bluuebunny/crossref_metadata_2025 huggingface dataset:
Small-form-factor LED-based light application surface for indocyanine green-mediated antibacterial photothermal therapy
Authors: Nikinmaa Sakari , Moilanen Niina , Sorsa Timo , Rantala Juha , Alapulli Heikki , Kotiranta Anja , Auvinen Petri , Kankuri Esko , Meurman Jukka , Pätilä Tommi
Published: September 2020

We present here a small-form-factor LED-based antimicrobial photothermal therapy (aPTT) applicator surface, and its clinical feasibility as well as efficacy for administration of indocyanine green (ICG)-assisted aPTT to the dental plaque.

Fifteen healthy adults were assigned to this four-day randomized study. After rinsing with ICG, 100J/cm2 of 810 nm light was applied to the aPTT-treatment area. Plaque area and gingival crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) were measured, and plaque bacteriomes before and after the study were analyzed using 16S rRNA sequencing.

aPTT administration was preformed successfully and plaque-specifically with the applicator surface. Total plaque area and endpoint MMP-8 levels were reduced on the aPTT-treatment side. aPTT reduced Streptococcus, Acinetobacteria, Capnocytophaga, and Rothia bacteria species in plaques. The applicator surface is feasible for aPTT self-administration, targets therapy to dental plaque, reduces plaque forming bacteria and exerts anti-inflammatory and –proteolytic effects.
Why women choose abortion through telemedicine outside the formal health sector in Germany? A mixed-methods study
Authors: Killinger Kristina , Günther Sophie , Atay Hazal , Gomperts Rebecca , Endler Margit
Published: September 2020

Introduction

In April 2019 the abortion telemedicine service Women on Web (WoW) opened their helpdesk to Germany and saw a progressive rise in consultations. Our aim was to understand the motivations, and perceived barriers to access, for women who choose telemedicine abortion outside the formal health sector in Germany.

Methods

We conducted a parallel convergent mixed-methods study among 1090 women in Germany, who requested medical abortion through WoW between January 1st and December 31st, 2019. We performed a cross-sectional study of data contained in online consultations and a content analysis of 108 email texts. Analysis was done until saturation; results were merged, and triangulation was used to validate results.

Results

Frequent reported reasons for choosing telemedicine abortion in the consultation forms were “I need to keep the abortion a secret from my partner or family” (48%) and “I would rather keep my abortion private” (48%). The content analysis developed two main themes and seven subsidiary categories: 1) internal motivations for seeking telemedicine abortion encompassing i) autonomy, ii) perception of external threat, iii) shame and stigma, and 2) external barriers to formal abortion care, encompassing: (iv) financial stress, v) logistic barriers to access vi) provider attitudes, and vii) vulnerability of foreigners). The findings in the quantitative and qualitative analysis were consistent.

Conclusion

Women in Germany who choose telemedicine abortion outside the formal health sector do so both from a place of empowerment and a place of disempowerment. Numerous barriers to abortion access exist in the formal sector which are of special relevance to vulnerable groups such as adolescents and undocumented immigrants.

Key message points

When Women on Web, an abortion telemedicine service operating outside the formal health care sector, opened in Germany in April 2019, 1205 women consulted the service in the first nine months.

Women who choose telemedicine abortion do so both from a position of empowerment, for reasons of autonomy, and from a position of disempowerment and lack of autonomy.

Numerous barriers to abortion access, as permitted by German law exist in the formal health sector, which may most impact vulnerable groups such as adolescents, women with low financial means, and undocumented immigrants.
The impact of COVID-19 restriction measures on loneliness among older adults in Austria
Authors: Stolz Erwin , Mayerl Hannes , Freidl Wolfgang
Published: September 2020

Background

To halt the spread of COVID-19, Austria implemented a 7-week ‘shut-down’ of public life in March/April 2020 which was followed by a gradual withdrawal of these restriction measures in May/June 2020. We expect that the ensuing reduction in social contacts led to increased loneliness among older adults (60+).

Methods

We conducted three analyses to assess the association between COVID-19 public health restriction measures and loneliness: (1) A comparison between pre-pandemic (SHARE: 2013–2017) and pandemic (May 2020) levels of loneliness (UCLA-3 scale), (2) an analysis of the correlation between being affected by COVID-19 restriction measures and loneliness based on cross-sectional survey data from early May 2020, and (3) a longitudinal analysis of weekly changes in loneliness (Corona panel data) from late March to early June 2020.

Results

We found (1) loneliness levels to have increased in 2020 in comparison with previous years, (2) an association between the number of restriction measures older adults reported to be affected from and loneliness, and (3) that loneliness was higher during ‘shut-down’ compared to the subsequent re-opening phase, particularly among those who live alone.

