bluuebunny/crossref_metadata_2025 huggingface dataset:
The psychometric validation of the Dutch version of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) after Traumatic Brain Injury (TBI)
Authors: Plass Anne Marie , Van Praag Dominique , Covic Amra , Gorbunova Anastasia , Real Ruben , Von Steinbüchel Nicole
Published: December 2018

Background
Traumatic brain injury (TBI) is one of the most common neurological conditions. It can have wide-ranging physical, cognitive and psychosocial effects. Most people recover within weeks to months after the injury, but a substantial proportion are at risk of developing lasting post-concussion symptoms. The Rivermead Post-Concussion Syndrome Questionnaire (RPQ) is a short validated 16-items self-report instrument to evaluate post-concussive symptoms. The aim of this study was to test psychometrics characteristics of the current Dutch translation of the RPQ.
Methods
To determine the psychometric characteristics of the Dutch RPQ, 472 consecutive patients six months after they presented with a traumatic brain injury in seven medical centers in the Netherlands (N=397), and in two in Belgium (Flanders) (N=75) took part in the study which is part of the large prospective longitudinal observational CENTER-TBI-EU-study. Psychometric properties at six months post TBI, were assessed using exploratory and confirmatory factor analyses. Sensitivity was analyzed by comparing RPQ scores of patients after mild vs. moderate and severe TBI.
Findings
The Dutch version of RPQ proved good, showing excellent psychometric characteristics: high internal consistency (Cronbach's α .93), and good construct validity, being sensitive to self-reported recovery status at six months post TBI. Moreover, data showed a good fit to the three dimensions structure of separate cognitive, emotional and somatic factors (Chi2=119; df=117; p=.4; CFI=.99; RMSEA=.006), reported earlier in the literature.
Discussion
Psychometric characteristics of the Dutch version of RPQ proved excellent to good, and can the instrument therefore be applied for research purposes and in daily clinical practice.
FilmArray Respiratory Panel Integrated in a field Point Of Care dispositive for the diagnosis of respiratory tract infections in rural areas in Senegal
Authors: Bassene Hubert , Edouard Sophie , Diatta Georges , Lagier Jean Christophe , Mediannikov Oleg , Fenollar Florence , Diallo Aldiouma , Ba El Hadji , Raoult Didier , Parola Philippe , Drancourt Michel , Sokhna Cheikh
Published: December 2018

The development of molecular syndrome-based kits for the diagnosis of respiratory infections offers rapid and sensitive detection of common respiratory pathogens and will have a significant impact on the care of patients. In this study, we present the results obtained after the introduction of the FilmArray respiratory panel in a field Point of care (POC) for the diagnosis of virus and bacteria responsible of respiratory tract infections in Senegal rural area. From February to August 2017, we collected nasal swabs from febrile patients that presented symptoms of respiratory tract infections in three health posts located in Niakhar. Specimens were tested on site by multiplex Polymerase Chain Reaction (PCR), using the FilmArray respiratory panel® that targets 20 pathogens, including 17 virus and 3 bacteria (bioMérieux). Nasal swabs were collected from 113 patients. The median age was 4 years (ranging from 4 months to 60 years) and 51 (45%) were males. The prevalence of respiratory pathogens was 37.5% (12/32) during the dry season and 54.3% (44/81) in the rainy season (p=0.16). The prevalence of respiratory pathogen carriage was higher in children under 5 years of age (38/55, 69.1%). The most prevalent micro-organisms detected were influenza B virus (16/113, 14%), human rhinovirus/enterovirus (10/113, 9%), parainfluenzae virus (9/113, 8%), respiratory syncytial virus (8/113, 7%), adenovirus (5/113, 4%), human metapneumovirus (3/113, 3%), Chlamydia pneumoniae (2/113, 2%) and Coronavirus (2/113, 2%). The study has demonstrated that the integration of the FilmArray respiratory panel into a field POC could significantly improve the management of respiratory tract infections in rural areas.
RAISS: Robust and Accurate imputation from Summary Statistics
Authors: Julienne Hanna , Shi Huwenbo , Pasaniuc Bogdan , Aschard Hugues
Published: December 2018

Motivation

Multi-trait analyses using public summary statistics from genome-wide association studies (GWAS) are becoming increasingly popular. A constraint of multi-trait methods is that they require complete summary data for all traits. While methods for the imputation of summary statistics exist, they lack precision for genetic variants with small effect size. This is benign for univariate analyses where only variants with large effect size are selected a posteriori. However, it can lead to strong p-value inflation in multi-trait testing. Here we present a new approach that improve the existing imputation methods and reach a precision suitable for multi-trait analyses.

Results

We fine-tuned parameters to obtain a very high accuracy imputation from summary statistics. We demonstrate this accuracy for small size-effect variants on real data of 28 GWAS. We implemented the resulting methodology in a python package specially designed to efficiently impute multiple GWAS in parallel.

Availability

The python package is available at: https://gitlab.pasteur.fr/statistical-genetics/raiss, its accompanying documentation is accessible here http://statistical-genetics.pages.pasteur.fr/raiss/.

