bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure before function: myosin binding protein‐C slow is a structural protein with regulatory properties
Authors: Geist Janelle , Ward Christopher W. , Kontrogianni‐Konstantopoulos Aikaterini
Published: June 2018

Myosin binding protein‐C slow (sMyBP‐C) comprises a family of accessory proteins in skeletal muscles that bind both myosin and actin filaments. Herein, we examined the role of sMyBP‐C in adult skeletal muscles using in vivo gene transfer and clustered regularly interspaced short palindromic repeats technology to knock down all known sMyBP‐C variants. Our findings, confirmed in two different skeletal muscles, demonstrated efficient knockdown (KD) of sMyBP‐C (>70%) resulting in notably decreased levels of thick, but not thin, filament proteins ranging from ~50% for slow and fast myosin to ~20% for myomesin. Consistent with this, A bands were selectively distorted, and sarcomere length was significantly reduced. Contrary to earlier in vitro studies showing that addition of recombinant sMyBP‐C slows down the formation of actomyosin crossbridges, our work demonstrates that KD of sMyBP‐C in intact myofibers results in decreased contraction and relaxation kinetics under no‐load conditions. Similarly, KD muscles develop markedly reduced twitch and tetanic force and contraction velocity. Taken together, our results show that sMyBP‐C is essential for the regular organization and maintenance of myosin filaments into A bands and that its structural role precedes its ability to regulate actomyosin crossbridges.—Geist, J., Ward, C. W., Kontrogianni‐Konstantopoulos, A. Structure before function: myosin binding protein‐C slow is a structural protein with regulatory properties. FASEB J. 32, 6385–6394 (2018). www.fasebj.org
Longitudinal Effects of Body Mass Index and Self-Esteem on Adjustment From Early to Late Adolescence: A Latent Growth Model
Authors: YUN Eun Kyoung , LEE Hanna , LEE Ji Uhn , PARK Jun Hee , NOH Young Min , SONG Yu Gil , PARK Jung Hwa
Published: June 2018

Background:

Mental and physical development during adolescence is a factor that may affect quality of life in adulthood.

Purpose:

The aims of this study were to investigate the developmental trajectories of body mass index (BMI), self-esteem, and adjustment among students from early to late adolescence and to examine the longitudinal relationships among these variables.

Methods:

Data from 2006 to 2012 were collected from the Korean Welfare Panel Study. Of the initial sample of 521 students, 487 completed a validated questionnaire measuring BMI, self-esteem, and adjustment. Latent growth curve modeling analyses were conducted to examine the relationships among the variables.

Results:

Univariate linear growth models showed a significant increase in BMI and significant declines in both self-esteem and adjustment across three time points from childhood to adolescence. The goodness of fit of the multivariate conditioned model supported the validity of the proposed longitudinal model (comparative fit index = .93, root mean square error of approximation = .08). Change in BMI was significantly linked with change in adjustment (β = .18, p < .05) but not with change in self-esteem, whereas change in self-esteem exerted a statistically significant effect on change in adjustment (β = .47, p < .001).

Conclusions/Implications for Practice:

Our findings indicate that BMI and self-esteem are key determinants of student adjustment in school settings. Therefore, future health education interventions should focus on enhancing the positive physical and mental self-concepts of students, which should improve health and social behavior among students and subsequently afford a better quality of life for these students in adulthood.
Atrial Fibrillation Is Not Associated With Thromboembolism in Left Ventricular Assist Device Patients: A Systematic Review and Meta-Analysis
Authors: Kittipibul Veraprapas , Rattanawong Pattara , Kewcharoen Jakrin , Chongsathidkiet Pakawat , Vutthikraivit Wasawat , Kanjanahattakij Napatt
Published: June 2018

Atrial fibrillation (AF) is a well-established risk factor of thromboembolism (TE). Thromboembolism is one of the most common complications in patients supported by continuous-flow left ventricular assisted devices (CF-LVADs). However, the association between AF and TE complications in this population is controversial. We conducted a systematic review and meta-analysis to assess the association between AF and overall TE, stroke, and device thrombosis events in CF-LVAD patients. We performed a comprehensive literature search through September 2017 in the databases of MEDLINE and EMBASE. Included studies were prospective or retrospective cohort studies that compared the risk of developing overall TE, stroke, and device thrombosis events in CF-LVAD patients with AF and those without AF. We calculated pooled risk ratio (RR) with 95% confidence intervals (CI) and I
2 statistic using the random-effects model. Eleven studies were included involving 6,351 patients who underwent CF-LVAD implantation. Overall, TE outcome was available in four studies involving 1,106 AF and 3,556 non-AF patients. Stroke outcome was available in seven studies (1,455 AF and 4,037 non-AF patients). Device thrombosis outcome was available in three studies (1,010 AF and 3,327 non-AF patients). There was no association between AF and TE events (RR = 0.95; 95% CI: 0.57–1.59, I
2 = 79%, p = 0.85), stroke (RR = 1.10; 95% CI: 0.74–1.64, I
2 = 73%, p = 0.65), and device thrombosis (RR = 0.97; 95% CI: 0.56–1.67, I
2 = 42%, p = 0.91). AF in CF-LVAD patients was not associated with overall TE, stroke, or device thrombosis events. These findings might be explained by the highly thrombogenic property of CF-LVADs that exceeds the thromboembolic risk driven by AF.
Comparison of Transcranial Motor Evoked Potential Amplitude Responses Between Intramuscular and Subcutaneous Needles in Proximal Thigh Muscle
Authors: Gonzalez Andres A. , Cheongsiatmoy Justin , Shilian Parastou , Parikh Pooja
Published: June 2018