Discussion

Our results provide evidence that COVID-19 restriction measures in Austria have indeed resulted in increased levels of loneliness among older adults. However, these effects seem to be short-lived, and thus we do not expect strong negative consequences for older adults’ mental health downstream. Nonetheless, effects of longer and/or repeated future restriction measures aiming at social distancing should be closely monitored.
Prevention of EAE by PEGylated Antigenic Peptides
Authors: Pfeil Jennifer , Simonetti Mario , Lauer Uta , von Thülen Bianca , Durek Pawel , Poulsen Christina , Pawlowska Justyna , Kröger Matthias , Krähmer Ralf , Leenders Frank , Hoffmann Ute , Hamann Alf
Published: September 2020

The treatment of autoimmune disorders such as multiple sclerosis (MS) so far relies largely on the use of non-specific immunosuppressive drugs, which are not able to cure the disease. Presently, approaches to induce antigen-specific tolerance e.g. by peptide-based tolerogenic “inverse” vaccines regain interest. We previously have shown that coupling of peptides to carriers can enhance their capacity to induce regulatory T cellsin vivo. We here investigated in an experimental autoimmune encephalomyelitis (EAE) model for chronic MS (MOG C57BL/6) whether the tolerogenic potential of immunodominant myelin T cell epitopes can be improved by conjugation to the synthetic carrier polyethylene glycol (PEG). Indeed, preventive administration of the PEGylated antigenic peptide could almost completely protect mice from EAE development, which was accompanied by reduced immune cell infiltration in the central nervous system (CNS). Depletion of Tregs abrogated the protective effect indicating that Tregs play a crucial role in induction of antigen-specific tolerance in EAE. Treatment during the acute phase was safe and did not induce immune activation. However, treatment at the peak of disease was not affecting the disease course, suggesting that either induction of Tregs is not occurring in the highly inflamed situation, or that the immune system is refractory to regulation in this condition. Thus, PEGylation of antigenic peptides is an effective and feasible strategy to improve tolerogenic (Treg-inducing) peptide-based vaccines, but application in overt disease might require modifications or combination therapies that simultaneously suppress effector mechanisms.
MorphOT: Transport-based interpolation between EM maps with UCSF ChimeraX
Authors: Ecoffet Arthur , Poitevin Frédéric , Dao Duc Khanh
Published: September 2020

Motivation

Cryogenic Electron-Microscopy offers the unique potential to capture conformational heterogeneity, by solving multiple 3D classes that co-exist within a single cryo-EM image dataset. To investigate the extent and implications of such heterogeneity, we propose to use an optimal-transport based metric to interpolate barycenters between EM maps and produce morphing trajectories. While standard linear interpolation mostly fails to produce realistic transitions, our method yields continuous trajectories that displace densities to morph one map into the other, instead of blending them.

Implementation

Our method is implemented as a plug-in forChimeraXcalledMorphOT, which allows the use of both CPU or GPU resources. The code is publicly available on GitHub (https://github.com/kdd-ubc/MorphOT.git), with documentation containing tutorial and datasets.

Contact

kdd@math.ubc.ca
Leaf form diversification in an heirloom tomato results from alterations in two differentHOMEOBOXgenes
Authors: Nakayama Hokuto , Rowland Steven D. , Cheng Zizhang , Zumstein Kristina , Kang Julie , Kondo Yohei , Sinha Neelima R.
Published: September 2020

Domesticated plants and animals display tremendous diversity in various phenotypic traits and often this diversity is seen within the same species. Tomato (Solanum lycopersicum; Solanaceae) cultivars show wide variation in leaf morphology, but the influence of breeding efforts in sculpting this diversity is not known. Here, we demonstrate that a single nucleotide deletion in the homeobox motif ofBIPINNATA, which is aBEL-LIKE HOMEODOMAINgene, led to a highly complex leaf phenotype in an heirloom tomato, Silvery Fir Tree (SiFT). Additionally, a comparative gene network analysis revealed that reduced expression of the ortholog ofWUSCHEL RELATED HOMEOBOX 1is also important for the narrow leaflet phenotype seen in SiFT. Phylogenetic and comparative genome analysis using whole-genome sequencing data suggests that thebipmutation in SiFT is likely ade novomutation, instead of standing genetic variation. These results provide new insights into natural variation in phenotypic traits introduced into crops during improvement processes after domestication.
Direct contribution of skeletal muscle mesenchymal progenitors to bone repair
Authors: Anais Julien , Anuya Kanagalingam , Jérome Megret , Marine Luka , Mickaël Ménager , Frédéric Relaix , Céline Colnot
Published: September 2020

