bluuebunny/crossref_metadata_2025 huggingface dataset:
Marker-assisted selection of trees withMALE STERALITY 1inCryptomeria japonicaD. Don
Authors: Moriguchi Yoshinari , Ueno Saneyoshi , Hasegawa Yoichi , Tadama Takumi , Watanabe Masahiro , Saito Ryunosuke , Hirayama Satoko , Iwai Junji , Konno Yukinori
Published: May 2020

Practical use of marker-assisted selection (MAS) is limited in conifers because of the difficulty with developing markers due to a rapid decrease in linkage disequilibrium, the limited genomic information available, and the diverse genetic backgrounds among breeding material collections. First, in this study, two families were produced by artificial crossing between two male-sterile trees, Shindai11 and Shindai12, and a plus tree, Suzu-2 (Ms1/ms1) (S11-S and S12-S families, respectively). The segregation ratio between male-sterile and male-fertile trees did not deviate significantly from the expected 1:1 ratio in either family. These results clearly suggested that the male-sterile gene of Shindai11 and Shindai12 isMALE STERALITY 1(MS1). Because some markers reported previously have not been linkage mapped, we constructed a partial linkage map of the region encompassingMS1using the S11-S and S12-S families. For the S11-S and S12-S families, 19 and 18 markers were mapped onto the partial linkage maps ofMS1region, respectively. There was collinearity (conserved gene order) between the two partial linkage maps. Two markers (CJt020762_ms1-1and reCj19250_2335) were mapped to the same position as theMS1locus on both maps. Of these markers, we used CJt020762 for MAS in this study. According to the MAS results for 650 trees from six prefectures of Japan (603 trees from breeding materials and 47 trees from the Ishinomaki natural population), five trees in Niigata Prefecture and one tree in Yamagata Prefecture had heterozygousms1-1, and three trees in Miyagi Prefecture had heterozygousms1-2. The results obtained in this study suggested that there may be geographical hotspots for thems1-1andms1-2alleles. Because MAS can be used effectively to reduce the labor and time required for selection of trees with a male-sterile gene, the number of breeding materials should increase in the future.
A multiplexed, automated evolution pipeline enables scalable discovery and characterization of biosensors
Authors: Townshend Brent , Xiang Joy , Manzanarez Gabriel , Hayden Eric , Smolke Christina
Published: May 2020

Biosensors are key components in engineered biological systems, providing a means of measuring and acting upon the large biochemical space in living cells. However, generating small molecule sensing elements and integrating them intoin vivobiosensors have been challenging. Using aptamer-coupled ribozyme libraries and a novel ribozyme regeneration method, we developedde novorapidin vitroevolution of RNA biosensors (DRIVER) that enables multiplexed discovery of biosensors. With DRIVER and high-throughput characterization (CleaveSeq) fully automated on liquid-handling systems, we identified and validated biosensors against six small molecules, including five for which no aptamers were previously found. DRIVER-evolved biosensors were applied directly to regulate gene expression in yeast, displaying activation ratios up to 33-fold. DRIVER biosensors were also applied in detecting metabolite production from a multi-enzyme biosynthetic pathway. This work demonstrates DRIVER as a scalable pipeline for engineeringde novobiosensors with wide-ranging applications in biomanufacturing, diagnostics, therapeutics, and synthetic biology.
Axon morphology is modulated by the local environment and impacts the non-invasive investigation of its structure-function relationship
Authors: Andersson Mariam , Kjer Hans Martin , Rafael-Patino Jonathan , Pacureanu Alexandra , Pakkenberg Bente , Thiran Jean-Philippe , Ptito Maurice , Bech Martin , Dahl Anders Bjorholm , Dahl Vedrana Andersen , Dyrby Tim B.
Published: May 2020

Axonal conduction velocity, which ensures efficient function of the brain network, is related to axon diameter. Non-invasive, in vivo axon diameter estimates can be made with diffusion magnetic resonance imaging, but the technique requires 3D validation. Here, high resolution, 3D synchrotron X-ray Nano-Holotomography images of white matter samples from the corpus callosum of a monkey brain reveal that blood vessels, cells and vacuoles affect axonal diameter and trajectory. Within single axons, we find that the variance in diameter and conduction velocity correlates with the mean diameter, contesting the value of precise diameter determination in larger axons. These complex 3D axon morphologies drive previously reported 2D trends in axon diameter and g-ratio. Furthermore, we find that these morphologies bias the estimates of axon diameter with diffusion magnetic resonance imaging and, ultimately, impact the investigation and formulation of the axon structure-function relationship.
HSP90 facilitates oncogenic alterations of metabolism in B-cell lymphomas
Authors: Calvo-Vidal M. Nieves , Zamponi Nahuel , Krumsiek Jan , Stockslager Max A. , Revuelta Maria V. , Phillip Jude M. , Marullo Rossella , Kotlov Nikita , Patel Jayeshkumar , Yang Shao Ning , Yang Lucy , Taldone Tony , Thieblemont Catherine , Leonard John P. , Martin Peter , Inghirami Giorgio , Chiosis Gabriela , Manalis Scott R. , Cerchietti Leandro
Published: May 2020

HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here, we described a novel role of HSP90 in the cytosolic compartmentalization of metabolic pathways in proliferating cancer cells. We found that HSP90 assists in the organization of metabolic enzymes into non-membrane-bound functional compartments termed metabosomes. Under experimental conditions that conserved the cellular proteostasis, we demonstrated that the compartmentalizing activity of HSP90 is critical to sustain the coordinated synthesis of multiple metabolites required for energy production, maintenance of the cellular biomass and secretion of immunometabolites. Conversely, inhibition of the nucleating capacity of HSP90 modified the topology of cytosolic metabosomes before protein degradation was apparent decreasing the efficiency of MYC-driven metabolic pathways. Inhibition of HSP90 decreases cancer metabolism in B-cell lymphoma cells and patients providing a novel mechanism of activity for this class of drugs.
Complement factor C1q mediates chronic neuron loss and inflammation post-brain injury
Authors: Holden Stephanie S , Aboubakr Oumaima , Higashikubo Bryan , Cho Frances S , Chang Andrew H , Morningstar Allison , Mathur Vidhu , Kuhn Logan J , Suri Poojan , Sankaranarayanan Sethu , Andrews-Zwilling Yaisa , Aronica Eleonora , Yednock Ted , Paz Jeanne T
Published: May 2020

While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of cortical injury that does not directly damage subcortical structures, we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with altered cortical rhythms. Blocking C1q counteracted most of these outcomes, suggesting that C1q is a disease modifier in TBI. Since the corticothalamic circuit is important for sensory processing, attention, cognition, and sleep, all of which can be impaired by TBI, this circuit could be a new target for treating TBI-related disabilities.
Conserved Roles for Receptor Tyrosine Kinase Extracellular Regions in Regulating Receptor and Pathway Activity
Authors: Gonzalez-Magaldi Monica , McCabe Jacqueline M. , Cartwright Haley N. , Sun Ningze , Leahy Daniel J.
Published: May 2020

Receptor Tyrosine Kinases (RTKs) comprise a diverse group of cell-surface receptors that mediate key signaling events during animal development and are frequently activated in cancer. Ligand-induced dimerization is the canonical mechanism by which RTKs are thought to be activated. We show here that deletion of the extracellular regions of 10 RTKs representing 7 RTK classes or their substitution with the dimeric immunoglobulin Fc region results in constitutive receptor phosphorylation but fails to result in phosphorylation of downstream signaling effectors Erk or Akt. Conversely, substitution of RTK extracellular regions with the extracellular region of the Epidermal Growth Factor Receptor (EGFR) results in increases in Erk and/or Akt phosphorylation in response to EGF. These results indicate that the activation signal generated by the EGFR extracellular region is capable of activating at least 7 different RTK classes. Failure of phosphorylated Fc-RTK chimeras to stimulate phosphorylation of downstream effectors indicates that either dimerization and receptor phosphorylationper seare insufficient to activate signaling or constitutive dimerization leads to pathway inhibition.
Switching On Static Gene Regulatory Networks to Compute Cellular Decisions
Authors: Pavillet Clara E. , Voukantsis Dimitrios , Buffa Francesca M.
Published: May 2020

Motivation

Gene networks are complex sets of regulators and interactions that govern cellular processes. Their perturbations can disrupt regular biological functions, translating into a change in cell behaviour and ability to respond to internal and external cues. Computational models of these networks can boost translation of our scientific knowledge into medical applications by predicting how cells will behave in health and disease, or respond to stimuli such as a drug treatment. The development of such models requires effective ways to read, manipulate and analyse the increasing amount of existing, and newly deposited gene network data.

Results

We developed BioSWITCH, a command-line program using the BioPAX standardised language to “switch on” static regulatory networks so that they can be executed in GINML to predict cellular behaviour. Using a previously published haematopoiesis gene network, we show that BioSWITCH successfully and faithfully automates the network de-coding and re-coding into an executable logical network. BioSWITCH also supports the integration of a BioPAX model into an existing GINML graph.

Availability

Source code available athttps://github.com/CBigOxf/BioSWITCH.