Purpose:

Successful intraoperative neurophysiological monitoring is predicated on the presence of adequate baseline–evoked potentials. We have observed that transcranial motor evoked potentials (TcMEPs) yield more robust responses in the distal muscles compared with proximal muscles. One possible explanation is the distance from the needle to the muscle generator. In this study, we investigate whether TcMEP amplitudes from the rectus femoris muscle are affected by changes in needle length.

Methods:

We analyzed rectus femoris TcMEP responses in surgical patients undergoing lumbar spinal surgery. Needles of two different sizes were placed simultaneously. A shorter 13-mm subcutaneous needle was inserted into the rectus femoris muscle subcutaneous group in addition to a longer 25-mm intramuscular needle (intramuscular group). Each limb was used as an independent control. Transcranial motor evoked potential amplitude responses were obtained using both needles, and statistical analysis was calculated using the Wilcoxon signed-rank test for paired data. Secondary analysis was performed to correlate between TcMEP amplitude and skinfold thickness.

Results:

Twenty-eight TcMEP responses from the rectus femoris (14 patients) were analyzed. We observed that TcMEP amplitude responses were higher in the intramuscular needle group compared with the subcutaneous group (N = 28, P < 0.0001). There was a mean difference of 604 μV between the intramuscular versus subcutaneous group (median 184 μV). There was also a significant correlation between TcMEP amplitude and skinfold thickness.

Conclusions:

Higher TcMEP amplitude responses are seen with longer needles compared with shorter needles placed in the same rectus femoris muscle. Transcranial motor evoked potential baselines may be optimized using longer needles. Skinfold thickness can be a good marker to determine appropriate needle size.
Effect of Electroconvulsive Therapy on Medial Prefrontal γ-Aminobutyric Acid Among Schizophrenia Patients
Authors: Xia Mengqing , Wang Junjie , Sheng Jianhua , Tang Yingying , Li Chunyan , Lim Kelvin , He Bin , Li Chunbo , Xu Yifeng , Wang Jijun
Published: June 2018

Objective

Electroconvulsive therapy (ECT) has often been applied to augment antipsychotics for schizophrenia patients. However, the underpinning mechanism is still unclear. Previous studies of major depressive disorder reported an increase in γ-aminobutyric acid (GABA) after ECT. The present study investigated the effects of ECT on medial prefrontal GABA in schizophrenia using a proton magnetic resonance spectroscopy.

Methods

Inpatients fulfilling the diagnostic criteria for schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were assigned to 2 groups, ECT group (n = 14) receiving ECT plus antipsychotic drugs (APD) and drug group (n = 17) only receiving antipsychotic drugs. Medial prefrontal GABA+/Cr concentrations of all patients were measured with magnetic resonance spectroscopy at baseline and after 4-week treatment. Sex- and age-matched healthy comparisons (n = 19) were scanned at baseline.

Results

γ-Aminobutyric acid level did not show a significant difference among 3 groups. However, when 2 patient groups were combined, their GABA level was significantly lower than that in healthy comparisons group. For schizophrenia patients, repeated measures analysis of variance revealed that both the group effect and group × time interaction were insignificant, but the time effect of baseline versus after treatment was significant. Exploratory post hoc paired t test found a significant increase of GABA only in ECT group, but not in drug group. No correlation was found between GABA change and clinical symptom improvement in either group.

Conclusions

γ-Aminobutyric acid level in the medial prefrontal lobe was reduced in schizophrenia patients. An increase in GABA concentration in the medial prefrontal cortex is more significantly associated with ECT plus antipsychotics than antipsychotics alone, possibly supporting the hypothesis of ECT augmentation for GABA mediated neural inhibition.
In ovo
yolk carotenoid and testosterone levels interactively influence female transfer of yolk antioxidants to her eggs
Authors: Giraudeau Mathieu , Ziegler Ann-Kathrin , Mcgraw Kevin J. , Okuliarová Monika , Zeman Michal , Tschirren Barbara
Published: June 2018