Tissue regeneration relies on the activation of tissue resident stem cells concomitant with a transient fibrous tissue deposition to allow functional tissue recovery. Bone regeneration involves skeletal stem/progenitors from periosteum and bone marrow, the formation of a fibrous callus followed by the deposition of cartilage and bone to consolidate the fracture. Here, we show that mesenchymal progenitors residing in skeletal muscle adjacent to the bone fracture play a crucial role in mediating the initial fibrotic response to bone injury and also participate in cartilage and bone formation in the fracture callus. Combined lineage and scRNAseq analyses reveal that skeletal muscle mesenchymal progenitors adopt a fibrogenic fate before they engage in a chondrogenic fate after fracture. In polytrauma, where bone and skeletal muscle are injured, skeletal muscle mesenchymal progenitors fail to undergo fibrogenesis and chondrogenesis. This leads to impaired healing and persistent callus fibrosis originating from skeletal muscle. Thus, essential bone-muscle interactions govern bone regeneration through the direct contribution of skeletal muscle as a source of mesenchymal progenitors driving the fibrotic response and fibrotic remodeling, and supporting cartilage and bone formation.
Sensitivity to Envelope Interaural Time Difference: Models of Diverse LSO Neurons
Authors: Brughera Andrew , Ballestero Jimena A. , McAlpine David
Published: September 2020

A potential auditory spatial cue, the envelope interaural time difference (ITDENV) is encoded in the lateral superior olive (LSO) of the brainstem. Here, we explore computationally modeled LSO neurons, in reflecting behavioral sensitivity to ITDENV. Transposed tones (half-wave rectified low-frequency tones, frequency-limited, then multiplying a high-frequency carrier) stimulate a bilateral auditory-periphery model driving each model LSO neuron, where electrical membrane impedance low-pass filters the inputs driven by amplitude-modulated sound, limiting the upper modulation rate for ITDENVsensitivity. Just-noticeable differences in ITDENVfor model LSO neuronal populations, each distinct to reflect the LSO range in membrane frequency response, collectively reproduce the largest variation in ITDENVsensitivity across human listeners. At each stimulus carrier frequency (4-10 kHz) and modulation rate (32-800 Hz), the top-performing model population generally reflects top-range human performance. Model neurons of each speed are the top performers for a particular range of modulation rate. Off-frequency listening extends model ITDENVsensitivity above 500-Hz modulation, as sensitivity decreases with increasing modulation rate. With increasing carrier frequency, the combination of decreased top membrane speed and decreased number of model neurons capture decreasing human sensitivity to ITDENV.
Integrative approaches to improve the informativeness of deep learning models for human complex diseases
Authors: Dey Kushal K. , Kim Samuel S. , Gazal Steven , Nasser Joseph , Engreitz Jesse M. , Price Alkes L.
Published: September 2020

Deep learning models have achieved great success in predicting genome-wide regulatory effects from DNA sequence, but recent work has reported that SNP annotations derived from these predictions contribute limited unique information for human complex disease. Here, we explore three integrative approaches to improve the disease informativeness of allelic-effect annotations (predicted difference between reference and variant alleles) constructed using several previously trained deep learning models: DeepSEA, Basenji and DeepBind (and a related machine learning model, deltaSVM). First, we employ gradient boosting to learn optimal combinations of deep learning annotations, using fine-mapped SNPs and matched control SNPs (on held-out chromosomes) for training. Second, we improve the specificity of these annotations by restricting them to SNPs implicated by (proximal and distal) SNP-to-gene (S2G) linking strategies, e.g. prioritizing SNPs involved in gene regulation. Third, we predict gene expression (and derive allelic-effect annotations) from deep learning annotations at SNPs implicated by S2G linking strategies — generalizing the previously proposed ExPecto approach, which incorporates deep learning annotations based on distance to TSS. We evaluated these approaches using stratified LD score regression, using functional data in blood and focusing on 11 autoimmune diseases and blood-related traits (averageN=306K). We determined that the three approaches produced SNP annotations that were uniquely informative for these diseases/traits, despite the fact that linear combinations of the underlying DeepSEA, Basenji, DeepBind and deltaSVM blood annotations were not uniquely informative for these diseases/traits. Our results highlight the benefits of integrating SNP annotations produced by deep learning models with other types of data, including data linking SNPs to genes.
Diversity and Function of the Eastern Oyster (Crassostrea virginica) Microbiome
Authors: Pimentel Zachary T. , Dufault-Thompson Keith , Russo Kayla T. , Scro Abigail K. , Smolowitz Roxanna M. , Gomez-Chiarri Marta , Zhang Ying
Published: September 2020