Contact

clara.pavillet@msdtc.ox.ac.uk;francesca.buffa@oncology.ox.ac.uk
Identifying drug response by combining measurements of the membrane potential, the cytosolic calcium concentration, and the extracellular potential in microphysiological systems
Authors: Jæger Karoline Horgmo , Charwat Verena , Wall Sam , Healy Kevin E. , Tveito Aslak
Published: May 2020

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a new means to study and understand the human cardiac action potential, and can give key insight into how compounds may interact with important molecular pathways to destabilize the electrical function of the heart. Important features of the action potential can be readily measured using standard experimental techniques, such as the use of voltage sensitive dyes and fluorescent genetic reporters to estimate transmembrane potentials and cytosolic calcium concentrations. Using previously introduced computational procedures, such measurements can be used to estimate the current density of major ion channels present in hiPSC-CMs, and how compounds may alter their behavior. However, due to the limitations of optical recordings, resolving the sodium current remains difficult from these data. Here we show that if these optical measurements are complemented with observations of the extracellular potential using multi electrode arrays (MEAs), we can accurately estimate the current density of the sodium channels. This inversion of the sodium current relies on observation of the conduction velocity which turns out to be straightforwardly computed using measurements of extracellular waves across the electrodes. The combined data including the membrane potential, the cytosolic calcium concentration and the extracellular potential further opens up for the possibility of accurately estimating the effect of novel drugs applied to hiPSC-CMs.
Gray and white matter morphology in substance use disorders: A neuroimaging systematic review and meta-analysis
Authors: Pando-Naude Victor , Toxto Sebastian , Fernandez-Lozano Sofia , Parsons E. Christine , Alcauter Sarael , Garza-Villarreal Eduardo A.
Published: May 2020

Substance use disorders (SUDs) are characterized by a compulsion to seek and consume one or more substances of abuse, with a perceived loss of control and negative emotional state. Repeated use of a substance results in synaptic and morphological changes, secondary to toxicity and SUD pathology in the dopamine striato-thalamo-cortical and limbic pathways. These neuroadaptations seem to vary between studies, which could be related to divergent effects of substances, consumption severity or other unknown factors. We therefore identified studies investigating the effects of SUDs using volumetric whole-brain voxel-based morphometry (VBM) in gray (GM) and white matter (WM). We performed a systematic review and meta-analysis of VBM studies using the anatomic likelihood estimation (ALE) method implemented in GingerALE (PROSPERO pre-registrationCRD42017071222). Fifty studies met inclusion criteria and were included in the final quantitative meta-analysis, with a total of 538 foci, 88 experiments and 4370 participants. We found convergence and divergence in brain regions and volume effects (higher vs lower volume) in GM and WM depending on the severity of consumption pattern and type of substance. Convergent pathology was evident across substances in GM of the insula, anterior cingulate cortex, putamen, and thalamus, and in WM of the thalamic radiation and internal capsule bundle. Divergent pathology between occasional use (cortical pathology) and addiction (cortical-subcortical pathology) provides evidence of a possible top-down neuroadaptation. Our findings indicate distinctive brain morphometry alterations in SUDs, which may inform our understanding of disease progression and ultimately therapeutic approaches.
The genome sequence ofAloe verareveals adaptive evolution of drought tolerance mechanisms
Authors: Jaiswal Shubham K. , Chakraborty Abhisek , Mahajan Shruti , Kumar Sudhir , Sharma Vineet K.
Published: May 2020

Aloe verais a species from Asphodelaceae plant family having unique characteristics such as drought resistance and also possesses numerous medicinal properties. However, the genetic basis of these phenotypes is yet unknown, primarily due to the unavailability of its genome sequence. In this study, we report the firstAloe veradraft genome sequence comprising of 13.83 Gbp and harboring 86,177 coding genes. It is also the first genome from the Asphodelaceae plant family and is the largest angiosperm genome sequenced and assembled till date. Further, we report the first genome-wide phylogeny of monocots withAloe verausing 1,440 one-to-one orthologs that resolves the genome-wide phylogenetic position ofAloe verawith respect to the other monocots. The comprehensive comparative analysis ofAloe veragenome with the other available high-quality monocot genomes revealed adaptive evolution in several genes of the drought stress response, CAM pathway, and circadian rhythm inAloe vera. Further, genes involved in DNA damage response, a key pathway in several biotic and abiotic stress response mechanisms, were found to be positively selected. This provides the genetic basis of the evolution of drought stress tolerance capabilities ofAloe vera. This also substantiates the previously suggested notion that the evolution of unique characters in this species is perhaps due to selection and adaptive evolution rather than the phylogenetic divergence or isolation.
Population studies of the wild tomato species Solanum chilense reveal geographically structured major gene-mediated pathogen resistance
Authors: Kahlon Parvinderdeep S. , Seta Shallet Mindih , Zander Gesche , Scheikl Daniela , Hückelhoven Ralph , Joosten Matthieu H. A. J. , Stam Remco
Published: May 2020