Mothers can influence prenatal conditions by varying the amount of nutrients, hormones or antioxidants they provide to their developing young. Some of these substances even affect the transfer of these compounds in the next generation, but it is less clear how different maternally transmitted compounds interact with each other to shape reproductive resource allocation in their offspring. Here, we found that female Japanese quails (
Coturnix japonica
) that were exposed to high carotenoid levels during embryonic development transferred lower concentrations of yolk antioxidants to their own eggs later in life. This effect disappeared when both testosterone and carotenoid concentrations were manipulated simultaneously, showing long-term and interactive effects of these maternally derived egg components on a female's own egg composition. Given that exposure to high levels of testosterone during embryo development stimulates the production of reactive oxygen species (ROS) and impairs antioxidant defenses, we propose that carotenoids act as
in ovo
antioxidants in an oxidatively stressful environment (i.e. when levels of testosterone are high) but might have prooxidant properties in an environment where they are not used to counteract an increased production of ROS. In line with this hypothesis, we previously showed that prenatal exposure to increased concentrations of yolk carotenoids leads to a rise of oxidative damage at adulthood, but only when yolk testosterone concentrations were not experimentally increased as well. As a consequence, antioxidants in the body may be used to limit oxidative damage in females exposed to high levels of carotenoids during development (but not in females exposed to increased levels of both carotenoids and testosterone), resulting in lower amounts of antioxidants being available for deposition into eggs. Since prenatal antioxidant exposure is known to influence fitness-related traits, the effect detected in this study might have transgenerational consequences.
Evolution in caves: selection from darkness causes spinal deformities in teleost fishes
Authors: Torres-Dowdall Julián , Karagic Nidal , Plath Martin , Riesch Rüdiger
Published: June 2018

Only few fish species have successfully colonized subterranean habitats, but the underlying biological constraints associated with this are still poorly understood. Here, we investigated the influence of permanent darkness on spinal-column development in one species (Midas cichlid,Amphilophus citrinellus) with no known cave form, and one (Atlantic molly,Poecilia mexicana) with two phylogenetically young cave forms. Specifically, fish were reared under a normal light : dark cycle or in permanent darkness (both species). We also surveyed wild-caught cave and surface ecotypes ofP. mexicana. In both species, permanent darkness was associated with significantly higher rates of spinal deformities (especially inA. citrinellus). This suggests strong developmental (intrinsic) constraints on the successful colonization of subterranean environments in teleost fishes and might help explain the relative paucity of cave-adapted lineages. Our results add depth to our understanding of the aspects of selection driving trait divergence and maintaining reproductive isolation in cave faunas.
A universal growth limit for circular lichens
Authors: Seminara Agnese , Fritz Joerg , Brenner Michael P. , Pringle Anne
Published: June 2018

Lichens fix carbon dioxide from the air to build biomass. Crustose and foliose lichens grow as nearly flat, circular disks. Smaller individuals grow slowly, but with small, steady increases in radial growth rate over time. Larger individuals grow more quickly and with a roughly constant radial velocity maintained over the lifetime of the lichen. We translate the coffee drop effect to model lichen growth and demonstrate that growth patterns follow directly from the diffusion of carbon dioxide in the air around a lichen. When a lichen is small, carbon dioxide is fixed across its surface, and the entire thallus contributes to radial growth, but when a lichen is larger carbon dioxide is disproportionately fixed at the edges of an individual, which are the primary drivers of growth. Tests of the model against data suggest it provides an accurate, robust, and universal framework for understanding the growth dynamics of both large and small lichens in nature.
Understanding the ontogeny of foraging behaviour: insights from combining marine predator bio-logging with satellite-derived oceanography in hidden Markov models
Authors: Grecian W. James , Lane Jude V. , Michelot Théo , Wade Helen M. , Hamer Keith C.
Published: June 2018

The development of foraging strategies that enable juveniles to efficiently identify and exploit predictable habitat features is critical for survival and long-term fitness. In the marine environment, meso- and sub-mesoscale features such as oceanographic fronts offer a visible cue to enhanced foraging conditions, but how individuals learn to identify these features is a mystery. In this study, we investigate age-related differences in the fine-scale foraging behaviour of adult (aged ≥ 5 years) and immature (aged 2–4 years) northern gannetsMorus bassanus. Using high-resolution GPS-loggers, we reveal that adults have a much narrower foraging distribution than immature birds and much higher individual foraging site fidelity. By conditioning the transition probabilities of a hidden Markov model on satellite-derived measures of frontal activity, we then demonstrate that adults show a stronger response to frontal activity than immature birds, and are more likely to commence foraging behaviour as frontal intensity increases. Together, these results indicate that adult gannets are more proficient foragers than immatures, supporting the hypothesis that foraging specializations are learned during individual exploratory behaviour in early life. Such memory-based individual foraging strategies may also explain the extended period of immaturity observed in gannets and many other long-lived species.
Dynamic analysis of liquid annular seals with herringbone grooves on the rotor based on the perturbation method
Authors: Zhai Lulu , Zhenjie Zhang , Zhonghuang Chi , Jia Guo
Published: June 2018

Annular seals have significant effects on the hydraulic and rotordynamic performances of turbomachinery. In this paper, an analysis method for calculating the leakage flow rates and dynamic characteristics of liquid annular seals with herringbone grooves on the rotor is proposed and verified. Leakage flow rates and dynamic characteristics of the model seals under different operating conditions are theoretically analysed and compared with those of plain and spiral-grooved seals of the same size. In addition, the influence of geometric parameters such as spiral angle and the lengths of the constituent parts on the sealing and rotordynamic coefficients of seals with herringbone grooves are also discussed. The results show that seals with herringbone grooves have better sealing performance, while providing better support actions and damping characteristics than the other two seal types under the same operating conditions. The seal geometric parameters including spiral angle, the lengths of the constituent parts and the clearance value have a significant influence on the dynamic characteristics of seals with herringbone grooves.
Genome-based population structure analysis of the strawberry plant pathogen Xanthomonas fragariae reveals two distinct groups that evolved independently before its species description
Authors: Gétaz Michael , Krijger Marjon , Rezzonico Fabio , Smits Theo H. M. , van der Wolf Jan M. , Pothier Joël F.
Published: June 2018