Marine invertebrate microbiomes play important roles in various host and ecological processes. However, a mechanistic understanding of host-microbe interactions is so far only available for a handful of model organisms. Here, an integrated taxonomic and functional analysis of the microbiome of the eastern oyster,Crassostrea virginica, was performed using 16S rRNA gene amplicon profiling, shotgun metagenomics, and genome-scale metabolic reconstruction. A relatively low number of amplicon sequence variants (ASVs) were observed in oyster tissues compared to water samples, while high variability was observed across individual oysters and among different tissue types. Targeted metagenomic sequencing of the gut microbiota led to further characterization of a dominant bacterial taxon, the classMollicutes, which was captured by the reconstruction of a metagenome-assembled genome (MAG). Genome-scale metabolic reconstruction of the oysterMollicutesMAG revealed a reduced set of metabolic functions and a high reliance on the uptake of host-derived nutrients. A chitin degradation and an arginine deiminase pathway were unique to the MAG as compared to other closely relatedMycoplasmagenomes, indicating a distinct mechanism of carbon and energy acquisition by the oyster- associatedMollicutes. A systematic reanalysis of public eastern oyster-derived microbiome data revealed theMollicutesas a ubiquitous taxon among adult oysters despite their general absence in larvae and biodeposit samples, suggesting potential horizontal transmission via an unknown mechanism.

IMPORTANCE

Despite well-documented biological significance of invertebrate microbiomes, a detailed taxonomic and functional characterization is frequently missing from many non-model marine invertebrates. By using 16S rRNA gene-based community profiling, shotgun metagenomics, and genome-scale metabolic reconstruction, this study provides an integrated taxonomic and functional analysis of the microbiome of the eastern oyster,Crassostrea virginica. Community profiling revealed a surprisingly low richness, as compared to surrounding seawater, and high variability among different tissue types and individuals. Reconstruction of aMollicutesMAG enabled the phylogenomic positioning and functional characterization of the oyster-associatedMollicutes. Comparative analysis of the adult oyster gut, biodeposits, and oyster larvae samples indicated the potentially ubiquitous associations of theMollicutestaxon with adult oysters. To the best of our knowledge, this study represented the first metagenomics derived functional inference of the eastern oyster microbiome. An integrated analytical procedure was developed for the functional characterization of microbiomes in other non-model host species.
Test-retest reliability and concurrent validity of the Adapted Short QUestionnaire to ASsess Health-enhancing physical activity (Adapted-SQUASH) in adults with disabilities
Authors: Seves Bregje L. , Hoekstra Femke , Schoenmakers Jorrit W.A. , Brandenbarg Pim , Hoekstra Trynke , Hettinga Florentina J. , Dekker Rienk , van der Woude Lucas H.V. , van der Schans Cees P.
Published: September 2020

The current study determined the test-retest reliability and concurrent validity of the Adapted Short QUestionnaire to ASsess Health-enhancing physical activity (Adapted-SQUASH) in adults with disabilities. Before filling in the Adapted-SQUASH twice with a recall period of two weeks, participants wore the Actiheart activity monitor up to one week. For the test-retest reliability (N = 68), Intraclass correlation coefficients (ICCs) were 0.67 (p < 0.001) for the total activity score (min x intensity/week) and 0.76 (p< 0.001) for the total minutes of activity (min/week). For the concurrent validity (N = 58), the Spearman correlation coefficient was 0.40 (p = 0.002) between the total activity score of the first administration of the Adapted-SQUASH and activity energy expenditure from the Actiheart (kcals kg−1 min−1). The ICC was 0.22 (p = 0.027) between the total minutes of activity assessed with the first administration of the Adapted-SQUASH and Actiheart. The Adapted-SQUASH is an acceptable measure to assess self-reported physical activity in large populations of adults with disabilities, but is not applicable at the individual level due to wide limits of agreement. Self-reported physical activity assessed with the Adapted-SQUASH does not accurately represent physical activity assessed with the Actiheart in adults with disabilities, as indicated with a systematic bias between both instruments in the Bland-Altman analysis.
Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma
Authors: Chiaro Jacopo , Kasanen Henna H. E. , Whalley Thomas , Capasso Cristian , Grönholm Mikaela , Feola Sara , Peltonen Karita D. , Hamdan Firas S. , Hernberg Micaela M. , Mäkelä Siru , Karhapää Hanna , Brown Paul E. , Martins Beatriz , Fusciello Manlio , Ylösmäki Erkko , Kreutzman Anna S. , Mustjoki Satu M. , Szomolay Barbara , Cerullo Vincenzo
Published: September 2020

Molecular mimicry is known to be one of the leading mechanisms by which infectious agents may induce autoimmunity. However, whether a similar mechanism triggers anti-tumor immune response is unexplored, and the role of anti-viral T-cells infiltrating the tumor has remained anecdotal. To address this question, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we showed that, in mice, viral pre-existing immunity enhanced the efficacy of cancer immunotherapy via molecular mimicry. Specifically, when treated with a cancer vaccine consisting of peptides with a high degree of homology with specific viral peptides, the mice with induced pre-existing immunity to these viral peptides showed significantly better anti-tumor response.