Natural plant populations encounter strong pathogen pressure and defense-associated genes are known to be under different selection pressure dependent on the pressure by the pathogens. Here we use wild tomato Solanum chilense populations to investigate natural resistance against Cladosporium fulvum, a well-known pathogenic fungus of domesticated tomatoes. We show that populations of S. chilense differ in resistance against the pathogen. Next, we explored the underlying molecular processes in a species wide-context. Then, focusing on recognition of the two prominent avirulence factors secreted by C. fulvum (Avr4 and Avr9) in central and northern populations of S. chilense we observed high complexity in the cognate homologues of Cladosporium resistance (Hcr9) locus underlying the recognition of these effectors. Presence of canonical genomic regions coding for Cf-4 and Cf-9, two major dominant resistance genes in the Hcr9 locus recognizing Avr4 and Avr9, respectively, does not meet prediction from Avr response phenotypes. We find both genes in varying fractions of the plant populations and we show possible co-existence of two functionally active resistance genes, previously thought to be allelic. Additionally, we observed the complete local absence of recognition of additional Avr proteins of C. fulvum. In the southern populations we attribute this to changes in the coregulatory network. As a result of loss of pathogen pressure or adaptation to extreme climatic conditions. This may ultimately explain the observed pathogen susceptibility in the southern populations. This work puts major gene mediated disease resistance in an ecological context.
In vivocontactless brain stimulation via non-invasive and targeted delivery of magnetoelectric nanoparticles
Authors: Nguyen Tyler , Gao Jianhua , Wang Ping , Nagesetti Abhignyan , Andrews Peter , Masood Sehban , Vriesmann Zoe , Liang Ping , Khizroev Sakhrat , Jin Xiaoming
Published: May 2020

Non-invasive brain stimulation is valuable for studying neural circuits and treating various neurological disorders in humans. However, the current technologies usually have low spatial and temporal precision and poor brain penetration, which greatly limit their application. A new class of nanoparticles known as magneto-electric nanoparticles (MENs) can be navigated to a targeted brain region with a magnetic field and is highly efficient in converting an externally applied magnetic wave into local electric fields for neuronal activity modulation. Here we developed a new method to fabricate MENs of CoFe2O4-BaTiO3core-shell structure that had excellent magneto-electrical coupling properties. Using calcium imaging of organotypic and acute cortical slices from GCaMP6s transgenic mice, we demonstrated their efficacy in reliably evoking neuronal responses with a short latency period. Forin vivonon-invasive delivery of MENs to brain, fluorescently labeled MENs were intravenously injected and guided to pass through the blood brain barrier to a targeted brain region by applying a magnetic field gradient. A magnetic field (∼450 Oe at 10 Hz) applied to mouse brain was able to reliably evoke cortical activities, as revealed byin vivotwo-photon and mesoscopic imaging of calcium signals at both cellular and global network levels. The effect was further confirmed by the increased number of c-Fos expressing cells after stimulation. Neither brain delivery of MENs nor the subsequent magnetic stimulation caused any significant increases in the numbers of GFAP and IBA1 positive astrocytes and microglia in the brain. This study demonstrates the feasibility of using MENs as a novel efficient and non-invasive technique of contactless deep brain stimulation that may have great potential for translation.
Telomere length is highly heritable and independent of growth rate manipulated by temperature in field crickets
Authors: Boonekamp Jelle , Rodríguez-Muñoz Rolando , Hopwood Paul , Zuidersma Erica , Mulder Ellis , Wilson Alastair , Verhulst Simon , Tregenza Tom
Published: May 2020

Many organisms are capable of growing faster than they do. Restrained growth rate has functionally been explained by negative effects on lifespan of accelerated growth. However, the underlying mechanisms remain elusive. Telomere attrition has been proposed as a causal agent and has been studied in endothermic vertebrates. We established that telomeres exist as chromosomal-ends in a model insect, the field cricket, using terminal restriction fragment andBal 31methods. Telomeres comprised TTAGGn repeats of 38kb on average, more than four times longer than the telomeres of human infants.Bal 31assays confirmed that telomeric repeats were located at the chromosome-ends. We tested whether rapid growth is achieved at the expense of telomere length by comparing crickets reared at 23°C with their siblings reared at 28°C, which grew three times faster. Surprisingly, neither temperature treatment nor age affected average telomere length. Concomitantly, the broad sense heritability of telomere length was remarkably high at ~100%. Despite high heritability, the evolvability (a mean standardized measure of genetic variance) was low relative to that of body mass. We discuss the different interpretations of these scaling methods in the context of telomere evolution. It is clear that some important features of vertebrate telomere biology are evident in an insect species dating back to the Triassic, but also that there are some striking differences. The apparent lack of an effect of growth rate and the total number of cell divisions on telomere length is puzzling, suggesting that telomere length could be actively maintained during the growth phase. Whether such maintenance of telomere length is adaptive remains elusive and requires further study investigating the links with fitness in the wild.
Light-induced difference FTIR spectroscopy of primate blue-sensitive visual pigment at 163 K
Authors: Hanai Shunpei , Katayama Kota , Imai Hiroo , Kandori Hideki
Published: May 2020