Xanthomonas fragariae is a quarantine organism in Europe, causing angular leaf spots on strawberry plants. It is spreading worldwide in strawberry-producing regions due to import of plant material through trade and human activities. In order to resolve the population structure at the strain level, we have employed high-resolution molecular typing tools on a comprehensive strain collection representing global and temporal distribution of the pathogen. Clustered regularly interspaced short palindromic repeat regions (CRISPRs) and variable number of tandem repeats (VNTRs) were identified within the reference genome of X. fragariae LMG 25863 as a potential source of variation. Strains from our collection were whole-genome sequenced and used in order to identify variable spacers and repeats for discriminative purpose. CRISPR spacer analysis and multiple-locus VNTR analysis (MLVA) displayed a congruent population structure, in which two major groups and a total of four subgroups were revealed. The two main groups were genetically separated before the first X. fragariae isolate was described and are potentially responsible for the worldwide expansion of the bacterial disease. Three primer sets were designed for discriminating CRISPR-associated markers in order to streamline group determination of novel isolates. Overall, this study describes typing methods to discriminate strains and monitor the pathogen population structure, more especially in the view of a new outbreak of the pathogen.
Comparative genomics and phylogeny of sequenced IncHI plasmids
Authors: Álvarez Senén
Published: June 2018

Conjugative plasmids from the IncHI incompatibility group are relevant vectors for multidrug resistance. Is the objective of this article the screening of the phylogeny of the first 44 publicly available sequences of IncHI plasmids from Enterobacteriaceae (1961-2013), because since there, a few hundred were registered in Genebank. A comparison of the similarities and differences between them revealed extensive conservation of their coding sequences. However, each genome had accessory regions with features of degradation or resistance to antibacterial agents. This article elucidates the IncHI1, IncHI2 and IncHI3 subgroup plasmids from the evolutive line based on multiple drug-resistant modules, explains the origin of the IncHI1 pAKU1-like composite transposon lineage, typifies the subgroup IncHI3, which is distantly related to IncHI1 and IncHI2 in phylogenetic analyses, confirms the relations within the transfer regions of H-group plasmids, and points to the divergence time of evolution with phylogenetic trees. Homology between subgroups, as measured by the molecular clock test, indicated that the contemporary IncHI1 and IncHI2 transfer region lineages diverged from an ancestral clone approximately 8,000 years ago (17,000 years ago if the divergent IncHI3 plasmids are included), although the IncH backbone was older. The uniformity of the composite transposon shared by most IncHI1 subgroup plasmids might be functionally equivalent to the heavy metal resistance that is mediated by some operons in the IncHI2 subgroup plasmids. A comparison of the DNA among these closely related plasmids provided insights on the horizontal and vertical transfers that were involved in their development.
Genome-wide association study reveals sex-specific genetic architecture of facial attractiveness
Authors: Hu Bowen , Shen Ning , Li James J. , Kang Hyunseung , Hong Jinkuk , Fletcher Jason , Greenberg Jan , Mailick Marsha R. , Lu Qiongshi
Published: June 2018

Facial attractiveness is a complex human trait of great interest in both academia and industry. Literature on sociological and phenotypic factors associated with facial attractiveness is rich, but its genetic basis is poorly understood. In this paper, we conducted a genome-wide association study to discover genetic variants associated with facial attractiveness using 3,928 samples in the Wisconsin Longitudinal Study. We identified two genome-wide significant loci and highlighted a handful of candidate genes, many of which are specifically expressed in human tissues involved in reproduction and hormone synthesis. Additionally, facial attractiveness showed strong and negative genetic correlations with BMI in females and with blood lipids in males. Our analysis also suggested sex-specific selection pressure on variants associated with lower male attractiveness. These results revealed sex-specific genetic architecture of facial attractiveness and provided fundamental new insights into its genetic basis.
Longitudinal data reveal strong genetic and weak non-genetic components of ethnicity-dependent blood DNA methylation levels
Authors: McKennan Chris , Naughton Katherine , Stanhope Catherine , Kattan Meyer , O’Connor George T. , Sandel Megan T. , Visness Cynthia M. , Wood Robert A. , Bacharier Leonard B. , Beigelman Avraham , Lovinsky-Desir Stephanie , Togias Alkis , Gern James E. , Nicolae Dan , Ober Carole
Published: June 2018