To understand whether this mechanism could partly explain immunotherapy-response in humans, we analyzed a cohort of melanoma patients undergoing PD1 treatment with high IgG titer for Cytomegalovirus (CMV). In this cohort of patients, we showed that high level of CMV-antibodies was associated with a prolonged progression free survival, and found that in some cases PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, T cell TCR sequencing revealed expansion of the same CD8+ T-cell clones, when PBMCs were pulsed with tumor- or homologous viral peptides.

In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could explain part of the response observed in immunotherapy. Most importantly, we have developed a tool able to identify tumor antigens and neoantigens based on their similarity to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T-cells in cancer vaccine development.

One Sentence Summary

Molecular mimicry can play a role in anti-tumor immune responses and should thus be further exploited in the development of novel cancer treatments.
Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks
Authors: Kitzbichler Manfred G , Aruldass Athina R , Barker Gareth J , Wood Tobias C , Dowell Nicholas G , Hurley Samuel A , McLean John , Correia Marta , Clarke Charlotte , Pointon Linda , Cavanagh Jonathan , Cowen Phil , Pariante Carmine , consortium NIMA , Cercignani Mara , Bullmore Edward T , Harrison Neil A
Published: September 2020

Peripheral inflammation can cause depressive symptoms – but how? Here, we measured brain MRI functional connectivity and micro-structural parameters, including proton density (PD, a measure of tissue water), at 360 cortical and 16 subcortical brain regions in 46 healthy controls and 83 depressed cases. Blood C-reactive protein (CRP) was positively correlated with PD in key precuneus/posterior cingulate cortex (pC/pCC) and medial prefrontal cortex (mPFC) components of the default mode network (DMN). CRP concentration was associated with increased connectivity within the DMN (nodes pC/pCC, mPFC and hippocampus), but decreased connectivity between DMN and non-DMN nodes. Depressed cases had reduced weighted degree, a metric of hubness, in anatomically co-located DMN regions. Our interpretation is that low-grade peripheral inflammation is associated with increased water (oedema) within a few highly connected but metabolically vulnerable medial cortical nodes, and this “rock in the pond” serves to perturb the functional connectivity of large-scale cortico-subcortical systems associated with depression.
Exhaled CO2 as COVID-19 infection risk proxy for different indoor environments and activities
Authors: Peng Zhe , Jimenez Jose L.
Published: September 2020

CO2 is co-exhaled with aerosols containing SARS-CoV-2 by COVID-19 infected people and can be used as a proxy of SARS-CoV-2 concentrations indoors. Indoor CO2 measurements by low-cost sensors hold promise for mass monitoring of indoor aerosol transmission risk for COVID-19 and other respiratory diseases. We derive analytical expressions of CO2-based risk proxies and apply them to various typical indoor environments. The relative infection risk in a given environment scales with excess CO2 level, and thus keeping CO2 as low as feasible in a space allows optimizing the protection provided by ventilation. We show that the CO2 level corresponding to a given absolute infection risk varies by over 2 orders of magnitude for different environments and activities. Although large uncertainties, mainly from virus exhalation rates, are still associated with infection risk estimates, our study provides more specific and practical recommendations for low-cost CO2-based indoor infection risk monitoring.

Table of Contents Graphic
Altered blood cell traits underlie a major genetic locus of severe COVID-19
Authors: Zhou Jingqi , Sun Yitang , Huang Weishan , Ye Kaixiong
Published: September 2020

Purpose

The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown.

Methods

To identify intermediate traits of the COVID-19 risk variant, we performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310,999 European individuals from UK Biobank. For candidate target genes, we examined associations between their expression and the polygenic score (PGS) of 1,263 complex traits in a meta-analysis of 31,684 blood samples.

Results

Our PheWAS identified and replicated multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07×10−8, 4.09×10−13), eosinophil count and percentage (p = 5.73×10−3, 2.20×10−3), and neutrophil percentage (p = 3.23×10−3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73×10−21, 5.08×10−19); CCR2 with monocytes (p = 2.40×10−10); and CCRl with monocytes and neutrophil (p = 1.78×10−6, 7.17×10−5).