Contact

hanna.julienne@pasteur.fr
The whole genome sequence and mRNA transcriptome of the tropical cyclopoid copepod Apocyclops royi
Authors: Jørgensen Tue Sparholt , Nielsen Bolette Lykke Holm , Petersen Bent , Browne Patrick Denis , Hansen Benni Winding , Hansen Lars Hestbjerg
Published: December 2018

Copepoda is one of the most ecologically important animal groups on Earth, yet very few genetic resources are available for this Subclass. Here, we present the first whole genome sequence (WGS, acc. UYDY01) and the first mRNA transcriptome assembly (TSA, Acc. GHAJ01) for the tropical cyclopoid copepod species Apocyclops royi. Until now, only the 18S small subunit of ribosomal RNA gene and the COI gene has been available from A. royi, and only one other cyclopoid copepod had WGS resources available. Overall, the provided resources are the 7th copepod species to have WGS available and the 19th copepod species with TSA information available. We analyze the length and GC content of the provided WGS scaffolds as well as the coverage and gene content of both the WGS and the TSA assembly. Finally, we place the resources within the copepod order Cyclopoida as a member of the Apocyclops genus. We estimate the total genome size of A. royi to 450 Mb, with 181 Mb assembled nonrepetitive, 76 Mb assembled repeats and 193Mb unassembled sequence. The TSA assembly consists of 29,737 genes and an additional 45,756 isoforms. In the WGS and TSA assemblies, >80% and >95% of core genes can be found, though many in fragmented versions. The provided resources will allow researchers to conduct physiological experiments on A. royi, and also increase the possibilities for copepod gene set analysis, as it adds substantially to the copepod datasets available.
Deep evolutionary origin of limb and fin regeneration
Authors: Darnet Sylvain , Dragalzew Aline C. , Amaral Danielson B. , Thompson Andrew W. , Cass Amanda N. , Lorena Jamily , de Freitas Sousa Josane , Costa Carinne M. , Sousa Marcos P. , Fröbisch Nadia B. , Schneider Patricia N. , Davis Marcus C. , Braasch Ingo , Schneider Igor
Published: December 2018

Salamanders and lungfishes are the only sarcopterygians (lobe-finned vertebrates) capable of complete limb and paired fin regeneration, respectively. Among actinopterygians (ray-finned fishes), regeneration after amputation at the fin endoskeleton has only been demonstrated in Polypterid fishes (Cladistia). Whether complete appendage regeneration in sarcopterygians and actinopterygians evolved independently or has a common origin remains unknown. Here we combine fin regeneration assays and comparative RNA-seq analysis to provide support for a common origin of a paired appendage regeneration in osteichthyes (bony vertebrates). We show that, in addition to Polypterids, regeneration after fin endoskeleton amputation occurs in extant representatives of all major actinopterygian clades: the American paddlefish, (Chondrostei), the spotted gar (Holostei), as well as in two cichlid species, the white convict and the oscar (Teleostei). Our comparative RNA-seq analysis of regenerating blastemas of axolotl and Polypterus reveals the activation of common genetic pathways and expression profiles, consistent with a pan-osteichthyes genetic program of appendage regeneration. Collectively, our findings support a deep evolutionary origin of paired appendage regeneration in osteichthyes and provide an evolutionary framework for studies on the genetic basis of appendage regeneration.
Trace impurities in test stimuli can seriously compromise chemosensory studies
Authors: Schorkopf Dirk Louis P. , Molnar Bela Peter , Solum Marit , Larsson Mattias C. , Millar Jocelyn G. , Karpati Zsolt , Dekker Teun
Published: December 2018

The discovery of olfactory receptors and major technological advances have greatly accelerated our understanding of chemosensory mechanisms. However, some of this rapid progress may be compromised by inadequate knowledge or characterization of the purity of chemical stimuli used to challenge olfactory or other chemoreceptors when mapping their response profiles. Here, we provide strong evidence that the presence of trace impurities in test stimuli can completely obscure true ligand-receptor relationships. DmOR7a, an olfactory receptor of the vinegar fly (Drosophila melanogaster) has been reported to respond to several long-chain aliphatic ligands such as a putative Drosophila pheromone, the pheromone of the silkworm moth Bombyx mori, and a common fatty acid, linoleic acid. By contrast, we show that DmOR7a responds with high sensitivity to volatile impurities and degradation products present in minute quantities in authentic standards of those compounds, but not to the standards themselves. Responses to impurities can easily go unnoticed due to two main factors. First, the sensitivity of receptors to key ligands may be greater than that of analytical chemistry instruments used to check sample purity. Second, the concentration of highly volatile impurities in an odour puff may be orders of magnitude higher than the main component of a sample, due to the large differences in vapour pressures between the impurities and the main component. Issues concerning impurities are not limited to studies on olfaction that use odour puffs to characterize receptor-ligand interactions, but may affect all studies on chemosensation, from molecular biology and in-silico predictions to behaviour. Purity, which is crucial in receptor-ligand studies, is always implied, but rarely checked rigorously. To avoid misinterpretations, a proper account of all compounds present in test stimuli and an unequivocal confirmation of ligand affinity should accompany chemosensory studies.
A circuit of protein-protein regulatory interactions enables polarity establishment in a bacterium
Authors: Zhao Wei , Duvall Samuel W. , Kowallis Kimberly A. , Tomares Dylan T. , Petitjean Haley N. , Childers W. Seth
Published: December 2018