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results not only indicate that race-associated DNAm patterns in blood are present at birth and are primarily genetically, and not environmentally, determined, but also that DNAm in blood cells overall is robust to many environmental exposures during the first 7 years of life.
A conformational change in the N terminus of SLC38A9 signals mTORC1 activation
Authors: Jinming Ma , Lei Hsiang-Ting , Gonen Tamir
Published: June 2018

mTORC1 is a central signal hub that integrates multiple environmental cues, such as cellular stresses, energy levels, nutrients and certain amino acids, to modulate metabolic status and cellular responses. Recently, SLC38A9, a lysosomal amino acid transporter, has emerged as a sensor for luminal arginine levels and as an activator of mTOCRC1. The activation of mTORC1 occurs through the N-terminal domain of SLC38A9. Here, we determined the crystal structure of SLC38A9 and surprisingly found its N-terminal fragment inserted deep into the transporter, bound in the substrate binding pocket where normally arginine would bind. Compared with our recent arginine bound structure of SLC38A9, a significant conformational change of the N-terminal domain was observed. A ball-and-chain model is proposed for mTORC1 activation where in the starved state the N-terminal domain of SLC38A9 is buried deep in the transporter but in the fed state the N-terminal domain could be released becoming free to bind the Rag GTPase complex and to activate mTORC1. This work provides important new insights into how SLC38A9 senses the fed state and activates the mTORC1 pathways in response to dietary amino acids.

One Sentence Summary

N-plug inserted state of SLC38A9 reveals mechanisms of mTORC1 activation and arginine-enhanced luminal amino acids efflux.
Structural Basis of Tubulin Recruitment and Assembly by Tumor Overexpressed Gene (TOG) domain array Microtubule Polymerases
Authors: Nithianantham Stanley , Cook Brian D , Chang Fred , Al-Bassam Jawdat
Published: June 2018

XMAP215/Stu2/Alp14 proteins accelerate microtubule plus-end polymerization by recruiting tubulins via arrays of Tumor Overexpressed Gene (TOG) domains. The underlying mechanism of these arrays as microtubule polymerases remains unknown. Here, we describe the biochemical and structural basis for TOG domain arrays in recruiting and polymerizing tubulins. Alp14 binds four tubulins via dimeric TOG1-TOG2 arrays, each with distinct exchange rates. X-ray structures reveal pseudo-dimeric square-shaped assemblies in which four TOG domains position four unpolymerized tubulins in a polarized wheel-like configuration. Crosslinking confirms square assemblies form in solution, and inactivation of their interfaces destabilizes square organizations without influencing tubulin binding. Using an approach to modulate tubulin polymerization, we determined a X-ray structure showing an unfurled assembly in which TOG1 and TOG2 uniquely bind two polymerized tubulins. Our findings suggest a new microtubule polymerase model in which TOG arrays recruit tubulins by forming square assemblies, which then unfurl facilitating their concerted polymerization into protofilaments.
Human Connectome Project resting state fMRI data organized into 60 fine-scaled retinotopically organized regions in cortical areas V1, V2 and V3
Authors: Dawson Debra Ann , Yin Zixuan , Lam Jack , Shmuel Amir
Published: June 2018

The data comprises 60 regions of interest (ROIs) from V1, V2, and V3 of the human visual cortex. Preprocessed data from the Human Connectome Project (HCP) 900 subjects public data release were utilized: 220 subjects were randomly selected, each with 4 scans of resting state fMRI data. Given that these subjects did not have retinotopy scans performed, the visual areas were defined using an anatomical template from Benson et al. (2014). Visual areas from each hemisphere were further divided along dorsal-ventral lines into quadrants, resulting in 4 quadrants per subject. Within each quadrant, fine scaled ROIs were defined by subdividing each visual area into 5 regions according to eccentricity. These data may be useful for studying retinotopically organized functional connectivity in the visual cortex using the HCP 3 Tesla dataset.
Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities
Authors: Fadason Tayaza , Schierding William , Lumley Thomas , O’Sullivan Justin M.
Published: June 2018

Clinical studies of non-communicable diseases identify multimorbidities that reflect our relatively limited fixed metabolic capacity. Despite the fact that we have ∼24000 genes, we do not understand the genetic pathways that contribute to the development of multimorbid non-communicable disease. We created a “multimorbidity atlas” of traits based on pleiotropy of spatially regulated genes using convex biclustering. Using chromatin interaction and expression Quantitative Trait Loci (eQTL) data, we analysed 20,782 variants (p < 5 × 10−6) associated with 1,351 phenotypes, to identify 16,248 putative eQTL-eGene pairs that are involved in 76,013 short- and long-range regulatory interactions (FDR < 0.05) in different human tissues. Convex biclustering of eGenes that are shared between phenotypes identified complex inter-relationships between nominally different phenotype associated SNPs. Notably, the loci at the centre of these inter-relationships were subject to complex tissue and disease specific regulatory effects. The largest cluster, 40 phenotypes that are related to fat and lipid metabolism, inflammatory disorders, and cancers, is centred on the FADS1-FADS3 locus (chromosome 11). Our novel approach enables the simultaneous elucidation of variant interactions with genes that are drivers of multimorbidity and those that contribute to unique phenotype associated characteristics.
3D Reconstruction of Bird Flight Trajectories Using a Single Video Camera
Authors: Srinivasan M.V. , Vo H.D. , Schiffner I.
Published: June 2018

