not the results (data collection is currently underway).

Methods/Design

The MiND project consists of two studies: the main study and a drug study. In the main study, we are recruiting 60 young and 100 older adults to perform behavioral tasks that measure sensory and cognitive function. They also participate in functional MRI (fMRI), MR spectroscopy (MRS), and diffusion weighted imaging (DWI) sessions, providing data on neural distinctiveness and GABA concentrations. In the drug study, we are recruiting 25 young and 25 older adults to compare neural distinctiveness, measured with fMRI, after participants take (1) a benzodiazepine (lorazepam) that should increase GABA activity or (2) a placebo.

Discussion

By collecting multimodal imaging measures (fMRI, MRS, DWI) along with extensive behavioral measures from the same subjects, we are linking individual differences in neurochemistry, neural representation, and behavioral performance, rather than focusing solely on group differences between young and old participants. Our findings have the potential to inform new interventions for age-related declines.
Amino Acids Changes and Muscle Damage During the 400 km Ultra Trail Gobi Race
Authors: Li Meng , Wu Yao , Huang Guangyuan , Chen Song , Li Shengting , Cao Jun , Ma Xiao , Du Yutao
Published: November 2018

Current researches demonstrated that completing the Ultra Trail Gobi (UTG) could lead to severe muscle damage. Our study was designed to analysis the muscle damage and amino acid changes reacted to a 400 km ultra-endurance race in experienced runners. Peripheral blood samples from 16 male athletes (mean age 40.3 ± 7.0 years, mean finish time 121.2 ± 21.8 hours), taken 48 h before and immediately after completing the Ultra Trail Gobi Race (UTG), were analyzed for 39 amino acids, 15 steroid hormones and 4 muscle damage factors. In all participants, the 4 biomarkers for muscle damage, i.e., creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) increased significantly after the race, whose mean post-race values were 13.7-, 7.3-, 4.7- and 1.5-fold higher than the pre-race values, respectively. 5 amino acids, i.e., alanine, valine, proline, ornithine and citrulline showed significant decrease, whose mean values decreased by 40.4 ± 18.7%, 38.9 ± 9.3%, 48.1 ± 15.2%, 44.8 ± 15.1% and 23.4 ± 30.8% after the race, respectively. Our study revealed that progressive decline in amino acids contents may further contribute to the factors increasing the muscle damage during the UTG.
Differential binding cell-SELEX method to identify cell-specific aptamers using high-throughput sequencing
Authors: Pleiko Karlis , Saulite Liga , Parfejevs Vadims , Miculis Karlis , Vjaters Egils , Riekstina Una
Published: November 2018

Aptamers have in recent years emerged as a viable alternative to antibodies. High-throughput sequencing (HTS) has revolutionized aptamer research by increasing the number of reads from a few (using Sanger sequencing) to millions (using an HTS approach). Despite the availability and advantages of HTS compared to Sanger sequencing, there are only 50 aptamer HTS sequencing samples available on public databases. HTS data in aptamer research are primarily used to compare sequence enrichment between subsequent selection cycles. This approach does not take full advantage of HTS because the enrichment of sequences during selection can be due to inefficient negative selection when using live cells. Here, we present a differential binding cell-SELEX (systematic evolution of ligands by exponential enrichment) workflow that adapts theFASTAptamertoolbox and bioinformatics tooledgeR, which are primarily used for functional genomics, to achieve more informative metrics about the selection process. We propose a fast and practical high-throughput aptamer identification method to be used with the cell-SELEX technique to increase the aptamer selection rate against live cells. The feasibility of our approach is demonstrated by performing aptamer selection against a clear cell renal cell carcinoma (ccRCC) RCC-MF cell line using the RC-124 cell line from healthy kidney tissue for negative selection.
Structure, dynamics and roX2-lncRNA binding of tandem double-stranded RNA binding domains dsRBD1,2 of Drosophila helicase Maleless
Authors: Jagtap Pravin Kumar Ankush , Müller Marisa , Masiewicz Pawel , von Bülow Sören , Hollmann Nele Merret , Simon Bernd , Thomae Andreas W. , Becker Peter B. , Hennig Janosch
Published: November 2018