Asymmetric cell division generates specialized daughter cells that play a variety of roles including tissue morphogenesis in eukaryotes and pathogenesis in bacteria. In the gram-negative bacteriumCaulobacter crescentus, asymmetric localization of two biochemically distinct signaling hubs at opposite cell poles provides the foundation for asymmetric cell division. Through a set of genetic, synthetic biology and biochemical approaches we have characterized the regulatory interactions between three scaffolding proteins. These studies have revealed that the scaffold protein PodJ functions as a central mediator for organizing the new cell signaling hub, including promoting bipolarization of the central developmental scaffold protein PopZ. In addition, we identified that the old pole scaffold SpmX serves as a negative regulator of PodJ subcellular accumulation. These two scaffold-scaffold regulatory interactions serve as the core of an integrated cell polarization circuit that is layered on top of the cell-cycle circuitry to coordinate cell differentiation and asymmetric cell division.
Regenerative Failure Following Rat Neonatal Chorda Tympani Transection is Associated with Geniculate Ganglion Cell Loss and Terminal Field Plasticity in the Nucleus of the Solitary Tract
Authors: Martin Louis J , Lane Amy H , Samson Kaeli K , Sollars Suzanne I
Published: December 2018

Neural insult during development results in recovery outcomes that vary dependent upon the system under investigation. Nerve regeneration does not occur if the rat gustatory chorda tympani nerve is sectioned (CTX) during neonatal (≤ P10) development. It is unclear how chorda tympani soma and terminal fields are affected after neonatal CTX. The current study determined the impact of neonatal CTX on chorda tympani neurons and brainstem gustatory terminal fields. To assess terminal field volume in the nucleus of the solitary tract (NTS), rats received CTX at P5 or P10 followed by chorda tympani label, or glossopharyngeal (GL) and greater superficial petrosal (GSP) label as adults. In another group of animals, terminal field volumes and numbers of chorda tympani neurons in the geniculate ganglion (GG) were determined by labeling the chorda tympani with DiI at the time of CTX in neonatal (P5) and adult (P50) rats. There was a greater loss of chorda tympani neurons following P5 CTX compared to adult denervation. Chorda tympani terminal field volume was dramatically reduced 50 days after P5 or P10 CTX. Lack of nerve regeneration after neonatal CTX is not caused by ganglion cell death alone, as approximately 30% of chorda tympani neurons survived into adulthood. Although the total field volume of intact gustatory nerves was not altered, the GSP volume and GSP-GL overlap increased in the dorsal NTS after CTX at P5, but not P10, demonstrating age-dependent plasticity. Our findings indicate that the developing gustatory system is highly plastic and simultaneously vulnerable to injury.
Direct capture of CRISPR guides enables scalable, multiplexed, and multi-omic Perturb-seq
Authors: Replogle Joseph M. , Xu Albert , Norman Thomas M. , Meer Elliott J. , Terry Jessica M. , Riordan Daniel , Srinivas Niranjan , Mikkelsen Tarjei S. , Weissman Jonathan S. , Adamson Britt
Published: December 2018

Pairing CRISPR-based genetic screens with single-cell transcriptional phenotypes (Perturb-seq) has advanced efforts to explore the function of mammalian genes and genetic networks. We present strategies for Perturb-seq that enable direct capture of CRISPR sgRNAs within 3’ or 5’ single-cell RNA-sequencing libraries using the 10x Genomics platform. This technology greatly expands the accessibility, scalability, and flexibility of Perturb-seq, specifically enabling use with programmed combinatorial perturbations and multiplexing with multi-omic measurements.
Thermosensitive alternative splicing senses and mediates temperature adaptation inDrosophila
Authors: Evantal Naveh , Anduaga Ane Martin , Bartok Osnat , Patop Ines Lucía , Weiss Ron , Kadener Sebastian
Published: December 2018

Circadian rhythms are generated by the cyclic transcription, translation and degradation of clock genes, includingtimeless(tim). Currently, little is known about the mechanisms by which the circadian clock senses and adapts to temperature changes. Here we show that temperature dramatically changes the splicing pattern oftim. We found that at 18°C TIM protein levels are diminished due to the induction of two cold-specific splicing isoforms (tim-coldandtim-short&cold). At 29°C, another isoform,tim-Mediumis strongly upregulated. We found that this isoform switching mechanism allows flies to regulate the levels and activity of TIM by setting miRNA-dependent thresholds for expression as well as by expressing isoforms with specific functions. Flies in which the production oftim-short&coldis abrogated display altered patterns of locomotor activity and alteredtimexpression. Interestingly, the introns oftimcarry the information for the temperature sensitivity, suggesting thattimsplicingper seis the temperature sensor.
Mechanistic interpretation of non-coding variants helps discover transcriptional regulators of drug response
Authors: Xie Xiaoman , Hanson Casey , Sinha Saurabh
Published: December 2018