Structural studies of color visual pigments lag far behind those of rhodopsin for scotopic vision. Using difference FTIR spectroscopy at 77 K, we report the first structural data of three primate color visual pigments, monkey red (MR), green (MG), and blue (MB), where the batho-intermediate (Batho) exhibits photoequilibrium with the unphotolyzed state. This photochromic property is highly advantageous for limited samples since the signal-to-noise ratio is improved, but may not be applicable to late intermediates, because of large structural changes to proteins. Here we report the photochromic property of MB at 163 K, where the BL intermediate, formed by the relaxation of Batho, is in photoequilibrium with the initial MB state. A comparison of the difference FTIR spectra at 77 and 163 K provided information on what happens in the process of transition from Batho to BL in MB. The coupled C11=C12HOOP vibration in the planer structure in MB is decoupled by distortion in Batho after retinal photoisomerization, but returns to the coupled C11=C12HOOP vibration in theall-transchromophore in BL. This suggests that BL harbors a planer all-transconfiguration of retinal. The Batho formation accompanies helical structural perturbation, which is relaxed in BL. The H-D unexchangeable X-H stretch weakens the hydrogen bond in Batho, but strengthens it in BL. Protein-bound water molecules that form an extended water cluster near the retinal chromophore change hydrogen bonds differently for Batho and BL, being stronger in the latter than in the initial state. In addition to structural dynamics, the present FTIR spectra at 163 K show no signals of protonated carboxylic acids as well as 77 K, suggesting that E181 is deprotonated in MB, Batho and BL.
Childhood conduct problems are associated with reduced white matter fibre density and morphology
Authors: Burley Daniel T. , Genc Sila , Silk Timothy J.
Published: May 2020

Childhood conduct problems are an important public health issue as these children are at-risk of adverse outcomes. Studies using diffusion Magnetic Resonance Imaging (dMRI) have found that conduct problems in adults are characterised by abnormal white-matter microstructure within a range of white matter pathways underpinning socio-emotional processing, while evidence within children and adolescents has been less conclusive based on non-specific diffusion tensor imaging metrics. Fixel-based analysis (FBA) provides measures of fibre density and morphology that are more sensitive to developmental changes in white matter microstructure. The current study used FBA to investigate whether childhood conduct problems were related both cross-sectionally and longitudinally to microstructural alterations within the fornix, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and the uncinate fasciculus (UF). dMRI data was obtained for 130 children across two time-points in a community sample with high levels of externalising difficulties (age: time-point 1 = 9.47 – 11.86 years, time-point 2 = 10.67 −13.45 years). Conduct problems were indexed at each time-point using the Conduct Problems subscale of the parent-informant Strengths and Difficulties Questionnaire (SDQ). Conduct problems were related to lower fibre density in the fornix at both time-points, and in the ILF at time-point 2. We also observed lower fibre cross-section in the UF at time-point 1. The change in conduct problems did not predict longitudinal changes in white-matter microstructure across time-points. The current study suggests that childhood conduct problems are related to reduced fibre-specific microstructure within white matter fibre pathways implicated in socio-emotional functioning.
A transcriptome based aging clock near the theoretical limit of accuracy
Authors: Meyer David H. , Schumacher Björn
Published: May 2020

Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such asCaenorhabditis elegansand it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization ofC. eleganstranscriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this transcriptome clock can also be applied to human age prediction with high accuracy. This transcriptome aging clock could therefore find wide application in genetic, environmental and therapeutic interventions in the aging process.
Unique retinal binding pocket of primate blue-sensitive visual pigment
Authors: Nonaka Yuki , Hanai Shunpei , Katayama Kota , Imai Hiroo , Kandori Hideki
Published: May 2020

The visual pigments of humans contain 11-cisretinal as the chromophore of light perception, and its photoisomerization to the all-transform initiates visual excitation in our eyes. It is well known that three isomeric states of retinal (11-cis, all-trans, and 9-cis) are in photoequilibrium at very low temperatures such as 77 K. Here we report the lack of formation of the 9-cisform in monkey blue (MB) at 77 K, as revealed by light-induced difference FTIR spectroscopy. This indicates that the chromophore binding pocket of MB does not accommodate the 9-cisform, even though it accommodates the all-transform by twisting the chromophore. Mutation of the blue-specific tyrosine at position 265 into tryptophan, which is highly conserved in other animal rhodopsins, led to formation of the 9-cisform in MB, suggesting that Y265 is one of the determinants of the unique photochemistry in blue pigments. We also found that 9-cisretinal does not bind to MB opsin, implying that the chromophore binding pocket does not accommodate the 9-cisform at physiological temperature. The unique property of MB is discussed based on the present results.
Validation of a smartphone embedded inertial measurement unit for measuring postural stability in older adults
Authors: De Groote Friedl , Vandevyvere Stefanie , Vanhevel Florian , Orban de Xivry Jean-Jacques
Published: May 2020

Background

Identifying older adults with increased fall risk due to poor postural control on a large scale is only possible through omnipresent and low cost measuring devices such as the inertial measurement units (IMU) embedded in smartphones. However, the correlation between smartphone measures of postural stability and state-of-the-art force plate measures has never been assessed in a large sample allowing us to take into account age as a covariate.