Maleless (MLE) is an evolutionary conserved member of the DExH family of helicases in Drosophila. Besides its function in RNA editing and presumably siRNA processing, MLE is best known for its role in remodelling non-coding roX RNA in the context of X chromosome dosage compensation in male flies. MLE and its human orthologue, DHX9 contain two tandem double-stranded RNA binding domains (dsRBDs) located at the N-terminal region. The two dsRBDs are essential for localization of MLE at the X-territory and it is presumed that this involves binding roX secondary structures. However, for dsRBD1 roX RNA binding has so far not been described. Here, we determined the solution NMR structure of dsRBD1 and dsRBD2 of MLE in tandem and investigated its role in double-stranded RNA (dsRNA) binding. Our NMR data show that both dsRBDs act as independent structural modules in solution and are canonical, non-sequence-specific dsRBDs featuring non-canonical KKxAK RNA binding motifs. NMR titrations combined with filter binding experiments document the contribution of dsRBD1 to dsRNA binding in vitro. Curiously, dsRBD1 mutants in which dsRNA binding in vitro is strongly compromised do not affect roX2 RNA binding and MLE localization in cells. These data suggest alternative functions for dsRBD1 in vivo.
Extensive mitochondrial population structure and haplotype-specific phenotypic variation in theDrosophilaGenetic Reference Panel
Authors: Bevers Roel P.J. , Litovchenko Maria , Kapopoulou Adamandia , Braman Virginie S. , Robinson Matthew R. , Auwerx Johan , Hollis Brian , Deplancke Bart
Published: November 2018

TheDrosophilaGenetic Reference Panel (DGRP) serves as a valuable resource to better understand the genetic landscapes underlying quantitative traits. However, such DGRP studies have so far only focused on nuclear genetic variants. To address this, we sequenced the mitochondrial genomes of >170 DGRP lines, identifying 229 variants including 21 indels and 7 frameshifts. We used our mitochondrial variation data to identify 12 genetically distinct mitochondrial haplotypes, thus revealing important population structure at the mitochondrial level. We further examined whether this population structure was reflected on the nuclear genome by screening for the presence of potential mito-nuclear genetic incompatibilities in the form of significant genotype ratio distortions (GRDs) between mitochondrial and nuclear variants. In total, we detected a remarkable 1,845 mito-nuclear GRDs, with the highest enrichment observed in a 40 kb region around the geneSex-lethal(Sxl). Intriguingly, downstream phenotypic analyses did not uncover major fitness effects associated with these GRDs, suggesting that a large number of mito-nuclear GRDs may reflect population structure at the mitochondrial level rather than actual genomic incompatibilities. This is further supported by the GRD landscape showing particular large genomic regions associated with a single mitochondrial haplotype. Next, we explored the functional relevance of the detected mitochondrial haplotypes through an association analysis on a set of 259 assembled, non-correlating DGRP phenotypes. We found multiple significant associations with stress- and metabolism-related phenotypes, including food intake in males. We validated the latter observation by reciprocal swapping of mitochondrial genomes from high food intake DGRP lines to low food intake ones. In conclusion, our study uncovered important mitochondrial population structure and haplotype-specific metabolic variation in the DGRP, thus demonstrating the significance of incorporating mitochondrial haplotypes in geno-phenotype relationship studies.
Translationally Controlled Tumor ProteinTCTPas Peptide Vaccine againstSchistosoma japonicum: an Immunoinformatics Approach
Authors: Abdalrahman Rayan A , Ahmed Shima S , Elnaeem Mahmoud A , Mohammed Marwa S , Jammie Nawraz M , Yousif Israa A , Mohamed Wala H , Nasr Sabreen Y , Awad-Elkareem Mawadda A , Hassan Mohamed A
Published: November 2018

Schistosoma japonicum is the most pathogenic causative form of schistosomiasis that causes a major health problem in its endemic countries. Until now, praziquantel is the only drug used to treat Schistosomiasis, but it does not prevent re-infection. So, repetition of the treatment is needed. Moreover, there is no effective vaccine against S. japonicum. Therefore, an urgent need for the development of vaccines is mandatory. This study aimed to analyze an immunogenic protein, Transitionally Controlled Tumor Protein (TCTP) using an immunoinformatics approach to design a universal peptide vaccine against Schistosoma japonicum. A set of 22 of TCTP sequences were retrieved from NCBI database. Conservancy of these sequences was tested and then conserved B cell and T cell epitopes were predicted using different tools available in IEBD. Epitopes having high scores in both B and T cell predicting tools were proposed. An epitope129YEHYI133was predicted as a most promising epitope with good prediction scores in surface accessibility and antigenicity. Besides that, epitopes129YEHYIGESM137and92YLKAIKERL100were predicted as the most promising epitopes concerning their binding to MHC I and MHC II allele respectively. The study revealed that our predicted epitopes could be used to develop an efficacious vaccine against Schistosoma japonicum in the future especially epitope YEHYIGESM as it is shared between MHC I and II alleles and overlapped with the most promising B cell epitope. Both in vitro and in vivo studies is recommended to confirm the efficacy of YEHYIGESM as a peptide vaccine.
Spatial epidemiology of gestational age and birth weight in Switzerland: Census-based linkage study
Authors: Skrivankova Veronika , Zwahlen Marcel , Adams Mark , Low Nicola , Kuehni Claudia E , Egger Matthias
Published: November 2018