Conclusions

Multiple blood cell traits, especially monocyte, eosinophil, and neutrophil numbers, are associated with the COVID-19 risk variant and the expression of its candidate target genes, representing probable mechanistic links between the genetic locus 3p21.31 and severe COVID-19.
The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease
Authors: Sundar Shirin V. , Zhou Xia , Magenheimer Brenda S. , Reif Gail A. , Wallace Darren P. , Georg Gunda I. , Jakkaraj Sudhakar R. , Tash Joseph S. , Yu Alan S.L. , Li Xiaogang , Calvet James P.
Published: September 2020

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl−secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation usingin vitroandin vivomodels of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl−channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement.In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in thePkd1flox/flox:Pkhd1-Cremouse model. Thus, H2-GMZ treatment decreases Cl−secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.
Age-related differences in the role of the prefrontal cortex in sensory-motor training gains: A tDCS study
Authors: Tan Si Jing , Filmer Hannah L. , Dux Paul E.
Published: September 2020

The ability to process multiple sources of information concurrently is particularly impaired as individuals age and such age-related increases in multitasking costs have been linked to impairments in response selection. Previous neuroimaging studies with young adults have implicated the left hemisphere prefrontal cortex (PFC) as a key neural substrate of response selection. In addition, several transcranial direct current stimulation studies (tDCS) have provided causal evidence implicating this region in response selection and multitasking operations. For example, Filmer at al. (2013b) demonstrated that typically observed response selection learning/training gains in young adults were disrupted via offline transcranial direct current stimulation (tDCS) of left, but not right, PFC. Here, considering evidence of functional dedifferentiation in the brains of older adults, we assessed if this pattern of response selection learning disruption via tDCS to the left PFC is observed in older adults, testing if this region remains a key response selection node as individuals age. In a pre-registered study with 58 older adults, we applied anodal, cathodal, and sham stimulation to left and right PFC, and measured performance as participants trained on low- and high-response selection load tasks. Active stimulation did not disrupt training in older adults as compared to younger adults. However, there was evidence of enhanced training gains via tDCS, which scaled with response selection task difficulty. The results highlight age-related differences in the casual neural substrates that subserve response selection and learning.
Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex
Authors: Otero Brittney A. , Poukalov Kiril , Hildebrandt Ryan P. , Thornton Charles A. , Jinnai Kenji , Fujimura Harutoshi , Kimura Takashi , Hagerman Katharine A. , Sampson Jacinda B. , Day John W. , Wang Eric T.
Published: September 2020

Myotonic dystrophy (dystrophia myotonica, DM) is caused by expanded CTG/CCTG microsatellite repeats, leading to multi-systemic symptoms in skeletal muscle, heart, gastrointestinal, endocrine, and central nervous systems (CNS), among others. For some patients, CNS issues can be as debilitating or more so than muscle symptoms; they include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Although transcriptomes from DM type 1 (DM1) skeletal muscle have provided useful insights into pathomechanisms and biomarkers, limited studies of transcriptomes have been performed in the CNS. To elucidate underlying causes of CNS dysfunction in patients, we have generated and analyzed RNA-seq transcriptomes from the frontal cortex of 21 DM1 patients, 4 DM type 2 (DM2) patients, and 8 unaffected controls. One hundred and thirty high confidence splicing changes were identified, most occurring exclusively in the CNS and not in skeletal muscle or heart. Mis-spliced exons were found in neurotransmitter receptors, ion channels, and synaptic scaffolds, and we identified an alternative exon in GRIP1 that modulates association with kinesins. Splicing changes exhibited a gradient of severity correlating with CTG repeat length, as measured by optical mapping of individual DNA molecules. All individuals studied, including those with modest splicing defects, showed extreme somatic mosaicism, with a subset of alleles having >1000 CTGs. Analyses of gene expression changes showed up-regulation of genes transcribed in microglia and endothelial cells, suggesting neuroinflammation, and downregulation of genes transcribed in neurons. Gene expression of RNAs encoding proteins detectable in cerebrospinal fluid were also found to correlate with mis-splicing, with implications for CNS biomarkers of disease severity. These findings provide a framework for future mechanistic and therapeutic studies of CNS issues in DM.
De Novo Design of Allosteric Control into Rotary Motor V1-ATPase by Restoring Lost Function
Authors: Kosugi Takahiro , Iida Tatsuya , Tanabe Mikio , Iino Ryota , Koga Nobuyasu
Published: September 2020