Identification of functional non-coding variants (polymorphisms) and their mechanistic interpretation is a major challenge of modern genomics, especially for precision medicine. Transcription factor (TF) binding profiles and epigenomic landscapes in reference samples can help us functionally annotate the genome, but do not provide ready answers regarding the effects of non-coding variants. A promising computational approach is to build models that predict TF-DNA binding from sequence, and use such models to score a variant’s impact on TF binding strength. Here, we asked if this mechanistic approach to variant interpretation can be combined with information on genotype-phenotype associations to discover important transcription factors regulating phenotypic variation among individuals. We developed a statistical approach that integrates phenotype, genotype, gene expression, TF ChIP-seq and Hi-C chromatin interaction data to answer this question. Using drug sensitivity measured in lymphoblastoid cell lines as the phenotype of interest, we tested if the non-coding variants statistically linked to the phenotype are enriched for strong predicted impact on DNA-binding strength of a TF, and used this test to identify TFs regulating individual differences in the phenotype. Our method relies on a new method for predicting variant impact on TF-DNA binding, that uses a combination of biophysical modelling and machine learning. We report statistical and literature-based support for many of the TFs discovered here as regulators of drug response variation. We show that the use of mechanistically driven variant impact predictors can identify TF-drug associations that would otherwise be missed. We examined in depth the evidence underlying one reported association – that of the transcription factor ELF1 with the drug doxorubicin – and identified several genes that may mediate this regulatory relationship.
The Epistasis Boundary: Linear vs. Nonlinear Genotype-Phenotype Relationships
Authors: Sverdlov Serge , Thompson Elizabeth A
Published: December 2018

Nonlinearity in the genotype-phenotype relationship can take the form of dominance, epistasis, or gene-environment interaction. The importance of nonlinearity, especially epistasis, in real complex traits is controversial. Network models in systems biology are typically highly nonlinear, yet the predictive power of linear quantitative genetic models is rarely improved by addition of nonlinear terms, and association studies detect few strong genegene interactions. We find that complex traits satisfying certain conditions can be well represented by a linear genetic model on an appropriate scale despite underlying biological complexity. Recent mathematical results in separability theory determine these conditions, which correspond to three biological criteria (Directional Consistency, Environmental Compensability, and Pathway Redundancy) together making up an Epistatic Boundary between systems suitable and unsuitable for linear modeling. For nonlinear traits, we introduce a classification of types of nonlinearity from a systems perspective, and use this to illustrate how upstream controlling genes, potentially more important to explaining biological function, can be intrinsically harder to detect by GWAS than their downstream controlled counterparts.
A biophysical computational model for memory trace transfer from hippocampus to neocortex
Authors: Liu Xin , Kuzum Duygu
Published: December 2018

The hippocampus plays important roles in memory formation and retrieval through sharp-wave-ripples. Recent studies have shown that certain neuron populations in the prefrontal cortex exhibit coordinated reactivations during awake ripple events. Also, the reactivation seems stronger during initial awake learning. These experimental findings suggest that the awake ripple is an important biomarker, through which the hippocampus interacts with the neocortex to assist the memory formation and retrieval. However, the computational mechanisms of this ripple based hippocampal-cortical coordination are still not clear. In this work, we build a biophysical model that includes both CA1 and layer V networks of the prefrontal cortex to investigate the possible mechanisms, by which the memory traces in the hippocampus can be transferred to prefrontal cortex. We first show that the local field potentials generated in the hippocampus and prefrontal cortex exhibit ripple range activities that are consistent with the recent experimental studies. Then, we find that the sequence information stored in the hippocampus can be successfully transferred to the prefrontal cortex recurrent networks through spike-timing dependent plasticity (STDP) and sequence replays. Further, we investigate the mechanisms of memory retrieval in the PFC network. Our findings suggest that the stored memory traces in the prefrontal cortex network can be retrieved through two different mechanisms, namely the cell-specific input and non-specific spontaneous background noise. Finally, we show that more SWRs and an optimal background noise level will both contribute to better sequence reactivations in the PFC network during memory retrieval. Our study presents a possible explanation for the memory trace transfer from the hippocampus to the neocortex through ripple coupling in awake states and reports two different mechanisms by which the stored memory traces can be successfully retrieved.
Hyocholic acid species and the risk of type 2 diabetes
Authors: Zheng Xiaojiao , Chen Tianlu , Jiang Runqiu , Zhao Aihua , Huang Fengjie , Zhang Yunjing , Han Xiaolong , Li Mengci , Wei Meilin , You Yijun , Wang Shouli , Ma Xiaojing , Bao Yuqian , Jiang Miao , Liu Jiajian , Zhao Qing , Ge Kun , Dong Bing , Li Defa , Liang Dandan , Lei Sha , Li Yitao , Lan Ke , Lu Aiping , Zhang Weituo , Wang Congrong , Yu Haoyong , Rajani Cynthia , Panee Jun , Xie Guoxiang , Jia Weiping , Jia Wei
Published: December 2018

Hyocholic acid (HCA) and its derivatives are found in only trace amounts in human blood, but constitute approximately 76 % of the bile acid (BA) pool in the pig, a species known for its exceptional resistance to type 2 diabetes mellitus (T2DM). Here we show that HCA species play a crucial role in maintaining glucose homeostasis and preventing T2DM. We found that in two cohort studies (n=1,213), both obesity and diabetes were associated with lower serum concentrations of HCA species. Serum HCA levels in apparently healthy individuals (n=132) were found to be strong predictors for metabolic health 10 years later. Oral administration of HCA increased serum fasting GLP-1, to a greater extent than metformin, in healthy and diabetic mouse models. HCA upregulated GLP-1 secretion in intestinal enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor, a unique mechanism that is not found in other BA species.
Structural Basis for eIF2B Inhibition in Integrated Stress Response
Authors: Kashiwagi Kazuhiro , Yokoyama Takeshi , Nishimoto Madoka , Takahashi Mari , Sakamoto Ayako , Yonemochi Mayumi , Shirouzu Mikako , Ito Takuhiro
Published: December 2018