Background

Gestational age and birth weight are strong predictors of infant morbidity and mortality. Understanding spatial variation can inform policies to reduce health inequalities. We examined small-area variation in gestational age and birth weight in Switzerland.

Methods

All singleton live births recorded in the Swiss Live Birth Register 2011 to 2014 were eligible. We deterministically linked the Live Birth Register with census and survey data to create datasets including neonatal and pregnancy-related variables, parental characteristics and geographical variables. We produced maps of 705 areas and fitted linear mixed-effect models to assess to what extent spatial variation was explained by these variables.

Results

We analysed all 315,177 eligible live births. Area-level averages of gestational age varied between 272-279 days, and between 3138-3467g for birth weight. The fully adjusted models explained 31% and 87% of spatial variation of gestational age and birth weight, respectively. Language region explained most of the variation, with shorter gestational age and lower birth weight in French- and Italian- than in German-speaking areas. Other variables explaining variation were, for gestational age, the level of urbanisation, the parents’ nationality and missing father. For birth weight, they were gestational age, altitude, born out of wedlock, and parental nationality. In a subset of 69,463 live births with data on parental education, levels of education were only weakly associated with gestational age or birth weight.

Conclusions

In Switzerland, small area variation in birth weight is largely explained, and variation in gestational age partially explained by geocultural, socio-demographic and pregnancy factors.

Strengths and limitations of this study

This study was based on a large sample with national coverage, with data on neonatal and pregnancy-related predictors of gestational age and birth weight, and precise spatial data.

No data were available on the mode of delivery, maternal smoking, mothers’ weight and height or gestational diabetes.

The fully adjusted model explained about 80% of the regional variation in birth weight and about 40% of the variation in gestational age.

Language region, a proxy for cultural, social and behavioural factors, was a strong explanatory factor, with lower birth weight and shorter gestation in the French and Italian compared to the German language region.

Unknown father was associated with shorter gestation and lower birth weight, indicating that children not recognised by their fathers may be at higher risk of poor outcomes.
The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2
Authors: Kozlova Nina , Mennerich Daniela , Samoylenko Anatoly , Dimova Elitsa Y. , Koivunen Peppi , Biterova Ekaterina , Richter Kati , Hassinen Antti , Kellokumpu Sakari , Manninen Aki , Miinalainen Ilkka , Glumoff Virpi , Ruddock Lloyd , Drobot Lyudmyla , Kietzmann Thomas
Published: November 2018

The EGFR-adaptor protein CIN85 has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill-defined. Here, we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SH3 domains of CIN85 interact with the proline-arginine rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF-degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9 edited cells affected growth and migration properties as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2, and uncovered an essential survival function in tumor cells linking growth factor adaptors with hypoxia signaling.
Prolonged Antibiotic Treatment Generates a Fluoroquinolone Resistant Gut Microbiome and Collateral Multi-Drug Resistance
Authors: Dubinsky Vadim , Reshef Leah , Bar Nir , Rabinowitz Keren , Godny Lihi , Tulchinsky Hagit , Gophna Uri , Dotan Iris
Published: November 2018

One Sentence Summary

The majority of the gut microbiome develops antibiotic resistance via point-mutations in addition to collateral resistance whereas its density is only moderately decreased following long-term antibiotic treatment.