Protein complexes exert various functions through allosterically controlled cooperative work. De novo design of allosteric control into protein complexes provides understanding of their working principles and potential tools for synthetic biology. Here, we hypothesized that an allosteric control can be created by restoring lost functions of pseudo-enzymes contained as subunits in protein complexes. This was demonstrated by computationally de novo designing ATP binding ability of the pseudo-enzyme subunits in a rotary molecular motor, V1-ATPase. Single molecule experiments with solved crystal structures revealed that the designed V1is allosterically accelerated than the wild-type by the ATP binding to the created allosteric site and the rate is tunable by modulating the binding affinity. This work opened up an avenue for programming allosteric control into proteins exhibiting concerted functions.
Metazoan-like kinetochore arrangement masked by the interphase RabI configuration
Authors: Jiménez-Martín Alberto , Pineda-Santaella Alberto , León-Periñán Daniel , Delgado-Gestoso David , Marín-Toral Laura , Fernández-Álvarez Alfonso
Published: September 2020

During cell cycle progression in metazoan, the kinetochore, the protein complex attached to centromeres which directly interacts with the spindle microtubules, the vehicle of chromosome segregation, is assembled at mitotic onset and disassembled during mitotic exit. This program is assumed to be absent in budding and fission yeast because kinetochore proteins are stably maintained at the centromeres throughout the entire cell cycle. In this work, we show that the assembly program at the mitotic onset of the Ndc80 complex, a crucial part of the outer kinetochore, is unexpectedly conserved inSchizosaccharomyces pombe. We have identified this behavior by removing the Rabl chromosome configuration during interphase, in which centromeres are permanently associated with the nuclear envelope beneath the spindle pole body. Hence, the Rabl configuration masks the presence of a program to recruit Ndc80 at mitotic onset in fission yeast, similar to that taking place in metazoan. Besides the evolutionary implications of our observations, we think that our work will help understand the molecular processes behind the kinetochore assembly program during mitotic entry using fission yeast as the model organism.
Mfge8 attenuates human gastric antrum smooth muscle contractions
Authors: Li Wen , Olseen Ashley , Xie Yeming , Alexandru Cristina , Perrino Brian A.
Published: September 2020

Coordinated gastric smooth muscle contraction is critical for proper digestion and is adversely affected by a number of gastric motility disorders. In this study we report that the secreted protein Mfge8 (milk fat globule-EGF factor 8) inhibits the contractile responses of human gastric antrum muscles to cholinergic stimuli by reducing the inhibitory phosphorylation of the MYPT1 (myosin phosphatase-targeting subunit 1) subunit of MLCP (myosin light chain phosphatase), resulting in reduced LC20 (smooth muscle myosin regulatory light chain 2) phosphorylation. We show that endogenous Mfge8 is bound to its receptor, α8β1 integrin, in human gastric antrum muscles, suggesting that human gastric antrum muscle mechanical responses are regulated by Mfge8. The regulation of gastric antrum smooth muscles by Mfge8 and α8 integrin functions as a brake on gastric antrum mechanical activities. Further studies of the role of Mfge8 and α8 integrin in regulating gastric antrum function will likely reveal additional novel aspects of gastric smooth muscle motility mechanisms.
Pervasive selection pressure in wild and domestic pigs
Authors: Leno-Colorado J. , Guirao-Rico S. , Pérez-Enciso M. , Ramos-Onsins S. E.
Published: September 2020