Research question

How reliably can postural stability be measured with a smartphone embedded IMU in comparison to a force plate?

Methods

We assessed balance in 97 adults aged 50 to 90 years in four different conditions (eyes open, eyes closed, semi-tandem and dual-task) in the anterio-posterior and medio-lateral directions. We used six different parameters (root mean square and average absolute value of COP displacement, velocity and acceleration) for the force plate and two different parameters (root mean square and average absolute value of COM acceleration) for the smartphone.

Results

Test-retest reliability was smaller for the smartphone than for the force plate (intra class correlation) but both devices could equally well detect differences between conditions (similar Cohen’s d). Parameters from the smartphone and the force plate, with age regressed out, were moderately correlated (robust correlation coefficients of around 0.5).

Significance

This study comprehensively documents test-retest reliability and effect sizes for stability measures obtained with a force plate and smartphone as well as correlations between force plate and smartphone measures based on a large sample of older adults. Our large sample size allowed us to reliably determine the strength of the correlations between force plate and smartphone measures. The most important practical implication of our results is that more repetitions or longer trials are required when using a smartphone instead of a force plate to assess balance.

Highlights

We compared balance measures simultaneously obtained from a phone and a force plate

For precision purposes, we included a large group of older participants (N=97).

Using age as covariate, we found a moderate correlation across the two devices.

Intra-class correlation coefficients were smaller for the smartphone.

Balance assessment with smartphones requires longer trials compared to force plates.
Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk geneCacna1c
Authors: Tigaret Cezar M. , Lin Tzu-Ching E. , Morrell Edward , Sykes Lucy , O’Donovan Michael C. , Owen Michael J. , Wilkinson Lawrence S. , Jones Matthew W. , Thomas Kerrie L. , Hall Jeremy
Published: May 2020

Genetic variation inCACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of alteredCacna1cdosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous forCacna1charbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+signaling in dendritic spines and decreased signaling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioral and synaptic plasticity deficits inCacna1c+/-rats. These results map a route through which genetic variation inCACNA1Ccan disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder.

One Sentence Summary

Neurotrophin receptor activation reveals that BDNF mimetic drugs have therapeutic potential to ameliorate genetic risk for psychiatric disorders.
Quantitative live-cell PALM reveals nanoscopic Faa4 redistributions and dynamics on lipid droplets during metabolic transitions of yeast
Authors: Adhikari Santosh , Moscatelli Joe , Puchner Elias M.
Published: May 2020

Lipid droplets (LDs) are dynamic lipid storage organelles needed for lipid homeostasis. Cells respond to metabolic changes by regulating the spatial distribution of LDs, as well as enzymes required for LD growth and turnover. Due to LD size below the optical diffraction limit, bulk fluorescence microscopy cannot observe the density and dynamics of specific LD enzymes. Here, we employ quantitative photo-activated localization microscopy (PALM) to study the density of the fatty acid activating protein Faa4 on LDs during log, stationary and lag phases in live yeast cells with single-molecule sensitivity and 30 nm resolution. During the log phase LDs co-localize with the Endoplasmic Reticulum (ER) where the highest Faa4 densities are measured. During transition to the stationary phase LDs translocate to the vacuolar surface and lumen with a ~2-fold increased surface area and a ~2.5-fold increase in Faa4 density, suggesting its role in LD expansion. The increased Faa4 density on LDs is caused by its ~5-fold increased expression level. When lipolysis is induced in stationary-phase cells by diluting them for 2 hrs in fresh medium, Faa4 shuttles to the vacuole through the two observed routes of ER- and lipophagy. The observed vacuolar localization of Faa4 may help activating fatty acids for membrane expansion and reduces Faa4 expression to levels found in the log phase.
Obesity phenotypes are preserved in intestinal stem cell enteroids from morbidly obese patients
Authors: Hasan Nesrin M. , Johnson Kelli F. , Yin Jianyi , Baetz Nicholas W. , Sherman Vadim , Blutt Sarah E. , Estes Mary K. , Kumbhari Vivek , Zachos Nicholas C. , Kovbasnjuk Olga
Published: May 2020