Antibiotic resistance in bacterial pathogens represents a growing threat to modern medicine. Limitation of lengthy and broad-spectrum antibacterial treatment regimens is generally recommended. Nevertheless, some conditions may require prolonged antibiotic treatment. The effects of such treatments on bacterial communities, specifically their resistome, is yet unknown. Here, we followed a unique cohort of patients with ulcerative colitis who underwent total large bowel resection and the formation of an ileal pouch from their normal small bowel. The majority of these patients tend to develop inflammation of this previously normal small bowel, known as “pouchitis”. Pouchitis is commonly treated with repeated or prolonged courses of broad-spectrum antibiotics. By using metagenomics of faecal samples obtained longitudinally from patients treated with antibiotics for prolonged periods, we hereby show that the majority of their gut commensal bacteria develop antibiotic resistance by point-mutations. In addition, some bacterial species had acquired multidrug resistance loci with genes that confer resistance to the drug used in the treatment (ciprofloxacin) but co-localized with genes encoding extended-spectrum β-lactamases and other resistance-conferring enzymes. We further show that bacterial density in faecal samples is only modestly reduced despite the long-term antibiotic treatment, thereby questioning the current rationale that antibiotic efficacy in treating pouch inflammation is due to the reduction of bacterial load. This study reveals the impact and dynamics of prolonged antibiotic treatment on human gut microbiomes and provides insights that may guide the development of future IBD therapies. It also provides novel insights into bacterial community recovery after cessation of such prolonged treatment, and highlights the increased risk of spreading mobile antibiotic resistance.
Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis
Authors: Zhu Jinsheng , Lau Kelvin , Harmel Robert K. , Puschmann Robert , Broger Larissa , Dutta Amit K. , Jessen Henning J. , Hothorn Ludwig A. , Fiedler Dorothea , Hothorn Michael
Published: November 2018

Many eukaryotic proteins regulating phosphate (Pi) homeostasis contain SPX domains. We have previously shown that these domains act as cellular receptors for inositol pyrophosphate (PP-InsP) signaling molecules, suggesting that PP-InsPs may regulate Pi homeostasis. Here we report that simultaneous deletion of two diphosphoinositol pentakisphosphate kinases VIH1 and 2 in Arabidopsis impairs plant growth and leads to constitutive Pi starvation responses. We demonstrate that VIH1 and VIH2 are bifunctional cytosolic enzymes able to generate and break-down PP-InsPs. Point-mutants targeting the kinase and phosphatase active sites have opposing effects on plant Pi content and Pi starvation responses, while VIH1 and VIH2 protein levels remain constant in different Pi growth conditions. Enzymatic assays reveal that ATP-Mg2+ substrate levels can shift the relative kinase and phosphatase activities of full-length diphosphoinositol pentakisphosphate kinases. Deletion of phosphate starvation response transcription factors rescues vih1 vih2 mutant phenotypes, placing diphosphoinositol pentakisphosphate kinases and PP-InsPs in plant phosphate signal transduction cascades. We propose that VIH1 and VIH2 relay changes in cellular ATP concentration to changes in PPInsP levels, allowing plants to maintain cellular Pi concentrations constant and to trigger Pi starvation responses.
Developing Future Biologists: creating and assessing a portable short course to engage underrepresented undergraduate students in developmental biology
Authors: Pinskey Justine M. , Dulka Eden A. , Ramos Andrea I. , Echevarría-Andino Martha L. , Lorberbaum David S. , Carpenter Brandon S. , Martinez-Marquez Jorge Y. , Budaitis Breane G. , Holloway Emily M. , Raj Samhitha , Chin Alana M. , Suarez Edu , Buttitta Laura A. , Gumucio Deb L. , Wellik Deneen M. , Insolera Ryan , Marty-Santos Leilani , Allen Benjamin L. , Barolo Scott
Published: November 2018

Many barriers discourage underrepresented students from pursuing science careers. To access graduate education, undergraduate students must first gain exposure to a particular subject and subsequently accumulate related coursework and research experience. Many underrepresented students lack exposure to developmental biology due to limited undergraduate course offerings and finite resources at smaller institutions. To address this disparity, a group of University of Michigan graduate students and postdoctoral fellows created a portable short course focusing on developmental biology, titled “Developing Future Biologists” (DFB). This weeklong educational initiative provides hands-on laboratory sessions, interactive lectures, and professional development workshops to teach students about developmental biology and increase awareness of scientific career options. To evaluate course effectiveness, we developed a pre-post assessment, incorporating main ideas from the BioCore Guide. Student understanding of basic concepts and perceived experience in developmental biology increased in DFB participants, despite the abbreviated nature of the course. Here, we provide all course materials and an in-depth analysis of the assessment we created. The DFB portable short course model is an easily adaptable tool that connects undergraduate students with opportunities for advanced study and lowers barriers for underrepresented students in science, technology, engineering, and mathematics.
Aged insulin resistant macrophages reveal dysregulated cholesterol biosynthesis, a pro-inflammatory profile and reduced foam cell formation capacity
Authors: Chabrier G , Hobson S , Yuldasheva N , Kearney M. T , Schurmans S , Pineda-Torra I , Gage M. C
Published: November 2018