Video cameras are finding increasing use in the study and analysis of bird flight over short ranges. However, reconstruction of flight trajectories in three dimensions typically requires the use of multiple cameras and elaborate calibration procedures. We present an alternative approach that uses a single video camera and a simple calibration procedure for the reconstruction of such trajectories. The technique combines prior knowledge of the wingspan of the bird with a camera calibration procedure that needs to be used only once in the lifetime of the system. The system delivers the exact 3D coordinates of the position of the bird at the time of every full wing extension and uses interpolated height estimates to compute the 3D positions of the bird in the video frames between successive wing extensions. The system is inexpensive, compact and portable, and can be easily deployed in the laboratory as well as the field.
Blocking the alternative sigma factor RpoN reduces virulence ofPseudomonas aeruginosaisolated from cystic fibrosis patients and increases antibiotic sensitivity in a laboratory strain
Authors: Lloyd MG , Vossler JL , Nomura CT , Moffat JF
Published: June 2018

Multidrug-resistant organisms (MDROs) are increasing in the health care setting, and there are few antimicrobial agents available to treat infections caused by these bacteria.Pseudomonas aeruginosais an opportunistic pathogen in burn patients and individuals with cystic fibrosis (CF), and a leading cause of nosocomial infections.P. aeruginosais inherently resistant to many antibiotics and can develop or acquire resistance to others, limiting options for treatment.P. aeruginosahas virulence factors that are regulated by sigma factors in response to the tissue microenvironment. The alternative sigma factor, RpoN (σ54), regulates many virulence genes and is linked to antibiotic resistance. Recently, we described a cis-acting peptide, RpoN*, which acts as a “molecular roadblock”, binding RpoN consensus promoters at the −24 site and blocking transcription. RpoN* reduces virulence ofP. aeruginosalaboratory strains bothin vitroandin vivo,but its effects in clinical isolates was not known. We investigated the effects of RpoN* on phenotypically variedP. aeruginosastrains isolated from cystic fibrosis patients. RpoN* expression reduced motility, biofilm formation, and pathogenesis in aP. aeruginosa – C. elegansinfection model. RpoN* expression increased susceptibility to several beta-lactam based antibiotics in the lab strainP. aeruginosaPA19660Xen5. Here, we show that using a cis-acting peptide to block RpoN consensus promoters has potential clinical implications in reducing virulence and enhancing the activity of antibiotics.
The probiotic effectiveness in experimental colitis is correlated with gut microbiome and host genetic features
Authors: Suwal Sharmila , Wu Qiong , Liu Wenli , Liu Qingya , Sun Hongxiang , Liang Ming , Gao Jing , Zhang Bo , Kou Yanbo , Liu Zhuanzhuan , Wei Yanxia , Wang Yugang , Zheng Kuiyang
Published: June 2018

Current evidence to support extensive use of probiotics in inflammatory bowel disease is limited and factors contribute to the inconsistent effectiveness of clinical probiotic therapy are not completely known. Here, as a proof-of-concept, we utilized Bifidobacterium longum JDM 301, a widely used commercial probiotic strain in China, to study potential factors that may influence the beneficial effect of probiotics in experimental colitis. We found that the probiotic therapeutic effect was varied across individual mouse even with the same genetic background and consuming the same type of food. The different probiotic efficacy was highly correlated with different microbiome features in each mouse. Consumption of a diet rich in fat can change the host sensitivity to mucosal injury-induced colitis but did not change the host responsiveness to probiotic therapy. Finally, the host genetic factor TLR2 was required for a therapeutic effect of B. longum JDM 301. Together, our results suggest that personalized microbiome and genetic features may modify the probiotic therapeutic effect.
Regulation of EGFR endocytosis by CBL during mitosis
Authors: Wee Ping , Wang Zhixiang
Published: June 2018

Endocytosis plays important roles in regulating EGFR signaling. We previously found that EGFR endocytosis during mitosis is mediated differently than during interphase. While the regulation of EGFR endocytosis in interphase is well understood, little is known regarding the regulation of EGFR endocytosis during mitosis. Here, we studied the mechanisms regulating mitotic EGFR endocytosis. We found that contrary to interphase cells, mitotic EGFR endocytosis is more reliant on the activation of the E3 ligase CBL. At high EGF doses, inhibition of inhibited EGFR endocytosis of mitotic cells, but not of interphase cells. Moreover, the endocytosis of mutant EGFR Y1045F-YFP was strongly delayed. The endocytosis of truncated EGFR Δ1044-YFP that does not bind to CBL was completely inhibited. EGF induced stronger ubiquitination of mitotic EGFR than interphase EGFR and mitotic EGFR is trafficked to lysosome for degradation. Furthermore, during mitosis low doses of EGF also stimulate EGFR endocytosis by NCE. Contrary to interphase, CBL and the CBL-binding regions of EGFR were required for mitotic EGFR endocytosis at low doses. This may be due to the mitotic ubiquitination of the EGFR even at low EGF doses. In conclusion, mitotic EGFR endocytosis solely proceed through CBL-mediated NCE.
The fungal-specific Hda2 and Hda3 proteins regulate morphological switches in the human fungal pathogenCandida albicans
Authors: Peterson Misty R. , Price Robert Jordan , Gourlay Sarah , May Alisha , Tullet Jennifer , Buscaino Alessia
Published: June 2018