A core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers methionylated initiator tRNA to the ribosome in a GTP-dependent manner. In contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor eIF2B, which leads to a deficiency of active eIF2 and resultant global translation repression. To unveil the mechanism by which the eIF2 phosphorylation status regulates the eIF2B nucleotide exchange activity, we determined cryo-electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. Intriguingly, the unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active “productive” and nucleotide exchange-inactive “nonproductive” modes, respectively. The nonproductive-mode phosphorylated eIF2, extending from one of the two eIF2B “central cavities”, not only prevents nucleotide exchange on itself, but also sterically prevents unphosphorylated eIF2 from productively binding on the other central cavity of eIF2B, which explains how phosphorylated eIF2 inhibits eIF2B.

One Sentence Summary

A drastic change in the binding mode of eIF2 to eIF2B induces translational control in stress.
From genotype to antibiotic susceptibility phenotype in Enterobacteriaceae: a clinical perspective
Authors: Ruppé Etienne , Cherkaoui Abdessalam , Girard Myriam , Schicklin Stephane , Lazarevic Vladimir , Schrenzel Jacques
Published: December 2018

Predicting the antibiotic susceptibility phenotype from genomic data is challenging, especially for some specific antibiotics in Enterobacteriaceae. Here we aimed to assess the performance of whole genomic sequencing (WGS) for predicting the antibiotic susceptibility in various Enterobacteriaceae species using the detection of antibiotic resistance genes (ARGs), specific mutations and a knowledge-based decision algorithm. We sequenced (Illumina MiSeq 2x250b) 187 clinical isolates from species possessing (n=98) or not (n=89) an intrinsic AmpC-type cephalosporinase. Antibiotic susceptibility was performed by the disc diffusion method. Reads were assembled by A5-miseq and ARGs were identified from the ResFinder database using Diamond. Mutations on GyrA and ParC topoisomerases were studied. We assessed the prediction rates for amoxicillin, co-amoxiclav, piperacillin, piperacillin-tazobactam, ceftazidime, cefepime, meropenem, amikacin, gentamicin and fluoroquinolones. A total of 1,870 isolate/antibiotic combinations were considered. In 295 cases (15.8%) no attempt of prediction was made. Among the 1,575 attempts, 1,537 (97.6%) were correct (1,011 for predicting susceptibility and 526 for predicting resistance), 15 (0.9%) were major errors (MEs) and 23 (1.5%) were very major errors (VMEs). The concordance rates were similar between non-AmpC and AmpC-producing Enterobacteriaceae (907/935 [97.0%] vs 630/640 [98.4%], Chi2 test p=0.07), but more VMEs were observed in non-AmpC producing strains than in those producing an AmpC (20/935 [2.1%] vs 3/640 [0.5%], Chi2 test p=0.007). The majority of VMEs were putatively due to the overexpression of chromosomal genes. In conclusion, the inference of antibiotic susceptibility from genomic data showed good performances for non-AmpC and AmpC-producing Enterobacteriaceae species.
A revisit of RSEM generative model and its EM algorithm for quantifying transcript abundances.
Authors: Vuong Hy , Truong Thao , Tran Thang , Pham Son
Published: December 2018

RSEM has been mainly known for its accuracy in transcript abundance quantification. However, its quantification time is extremely high compared to that of recent quantification tools. In this paper, we revised the RSEM's EM algorithm. In particular, we derived accurate M-step updates to eliminate incorrect heuristic updates in RSEM. We also implement some optimizations that reduce the quantification time about a hundred times while still have better accuracy compared to RSEM. In particular, we noticed that different parameters have different convergence rates, therefore we identified and removed early converged parameters to significantly reduce the model complexity in further iterations, and we also use SQUAREM method to further speed up the convergence rate. We implemented these revisions in a packaged named Hera-EM, with source code available at: https://github.com/bioturing/hera/tree/master/hera-EM
Phosphorylation regulates auto-inhibition of kinesin KIF3A
Authors: Chen Kunning , Saw Wuan-Geok , Lama Dilraj , Verma Chandra , Grüber Gerhard , Koh Cheng-Gee
Published: December 2018

Kinesin are molecular motors that move along the microtubules. They function to transport cargoes, vesicles and organelles to designated locations in the cells. KIF3A belongs to the Kinesin-2 family and forms a heterotrimeric complex with KIF3B and KAP3. We have earlier shown that the cargo trafficking activity of KIF3 motor can be regulated by CaMKII kinase and POPX2 phosphatase. In this study, we elucidated the mechanism of KIF3A regulation. We find that KIF3A adopts an auto-inhibited state through the interaction between the motor and tail domains. The motor-tail interaction also hinders the ATPase activity of the motor domain. We show that the phosphorylation status of serine-689/690 (mouse/human) at the C-terminal region of KIF3A is crucial for the motor-tail interaction. The motor domain does not interact well with the tail domain when serine-689 is phosphorylated by CaMKII or mutated to aspartic acid to mimic phosphorylation. Molecular dynamics simulations suggest that the non-phosphorylated tail domain folds into the hydrophobic pocket formed by the motor dimers. Phosphorylation of serine-689 results in conformational changes that leads to the relieve of auto-inhibition.
Navigating the structural landscape ofde novoα–helical bundles
Authors: Rhys Guto G. , Wood Christopher W. , Beesley Joseph L. , Zaccai Nathan R. , Burton Antony J. , Brady R. Leo , Thomson Andrew R. , Woolfson Derek N.
Published: December 2018