Obesity and obesity-related comorbidities are significant health care challenges. Bariatric surgery (BS) is the most effective therapy for treating obesity and type 2 diabetes. A barrier in the development of therapeutic alternatives is incomplete mechanistic understanding of the benefits of BS and the lack of human intestinal models that recapitulate the pathophysiology of obesity. Using adult intestinal stem cell-derived enteroid cultures established from healthy lean subjects and morbidly obese patients, including post-BS cases, four phenotypes correlating patient BMI and intestinal glucose absorption were identified suggesting that enteroids retain patient phenotype heterogeneity associated with healthy and diseased state. In a sub-population of obese patients, increased dietary glucose absorption and gluconeogenesis was due to significantly higher expression of intestinal carbohydrate transporters (SGLT1, GLUT2 and GLUT5) and gluconeogenic enzymes (PEPCK1 and G6Pase) compared to enteroids from lean subjects that demonstrated low glucose absorption and lacked gluconeogenesis. Enteroids established from successful BS cases exhibited low glucose absorption similar to that observed in lean subjects. These data show that human enteroids preserve the patient phenotype in long-term cultures and represent a reliable preclinical model to study the heterogeneity of the obesity mechanisms, which is necessary to determine the efficacy of therapeutic interventions.
Investigations of dimethylglycine (DMG), glycine betaine and ectoine uptake by a BCCT family transporter with broad substrate specificity inVibriospecies
Authors: Gregory Gwendolyn J. , Dutta Anirudha , Parashar Vijay , Boyd E. Fidelma
Published: May 2020

Fluctuations in osmolarity are one of the most prevalent stresses to which bacteria must adapt, both hypo- and hyper-osmotic conditions. Most bacteria cope with high osmolarity by accumulating compatible solutes (osmolytes) in the cytoplasm to maintain the turgor pressure of the cell.Vibrio parahaemolyticus, a halophile, utilizes at least six compatible solute transporters for the uptake of osmolytes: two ABC family ProU transporters and four betaine-carnitine-choline transporter (BCCT) family transporters. The full range of compatible solutes transported by this species has yet to be determined. Using an osmolyte phenotypic microarray plate for growth analyses, we expanded known osmolytes used byV. parahaemolyticusto include N-N dimethylglycine (DMG) amongst others. We showed thatV. parahaemolyticusrequires a BCCT transporter for DMG uptake, carriers that were not known to transport DMG. Growth pattern analysis of four triple-bccTmutants, possessing only one functional BCCT, indicated that BccT1 (VP1456), BccT2 (VP1723), and BccT3 (VP1905) transported DMG, which was confirmed by functional complementation inE. colistrain MKH13. BccT1 was unusual in that it could uptake both compounds with methylated head groups (glycine betaine (GB), choline and DMG) and cyclic compounds (ectoine and proline). Bioinformatics analysis identified the four coordinating residues for glycine betaine in BccT1.In silicomodelling analysis demonstrated that glycine betaine, DMG, and ectoine docked in the same binding pocket in BccT1. Using site-directed mutagenesis, we showed that a strain with all four resides mutated resulted in loss of uptake of glycine betaine, DMG and ectoine. We showed three of the four residues were essential for ectoine uptake whereas only one of the residues was essential for glycine betaine uptake. Overall, we have demonstrated that DMG is a highly effective compatible solute forVibriospecies and have elucidated the amino acid residues in BccT1 that are important for coordination of glycine betaine, DMG and ectoine transport.

Importance

Vibrio parahaemolyticuspossesses at least six osmolyte transporters, which allow the bacterium to adapt to high salinity conditions. In this study, we identified several novel osmolytes that are utilized byV. parahaemolyticus. We demonstrated that the compound dimethylglycine (DMG), which is abundant in the marine environment, is a highly effective osmolyte forVibriospecies. We determined that DMG is transported via BCCT-family carriers, which have not been shown previously to uptake this compound. BccT1 was a carrier for glycine betaine, DMG and ectoine and we identified the amino acid residues essential for coordination of these compounds. The data suggest that for BccT1, glycine betaine is more easily accommodated than ectoine in the transporter binding pocket.
animalcules: Interactive Microbiome Analytics and Visualization in R
Authors: Zhao Yue , Federico Anthony , Faits Tyler , Manimaran Solaiappan , Monti Stefano , Johnson W. Evan
Published: May 2020

Background

Microbial communities that live in and on the human body play a vital role in health and disease. Recent advances in sequencing technologies have enabled the study of microbial communities at unprecedented resolution. However, these advances in data generation have presented novel challenges to researchers attempting to analyze and visualize these data.

Results

To address some of these challenges, we have developedanimalcules, an easy-to-use interactive microbiome analysis toolkit for 16S rRNA sequencing data, shotgun DNA metagenomics data, and RNA-based metatranscriptomics profiling data. This toolkit combines novel and existing analytics, visualization methods, and machine learning models. For example, traditional microbiome analyses such as alpha/beta diversity and differential abundance analysis are enhanced in the toolkit, while new methods such as biomarker identification are introduced. Powerful interactive and dynamic figures generated byanimalculesenable users to understand their data and discover new insights.animalculescan be used as a standalone command-line R package or users can explore their data with the accompanying interactive R Shiny interface.