The human fungal pathogenCandida albicansis responsible for millions of infections annually. Due to the few available anti-fungal drugs and the increasing incidence of drug resistance, the number ofC. albicansinfections is dramatically increasing. Morphological switches, such as the white-opaque switch and the yeast-hyphae switch, are key for the development ofC. albicanspathogenic traits. Lysine deacetylases are emerging as important regulators of morphological switches. Yet, targeting lysine deacetylases for drug development is problematic due to the high homology between the fungal and human proteins that could result in toxicity. Here we provide evidence that the fungal specific proteins Hda2 and Hda3 interact with the lysine deacetylase Hda1. By combining phenotypic analyses with genome-wide transcriptome analyses, we demonstrate that Hda2 and Hda3 controlC. albicansmorphological switches. Under nutrient-rich conditions, deletion ofHDA2orHDA3leads to moderate overexpression of the master regulator of white-opaque switchingWOR1and increase switching frequency. Under hyphae inducing conditions, deletion ofHDA2andHDA3block hyphae development. However, deletion ofHDA2andHDA3does not affect hyphae-formation and virulencein vivo. We propose that Hda2 and Hda3 are good targets for the development of anti-fungal drugs to be used in combination therapy.
“Small and many” is the strategy for robust and efficient information transfer in dendritic spines
Authors: Tottori Takehiro S. , Fujii Masashi , Kuroda Shinya
Published: June 2018

A dendritic spine is a small structure on the dendrites of a neuron that processes input timing information from other neurons. Tens of thousands of spines are present on a neuron. Why are spines so small and many? Because of the small number of molecules in the spine volume, biochemical reactions become stochastic. Therefore, we used the stochastic simulation model of N-methyl-D-aspartate receptor (NMDAR)-mediated Ca2+ increase to address this issue. NMDAR-mediated Ca2+ increase codes the input timing information between prespiking and postspiking. We examined how much the input timing information is encoded by Ca2+ increase against prespiking fluctuation. We found that the input timing information encoded in the spine volume (10-1 μm3) is more robust against prespiking fluctuation than that in the cell volume (103 μm3). We further examined the mechanism of the robust information transfer in the spine volume. We demonstrated that the necessary and sufficient condition for robustness is that the stochastic NMDAR-mediated Ca2+ increase (intrinsic noise) becomes much larger than the prespiking fluctuation (extrinsic noise). The condition is satisfied in the spine volume, but not in the cell volume. Moreover, we compared the information transfer in many small “spine-volume” spines with that in a single large “cell-volume” spine. We found that many small “spine-volume” spines is much more efficient for information transfer than a single large “cell-volume” spine when prespiking fluctuation is large. Thus, robustness and efficiency are two functional reasons why dendritic spines are so small and many.

Significance

A dendritic spine is a small platform for information processing in a neuron, and tens of thousands of spines are present on a neuron. Why are spines so small and many? Here we addressed this issue using stochastic simulation of NMDAR-mediated Ca2+ increase in a spine. We demonstrated that smallness of a spine enables the robust information transfer against input fluctuation, and that many small spines are much efficient for information transfer than a single large cell. This is the first demonstration that shows the advantage of the “small and many” of spines in information processing. The “small and many” strategy may be used not only in spines of a neuron, but also in other small and many intracellular organelles.
ER shaping proteins regulate mitochondrial fission, outer membrane permeabilization and apoptosis
Authors: Milani Mateus , Cohen Gerald M , Varadarajan Shankar
Published: June 2018

The mitochondrial fission machinery, comprising a dynamin-related GTPase, DRP-1, is crucial for the regulation of mitochondrial membrane dynamics. Recent reports suggest that the tubular architecture of the endoplasmic reticulum (ER) marks the constriction sites on the mitochondria to facilitate DRP-1-mediated mitochondrial fission. However, the role of several ER shaping proteins that maintain the elaborate network of tubes and sheets in mitochondrial constriction and fission is not yet known. In this report, we demonstrate that modulation of the expression levels of key ER shaping proteins, namely Reticulon1 (RTN-1), Reticulon 4 (RTN-4), Lunapark-1 (LNP-1) and CLIMP-63, markedly decreased the extent of mitochondrial fission mediated by BH3 mimetics, despite no detectable changes in DRP-1 recruitment to the mitochondria. Furthermore, modulation of ER shaping proteins significantly decreased other hallmarks of apoptosis, such as mitochondrial outer membrane permeabilization, caspase activation and phosphatidylserine externalization, and functioned independently of mitochondrial cristae remodeling, thus demonstrating a requirement of ER shaping proteins and ER structural integrity for the efficient execution of the instrinsic apoptotic pathway.
Effects of sublethal concentrations and application concentration of SYP-9625 on Tetranychus cinnabarinus (Boisduval) and its natural enemy, Neoseiulus californicus (McGregor)
Authors: Ouyang Jingqi , Tian Yajing , Jiang Chunxian , Yang Qunfang , Wang Haijian , Li Qing
Published: June 2018

Objective

Exploring the effects of acaricides on predatory mites is crucial for the combination of biological and chemical control of pests. In this study, sublethal effects of the new acaricide SYP-9625 on Tetranychus cinnabarinus (Boisduval), effects of application concentration of SYP-9625 on the predatory mite Neoseiulus californicus (McGregor) and functional responses of N. californicus were assessed. The aim of the present study was to evaluate and explore the application of new acaricide SYP-9625 with natural enemy N. californicus.