The association of amphipathicαhelices in water leads to α-helical-bundle protein structures. However, the driving force for this—the hydrophobic effect—is not specific and does not define the number or the orientation of helices in the associated state. Rather, this is achieved through deeper sequence-to-structure relationships, which are increasingly being discerned. For example, for one structurally extreme but nevertheless ubiquitous class of bundle—the α-helical coiled coils—relationships have been established that discriminate between all-parallel dimers, trimers and tetramers. Association states above this are known, as are antiparallel and mixed arrangements of the helices. However, these alternative states are less-well understood. Here, we describe a synthetic-peptide system that switches between parallel hexamers and various up-down-up-down tetramers in response to single-amino-acid changes and solution conditions. The main accessible states of each peptide variant are characterized fully in solution and, in most cases, to high-resolution X-ray crystal structures. Analysis and inspection of these structures helps rationalize the different states formed. This navigation of the structural landscape of α-helical coiled coils above the dimers and trimers that dominate in nature has allowed us to design rationally a well-defined and hyperstable antiparallel coiled-coil tetramer (apCC-Tet). This robustde novoprotein provides another scaffold for further structural and functional designs in protein engineering and synthetic biology.
Dynamics of centriole amplification in centrosome-depleted brain multiciliated progenitors
Authors: Mercey Olivier , Jord Adel Al , Rostaing Philippe , Mahuzier Alexia , Fortoul Aurélien , Boudjema Amélie-Rose , Faucourt Marion , Spassky Nathalie , Meunier Alice
Published: December 2018

Centrioles are essential microtubule-based organelles organizing cilia and centrosomes. Their mode of biogenesis is semi-conservative: each pre-existing centriole scaffolds the formation of a new one, a process coordinated with the cell cycle. By contrast, multiciliated progenitors with two centrosomal centrioles massively amplify centrioles to support the nucleation of hundred of motile cilia and transport vital fluids. This occurs through cell type-specific organelles called deuterosomes, composed of centrosome-related elements, and is regulated by the cell cycle machinery. Deuterosome-dependent centriole amplification was proposed for decades to occur de novo, i.e. independently from pre-existing centrioles. Challenging this hypothesis, we recently reported an accumulation of procentriole and deuterosome precursors at the centrosomal daughter centriole during centriole amplification in brain multiciliated cells. Here we further investigate the relationship between the centrosome and the dynamic of centriole amplification by (i) characterizing the centrosome behavior during the centriole amplification dynamics and (ii) assessing the dynamics of amplification in centrosome-depleted cells. Surprisingly, although our data strengthen the centrosomal origin of amplified centrioles, we show limited consequences in deuterosome/centriole number when we deplete centrosomal centrioles. Interestingly, in absence of centrosomal centrioles, procentrioles are still amplified sequentially from a single focal region, characterized by microtubule convergence and pericentriolar material (PCM) self-assembly. The relevance of deuterosome association with the daughter centriole as well as the role of the PCM in the focal and sequential genesis of centrioles in absence of centrosomal centrioles are discussed.
Mapping axon conduction delaysin vivofrom microstructural MRI
Authors: Drakesmith Mark , Jones Derek K
Published: December 2018

The conduction velocity (CV) of action potentials along axons is a key neurophysiological property central to neural communication. The ability to estimate CV in humansin vivofrom non-invasive MRI methods would therefore represent a significant advance in neuroscience. However, there are 2 major challenges that this paper aims to address: (1) much of the complexity of the neurophysiology of action potentials cannot be captured with currently available MRI techniques. Therefore, we seek to establish the variability in CV thatcanbe captured when predicting CV purely from parameters that can be estimated from MRI (axon diameter and g-ratio); and (2) errors inherent in existing MRI-based biophysical models of tissue will propagate through to estimates of CV, the extent to which is currently unknown.

Issue (1) is investigated by performing a sensitivity analysis on a comprehensive model of axon electrophysiology and determining the relative sensitivity to various morphological and electrical parameters.

The investigations suggest that 89.2 % of the variance in CV is accounted for by variation in AD and g-ratio. The observed dependency of CV on AD and g-ratio is well characterised by a previously reported model by Rushton.

Issue (2) is investigated through simulation of diffusion and relaxometry MRI data for a range of axon morphologies, applying models of restricted diffusion and relaxation processes to derive estimates of axon volume fraction (AVF), AD and g-ratio and estimating CV from the derived parameters. The results show that errors in the AVF have the biggest detrimental impact on estimates of CV, particularly for sparse fibre populations (AVF<0.3). CV estimates are most accurate (below 5% error) where AVF is above 0.3, g-ratio is between 0.6 and 0.85 and AD is below 10 µm. Fortunately, these parameter bounds are typically satisfied by most myelinated axons.