Insulin resistance is the central defining feature of type 2 diabetes and an independent risk factor for the development of atherosclerosis. In addition, aging is a major risk factor in the development of insulin resistance and cardiovascular disease. Macrophages play a pivotal roles the the developments of diabetes and atherosclerosis and express insulin receptors. Despite their relevance however, the effect of insulin and insulin resistance on macrophages regarding their inflammatory status, foam cell formation capacity and affect on atherosclerosis are unclear. By taking advantage of a mouse model that recapitulates the effects of chronic PI3K pathway hyperstimulation in macrophages through SHIP2 knock-down, we show that insulin resistance in aged macrophages promotes a proinflammatory phenotype while modulating the cholesterol biosynthesis pathway. These altered characteristics may contribute to the development of chronic inflammatory disease frequently observed with age. Moreover, aged insulin-resistant proinflammatory macrophages display an altered response to acute inflammatory stimulus and reduced foam cell formation capacity. Our work also highlights for the first time, the complex and contrasting immunomodulatory effects of insulin on macrophages in aged mice.

Significance

First study to explore the effects of macrophage insulin resistance in aged cells.

Insulin resistance in aged macrophages results in the reprogramming of the transcriptome with more than 4000 genes being differentially regulated.

Insulin resistance in aged macrophages results in upregulation of IFN signalling pathway, cholesterol biosynthesis pathway and inflammasome gene expression.

Insulin directly regulates macrophage cholesterol biosynthesis, IFN and inflammasome gene expression in a time- and dose-dependent manner.

Insulin resistant aged macrophages exhibit reduced capacity to become foam cells.
Novel Linguistic Evaluation of Prefrontal Synthesis (LEPS) test measures prefrontal synthesis acquisition in neurotypical children and predicts high-functioning versus low-functioning class assignment in individuals with autism
Authors: Vyshedskiy Andrey , Radi Katarina , DuBois Megan Catherine , Mugford Emma , Maslova Victoria , Braverman Julia , Piryatinsky Irene
Published: November 2018

In order to grasp the difference between “the cat on the mat” and “the mat on the cat,” understanding the words and the grammar is not enough. Rather it is essential to visually synthesize the cat and the mat together in front of the mind’s eye to appreciate their relations. This type of voluntary imagination, which involves juxtaposition of mental objects is conducted by the prefrontal cortex and is therefore called Prefrontal Synthesis (PFS). While PFS is essential for understanding of complex language, its acquisition has a strong experience-dependent critical period putting children with language delay in danger of never acquiring PFS and, consequently, not mastering complex language comprehension. In typical children, the timeline of PFS acquisition correlates with vocabulary expansion. Conversely, atypically developing children may learn hundreds of words but never acquire PFS. In these individuals, common tests of intelligence based on vocabulary assessment may miss the profound deficit in PFS. Accordingly, we developed a 5-minute test specific for PFS – Linguistic Evaluation of Prefrontal Synthesis or LEPS – and administered it to 50 neurotypical children, age 2 to 7 years (4.1±1.3) and to 23 individuals with impairments, age 8-21 years (16.4±3.0). All neurotypical children older than 4 years received the LEPS score 7/10 or greater indicating good PFS ability. Among individuals with impairments only 9 of 23 (39%) received the LEPS score 7/10 or greater. LEPS score was 90% correct in predicting high-functioning vs. low-functioning class assignment in individuals with autism, while full-scale IQ score was only 50% correct.
Evolutionary Models of Amino Acid Substitutions Based on the Tertiary Structure of their Neighborhoods
Authors: Primetis Elias , Chavlis Spyridon , Pavlidis Pavlos
Published: November 2018

Intra-protein residual vicinities depend on the involved amino acids. Energetically favorable vicinities (or interactions) have been preserved during evolution, while unfavorable vicinities have been eliminated. We describe, statistically, the interactions between amino acids using resolved protein structures. Based on the frequency of amino acid interactions, we have devised an amino acid substitution model that implements the following idea: amino acids that have similar neighbors in the protein tertiary structure can replace each other, while substitution is more difficult between amino acids that prefer different spatial neighbors. Using known tertiary structures for α-helical membrane (HM) proteins, we build evolutionary substitution matrices. We constructed maximum likelihood phylogenies using our amino acid substitution matrices and compared them to widely-used methods. Our results suggest that amino acid substitutions are associated with the spatial neighborhoods of amino acid residuals, providing, therefore, insights into the amino acid substitution process.