Method

All the experiments were under laboratory conditions [25 ± 1 °C, 16:8 (L:D) h and 75 ± 5% RH] and based on an age-stage, two-sex life table. The sublethal concentrations against T. cinnabarinus, including LC10 (0.375 μg/mL) and LC30 (0.841 μg/mL) and the application concentration (100 μg/mL) of SYP-9625, were used to evaluate effects on population parameters of N. californicus.

Result

T. cinnabarinus females treated with LC30 exhibited significantly reduced net reproductive rates (R0=11.02) of offspring compared to females treated with LC10 (R0=14.96) and untreated females (>R0=32.74). However, the intrinsic rate of increase (rm) and finite rate of increase (λ) of N. californicus indicated that the application concentration of SYP-9625 had no significant negative effect on treated N. californicus eggs (rm=0.277, λ=1.319) compared to the control (rm=0.292, λ=1.338). Additionally, the sublethal concentrations against T. cinnabarinus including LC10 and LC30 showed a dose-dependent mechanism on the predatory mite. SYP-9625 also stimulated the predatory capacity of N. californicus against immobile stages such as eggs and larvae.

Conclusion

It is demonstrated that sublethal concentrations of SYP-9625 can inhibit population growth of T. cinnabarinus. And the sublethal concentrations and application concentration had little effect on the population growth of N. californicus. The two advantages showed great commercial potential of this new acaricide. Therefore, N. californicus can manage T. cinnabarinus populations effectively with appropriate SYP-9625 concentrations.
Assessment of self stigma and medication adherence among patients with mental illness who had been treated at Jimma University Specialized Hospital, South west Ethiopia: community based cross sectional study, 2017
Authors: Golja Eba Abdisa , Girma Shimelis
Published: June 2018

Background

self Stigma associated with psychiatric disorders and its treatment toward patients with mental illness is the main challengers for early and successful treatment outcome.

Objective

To assess the association between self stigma and level of medication adherence among patients with mental illness who have been treated at psychiatric clinic, JUSH, South West Ethiopia, 2017.

Methods

This study is a community based cross sectional study design using a case tracing method to identify patients in the community. To get the study subject, tracing method was carried to get the patients who had history of treatment at psychiatric clinic, Jimma University Teaching Hospital. Interview based Questionnaire was used to get information from the participants. The relationship was checked by doing both bivariate and multi variables linear regression.

Result

Of the total respondents, males were185 (61.7%), females 115 (38.3%), and the mean age of the respondents was 34.99 (SD=11.51) years. From the total (n=300) respondents, more than half of them, 182 (60.7%) were adherent to their psychotropic medication. Among adherent respondents, of all types of stigma, minimal stigma was 63.2% whereas moderate to high stigma was 22.4%.

Conclusion

It was identified that there was high self stigma related to medication non adherent among patients with mental illness. Therefore, mental health professionals and the health care policy shall work to increase the level of psychotropic medication adherence so as to decrease self stigma associated with mental illness.
Software-aided workflow for predicting protease-specific cleavage sites using physicochemical properties of the natural and unnatural amino acids in peptide-based drug discovery: Peptide cleavage sites prediction workflow
Authors: Radchenko Tatiana , Fontaine Fabien , Morettoni Luca , Zamora Ismael
Published: June 2018

Peptide drugs have been used in the treatment of multiple pathologies. During peptide discovery, it is crucially important to be able to map the potential sites of cleavages of the proteases. This knowledge is used to later chemically modify the peptide drug to adapt it for the therapeutic use, making peptide stable against individual proteases or in complex medias. In some other cases it needed to make it specifically unstable for some proteases, as peptides could be used as a system to target delivery drugs on specific tissues or cells. The information about proteases, their sites of cleavages and substrates are widely spread across publications and collected in databases such as MEROPS. Therefore, it is possible to develop models to improve the understanding of the potential peptide drug proteolysis. We propose a new workflow to derive protease specificity rules and predict the potential scissile bonds in peptides for individual proteases. WebMetabase stores the information from experimental or external sources in a chemically aware database where each peptide and site of cleavage is represented as a sequence of structural blocks connected by amide bonds and characterized by its physicochemical properties described by Volsurf descriptors. Thus, this methodology could be applied in the case of non-standard amino acid. A frequency analysis can be performed in WebMetabase to discover the most frequent cleavage sites. These results were used to train several models using logistic regression, support vector machine and ensemble tree classifiers to map cleavage sites for several human proteases from four different families (serine, cysteine, aspartic and matrix metalloproteases). Finally, we compared the predictive performance of the developed models with other available public tools PROSPERous and SitePrediction.