In conclusion, we demonstrate that accurate CV estimates can be inferred in axon populations across a range of configurations, except in some exceptional cases or where axonal density is low. As a proof of concept, for the first time, we generated anin vivomap of conduction velocity in the human corpus callosum with estimates consistent with values previously reported from invasive electrophysiology in primates.
Cell division history determines hematopoietic stem cell potency
Authors: Arai Fumio , Stumpf Patrick S , Ikushima Yoshiko M , Hosokawa Kentaro , Roch Aline , Lutolf Matthias P , Suda Toshio , MacArthur Ben D
Published: December 2018

Loss of stem cell self-renewal may underpin aging. Here, we combined single cell profiling, deep-learning, mathematical modelling and in vivo functional studies to explore how hematopoietic stem cell (HSC) division patterns evolve with age. We trained an artificial neural network (ANN) to accurately identify cell types in the hematopoietic hierarchy and predict their age from their gene expression patterns. We then used this ANN to compare daughter cell identities immediately after HSC divisions, and found that HSC self-renewal declines sharply with age. Furthermore, while HSC cell divisions are deterministic and intrinsically-regulated in young and old age, they become stochastic and niche-sensitive in mid-life. Analysis of evolving division patterns indicated that the self-renewal ability an individual HSC depends upon number times it has divided previously. We propose a model of HSC proliferation that accurately predicts the accumulation of HSCs with age, and reconciles the stochastic and instructive views of fate commitment.
Genetic approaches in mice demonstrate that neuro-mesodermal progenitors express T/Brachyury but not Sox2
Authors: Mugele Dorothee , Moulding Dale , Savery Dawn , Mole Matteo , Greene Nicholas , Martinez-Barbera Juan Pedro , Copp Andrew
Published: December 2018

Neural tube and somites have long been thought to derive from separate germ layers: the ectoderm and mesoderm. This concept was challenged by the discovery of neuro-mesodermal progenitors, a bi-potent cell population that gives rise to both spinal neural tube and somites. In line with their proposed potency, these cells are considered to co-express the neural marker Sox2 and the mesodermal marker T/Brachyury. We performed genetic lineage tracing in mouse embryos and confirmed that T-expressing cells give rise to both neural tube and mesoderm. Surprisingly, however, Sox2-expressing cell derivatives colonise only the neural tube after embryonic day 8.5. Deletion of Sox2 in T-expressing cells was compatible with an otherwise normal neural tube and paraxial mesoderm. Moreover, Sox2 expression is absent from the chordoneural hinge, where neuro-mesodermal progenitors are located. Our findings demonstrate that neuro-mesodermal progenitors express T but not Sox2, suggesting the need for re-evaluation of the neuro-mesodermal progenitor hypothesis.
A New Uranium Bioremediation Approach using Radio-tolerant Deinocoocus radiodurans Biofilm
Authors: Manobala T , Shukla Sudhir , Rao Toleti Subba , Kumar M Dharmedira
Published: December 2018

Deinococcus radiodurans, is the most radiation tolerant organism ever known, it has gained importance in recent years as a potential candidate for bioremediation of heavy metals, especially radioactive ones. This study investigates the efficiency of a recombinant D. radiodurans (DR1-bf+) strain with an ability to form biofilm for uranium remediation. The modified Arsenazo III dye method was used to estimate the uranium concentration. Uranyl nitrate aqueous solution is generated during the operation of nuclear fuel reprocessing. The D. radiodurans biofilm (DR1-bf+) grown in the presence of 20 mM Ca2+ showed remarkable ability of uranyl ion removal. DR1-bf+ (+Ca2+) biofilm removed ~75% of 1000 mg/L uranium within 30 minutes post treatment from uranyl nitrate aqueous solution. U removal rate was also found to be directly proportional to biofilm age. This study discusses the ability of D. radiodurans biofilm in uranium removal.
Genotypic variation in root distribution changes and physiological responses of sugarcane induced by drought stress
Authors: Namwongsa Jariya , Jongrungklang Nuntawoot , Songsri Patcharin
Published: December 2018

Drought is an important factor reducing yield and quality of sugarcane. Root growth and physiological traits are important for maximizing water uptake to improve drought resistance. This study compared the root, shoot and physiological traits under drought stress (DS) and well-watered (WW) conditions of various sugarcane varieties grown in rhizoboxes in a greenhouse at the Field Crops Research Station of Khon Kaen University, Khon Kaen, Thailand. Data were recorded for the root, shoot and physiological traits (relative water content, stomatal conductance, SPAD chlorophyll meter reading and chlorophyll fluorescence) at 90 days after transplanting. Root samples were recovered from 11 soil layers at 10 cm intervals from the top to the bottom of the rhizobox, for root length and root dry weight measurements. Drought was imposed on sugarcane at early growth stages altered the root distribution patterns, and differences were evident among the sugarcane genotypes. The sugarcane genotypes adapted to water stress by increasing root length into deeper soil layers. Drought led to increased total root length in KK3, MPT06-166, K88-92, CP38-22, Kps01-12 and KPK98-40. Root lengths and stomatal conductance were positively correlated under WW and DS conditions. Root distribution in the lower soil layers and the percentage of root distribution were higher than those under well-watered conditions. The knowledge gained from this study will aid parental selection in sugarcane breeding programs for drought resistance as the findings strongly suggest that the physiological modification in the root system is a useful drought-resistant mechanism.
Structural basis for the inhibition of translation through eIF2α phosphorylation
Authors: Gordiyenko Yuliya , Llácer José Luis , Ramakrishnan Venki
Published: December 2018