Conclusions

We presentanimalcules, an R package for interactive microbiome analysis through either an interactive interface facilitated by R Shiny or various command-line functions. It is the first microbiome analysis toolkit that supports the analysis of all 16S rRNA, DNA-based shotgun metagenomics, and RNA-sequencing based metatranscriptomics datasets.animalculescan be freely downloaded from GitHub athttps://github.com/compbiomed/animalculesor installed through Bioconductor athttps://www.bioconductor.org/packages/release/bioc/html/animalcules.html.
CryoEM map ofPseudomonas aeruginosaPilQ enables structural characterization of TsaP
Authors: McCallum Matthew , Tammam Stephanie , Rubinstein John L. , Burrows Lori L. , Howell P. Lynne
Published: May 2020

The type IV pilus machinery is a multi-protein complex that polymerizes and depolymerizes a pilus fibre used for attachment, twitching motility, phage adsorption, natural competence, protein secretion, and surface-sensing. An outer membrane secretin pore is required for passage of the pilus fibre out of the cell. Herein, the structure of the tetradecameric secretin, PilQ, from thePseudomonas aeruginosatype IVa pilus system was determined to 4.3 Å and 4.4 Å resolution in the presence and absence of C7symmetric spokes, respectively. The heptameric spokes were found to be the two tandem C-terminal domains of TsaP. TsaP forms a belt around PilQ and while the protein is not essential for twitching motility, over-expression of TsaP triggers a signal cascade upstream of PilY1 leading to cyclic di-GMP up-regulation. These results resolve the identity of the spokes identified with Proteobacterial PilQ homologs and may reveal a new component of the surface-sensing cyclic di-GMP signal cascade.

IMPACT STATEMENT

The type IV pilus is critical for bacterial virulence. The co-structure of the pilus secretin PilQ and TsaP is determined. Characterization of TsaP implicates it in surface-sensing signal transduction.
Coordinated evolution between N2 neuraminidase and H1 and H3 hemagglutinin genes increased influenza A virus genetic diversity in swine
Authors: Zeller Michael A. , Chang Jennifer , Vincent Amy L. , Gauger Phillip C. , Anderson Tavis K.
Published: May 2020

Abstract

The neuraminidase (NA) and hemagglutinin (HA) of influenza A virus (IAV) are essential surface glycoproteins. In this study, the evolution of subtype N2 NA paired with H1 and H3 subtype HA in swine was evaluated to understand if genetic diversity of HA and NA were linked. Using time-scaled Bayesian phylodynamic analyses, the relationships of paired swine N2 with H1 or H3 from 2009 to 2018 were evaluated. These data demonstrated increased relative genetic diversity within the major N2 clades circulating in swine (N2.1998 between 2014-2017 and N2.2002 between 2010-2016). Relative genetic diversity of NA-HA pairs (e.g., N2.1998B/ H1.Delta1B) were correlated, suggesting intergene epistasis. Preferential pairing was observed among specific NA and HA genetic clades and this was associated with gene reassortment between cocirculating influenza A strains. Using the phylogenetic topology of inferred N2 trees, the expansion of genetic diversity in the NA gene was quantified and increases in diversity were observed subsequent to NA-HA reassortment events. The rate of evolution among NA-N2 clades and HA-H1 and HA-H3 clades were similar. The frequent regional movement of pigs and their influenza viruses is a possible explanation driving this pattern of drift, reassortment, and rapid evolution. Bayesian phylodynamic analyses demonstrated strong spatial patterns in N2 genetic diversity, and that frequent interstate movement of N2 clades homogenized diversity. The reassortment and evolution of NA and its influence on HA evolution may affect antigenic drift, impacting vaccine control programs and animal health.
Lynx1 modulates the activity of nAChRs to slow NMJ and muscle fiber degeneration during aging
Authors: Doss Sydney V. , Barbat-Artigas Sébastien , Myers Tracey , Pradhan Bhola Shankar , Prószyński Tomasz J. , Robitaille Richard , Valdez Gregorio
Published: May 2020

The authors have withdrawn their manuscript to revisit some of the data, interpretations and conclusions. Therefore, the authors do not wish this work to be cited as a reference. If you have any questions, please contact the corresponding author.
Dynamic cerebellar network organization across the human menstrual cycle
Authors: Fitzgerald Morgan , Pritschet Laura , Santander Tyler , Grafton Scott T. , Jacobs Emily G.
Published: May 2020

The cerebellum contains the vast majority of neurons in the brain and houses distinct functional networks that constitute at least two homotopic maps of the cerebrum. While the functional organization of the human cerebellum has been characterized, the influence of sex steroid hormones on intrinsic cerebellar network dynamics has yet to be established. Here, we investigated the extent to which endogenous fluctuations in estradiol and progesterone alter functional cerebellar networks at rest in a woman densely sampled over a complete menstrual cycle (30 consecutive days). Edgewise regression analysis revealed negative associations between sex hormones and cerebellar coherence, with progesterone showing more pronounced negative associations relative to estradiol. Graph theory metrics probed sex hormones’ influence on topological brain states, revealing relationships between sex hormones and intra- and inter-network integration in Ventral Attention, Dorsal Attention, and Somato-Motor Networks. Together, these results suggest that the intrinsic dynamics of the cerebellum are intimately tied to day-by-day changes in sex hormones.