One of the responses to stress by eukaryotic cells is the down-regulation of protein synthesis by phosphorylation of translation initiation factor eIF2. Phosphorylation results in low availability of the eIF2 ternary complex (eIF2-GTP-tRNAi) by affecting its interaction with its GTP-GDP exchange factor eIF2B. We have determined the cryo-EM structure of eIF2B in complex with phosphorylated eIF2 at an overall resolution of 4.15 Å. Two eIF2 molecules bind opposite sides of an eIF2B hetero-decamer through eIF2α-D1, which contains the phosphorylated Ser51. eIF2α-D1 is mainly inserted between the N-terminal helix bundle domains of δ and α subunits of eIF2B. Phosphorylation of Ser51 enhances binding to eIF2B through direct interactions of phosphate groups with residues in eIF2Bα and indirectly by inducing contacts of eIF2α helix 58-63 with eIF2Bδ leading to a competition with Met-tRNAi.
Whole-tree heartwood inducing technique for Dalbergia odorifera
Authors: Wei Jianhe , Meng Hui , Chen DeLi , Zhao Xiangsheng , Zhang Zheng , Liu Yangyang , Gao Zhihui , Liu Peiwei , Feng Jian , Yang Yun ,   Hui Meng, DeLi Chen, Xiangsheng Zhao, Zheng Zhang, Yangyang Liu, Zhihui Gao, Peiwei Liu, Jian Feng,
Published: December 2018

The dried heartwood of Dalbergia odorifera is a very important traditional Chinese medicine. In nature, D. odorifera heartwood forms slowly over several decades, and excessive harvesting has caused large-scale reductions of its wild populations. To date, there have been no studies on artificial methods to induce heartwood formation in trees that have not already begun producing heartwood. We have published a patent for a whole-tree heartwood inducing technique for D. odorifera (the “Dodor-Wit” method); here, we describe and analyze its efficacy. Trees in four plantations in China were treated using this method. After two years, in 2016 and 2017, they were harvested and analyzed. Average heartwood yield per tree was 3,161.95 g. Heartwood induction rate (dry heartwood weight to total dry trunk weight after peeling) was 21.60%. Average volatile oil content per tree was 1.42%. Alcohol-soluble extract of the induced heartwood was 15.77%, exceeding the Chinese Pharmacopoeia standard. This is the first report on the Dodor-Wit method and heartwood induction in D. odorifera trees aged 5–8 years. The heartwood induced by Dodor-Wit satisfies the requirements of the Chinese Pharmacopoeia. The Dodor-Wit method has an important role in solving the extreme scarcity of Chinese medicinal herbs.
Strong selective sweeps before 45,000BP displaced archaic admixture across the human X chromosome
Authors: Skov L. , Macià M.C. , Lucotte E. , Cavassim M.I.A. , Castellano D. , Mailund T. , Schierup M.H. , Munch K.
Published: December 2018

The X chromosome in non-African populations has less diversity and less Neanderthal introgression than expected. We analyzed X chromosome diversity across the globe and discovered seventeen chromosomal regions, where haplotypes of several hundred kilobases have recently reached high frequencies in non-African populations only. The selective sweeps must have occurred more than 45,000 years ago because the ancient Ust’-Ishim male also carries its expected proportion of these haplotypes. Surprisingly, the swept haplotypes are entirely devoid of Neanderthal introgression, which implies that a population without Neanderthal admixture contributed the swept haplotypes. It also implies that the sweeps must have happened after the main interbreeding event with Neanderthals about 55,000 BP. These swept haplotypes may thus be the only genetic remnants of an earlier out-of-Africa event.

One Sentence Summary

After humans expanded out of Africa, the X chromosome experienced a burst of extreme natural selection that removed Neanderthal admixture.
Accounting for measurement error to assess the effect of air pollution on omic signals
Authors: Ponzi Erica , Vineis Paolo , Chung Kian Fan , Blangiardo Marta
Published: December 2018

Studies on the effects of air pollution and more generally environmental exposures on health require measurements of pollutants, which are affected by measurement error. This is a cause of bias in the estimation of parameters relevant to the study and can lead to inaccurate conclusions when evaluating associations among pollutants, disease risk and biomarkers. Although the presence of measurement error in such studies has been recognized as a potential problem, it is rarely considered in applications and practical solutions are still lacking.

In this work, we formulate Bayesian measurement error models and apply them to study the link between air pollution and omic signals. The data we use stem from the “Oxford Street II Study”, a randomized crossover trial in which 60 volunteers walked for two hours in a traffic-free area (Hyde Park) and in a busy shopping street (Oxford Street) of London. Metabolomic measurements were made in each individual as well as air pollution measurements, in order to investigate the association between short-term exposure to traffic related air pollution and perturbation of metabolic pathways. We implemented error-corrected models in a classical framework and used the flexibility of Bayesian hierarchical models to account for dependencies among omic signals, as well as among different pollutants. Models were implemented using traditional MCMC simulative methods as well as integrated Laplace approximation.

The inclusion of a classical measurement error term resulted in variable estimates of the association between omic signals and traffic related air pollution (TRAP) measurements, where the direction of the bias was not predictable a priori. The models were successful in including and accounting for different correlation structures, both among omic signals and among different pollutant exposures. In general, more associations were identified when the correlation among omics and among pollutants were modeled, and their number increased when a measurement error term additionally included in the multivariate models (particularly for the associations between metabolomics and NO2).