Animal domestication typically affected numerous polygenic quantitative traits, such as behaviour, development and reproduction. However, uncovering the genetic basis of quantitative trait variation is challenging, since it is probably caused by small allele-frequency changes. To date, only a few causative mutations related to domestication processes have been reported, strengthening the hypothesis that small effect variants have a prominent role. So far, the studies on domestication have been limited to the detection of the global effect of domestication on deleterious mutations and on strong beneficial variants, ignoring the importance of variants with small selective effects. In addition, very often, the study of the effects of selection are conducted on genome sequences that contain a non-negligible fraction of missing data, especially in non-model organisms. Hence, appropriate methods to account for these positions are needed. To overcome these difficulties, here we propose to estimate the proportion of beneficial variants using the asymptotic MacDonald-Kreitman (MK) method based on estimates of variability that summarizes the site frequency spectrum (SFS) while accounting for missing data and use them to perform an Approximate Bayesian Computation (ABC) analysis to infer the Distribution of Fitness Effects (DFE) of each population. We applied this approach to 46 genome sequences of pigs from three different populations, one wild and two domestics, with very different demographic histories and selective pressures. The obtained results showed that domestic and wild pig populations do not differ in nonsynonymous fixed mutations. Therefore, differences inαestimation among breeds are determined by their polymorphisms. The comparison ofαfor total and exclusive mutations suggests that the different domestic populations have suffered recent divergent changes in their functional versus neutral polymorphisms ratio, while the wild population is compatible withα=0. Besides, the DFE inferred with ABC indicates that both wild and domestic pigs display a large number of deleterious mutations at low frequency and a high number of neutral and/or nearly-neutral mutations that may have a significant effect on the evolution of domestic and wild populations. In addition, models not considering beneficial mutations have higher posterior probabilities, suggesting that beneficial mutations are difficult to detect or are scarce. Indeed, for all three populations, the median proportion of the strong favourable mutations are very low (≤ 0.1%) in those models that includes positive selection, with the average values of weak beneficial mutations around 0.6% for wild boar and 0.8-1.0% for the domestic pigs. Lastly, the analysis based on exclusive mutations showed that recent demographic changes may have severely affected the fitness of populations, especially that of the local Iberian breed.
Host adaptation in gut Firmicutes is associated with sporulation loss and altered colonisation patterns
Authors: Browne Hilary P. , Almeida Alexandre , Kumar Nitin , Vervier Kevin , Adoum Anne T. , Viciani Elisa , Dawson Nicholas JR , Forster Samuel C. , Cormie Claire , Goulding David , Lawley Trevor D.
Published: September 2020

Human-to-human transmission of symbiotic, anaerobic bacteria is a fundamental evolutionary adaptation essential for membership of the human gut microbiota. However, despite its importance, the genomic and biological adaptations underpinning symbiont transmission remain poorly understood. Here, we show that sporulation ability, which promotes transmission of anaerobic bacteria, has been independently lost in many distinct evolutionary lineages of gut bacteria belonging to the Firmicutes phyla. Analysis of 1358 genome-sequenced Firmicutes reveals loss of sporulation is associated with features of host-adaptation such as genome reduction and specialized metabolic capabilities. Consistent with these data, analysis of 28,000 gut metagenomes from people around the world demonstrates that bacteria now incapable of sporulation are more abundant but less prevalent in the human population compared to spore-forming bacteria. Our results suggest host adaptation in gut Firmicutes is an evolutionary trade-off between transmission range and colonisation abundance, leading to distinct transmission cycles. We reveal host transmission as an underappreciated process that shapes the evolution, assembly and functions of gut Firmicutes.
The FlhA linker mediates flagellar protein export switching during flagellar assembly
Authors: Inoue Yumi , Kida Mamoru , Kinoshita Miki , Takekawa Norihiro , Namba Keiichi , Imada Katsumi , Minamino Tohru
Published: September 2020

The flagellar protein export apparatus switches export specificity from hook-type to filament-type upon completion of hook assembly, thereby initiating filament assembly at the hook tip. The C-terminal cytoplasmic domain of FlhA (FlhAC) forms a homo-nonameric ring structure that serves as a docking platform for flagellar export chaperones in complex with their cognate filament-type substrates. Interactions of the flexible linker of FlhA (FlhAL) with its nearest FlhACsubunit in the ring allow the chaperones to bind to FlhACto facilitate filament-type protein export, but it remains unclear how it occurs. Here, we report that FlhALacts as a switch that brings the order to flagellar assembly. The crystal structure of FlhAC(E351A/D356A) showed that Trp-354 in FlhALbound to the chaperone-binding site of its neighboring subunit. We propose that FlhALbinds to the chaperon-binding site of FlhACto suppress the interaction between FlhACand the chaperones until hook assembly is completed.
Automated deep lineage tree analysis using a Bayesian single cell tracking approach
Authors: Ulicna Kristina , Vallardi Giulia , Charras Guillaume , Lowe Alan R.
Published: September 2020

Single-cell methods are beginning to reveal the intrinsic heterogeneity in cell populations, which arises from the interplay or deterministic and stochastic processes. For example, the molecular mechanisms of cell cycle control are well characterised, yet the observed distribution of cell cycle durations in a population of cells is heterogenous. This variability may be governed either by stochastic processes, inherited in a deterministic fashion, or some combination of both. Previous studies have shown poor correlations within lineages when observing direct ancestral relationships but remain correlated with immediate relatives. However, assessing longer-range dependencies amid noisy data requires significantly more observations, and demands the development of automated procedures for lineage tree reconstruction. Here, we developed an open-source Python library,btrack, to facilitate retrieval of deep lineage information from live-cell imaging data. We acquired 3,500 hours of time-lapse microscopy data of epithelial cells in culture and used our software to extract 22,519 fully annotated single-cell trajectories. Benchmarking tests, including lineage tree reconstruction assessments, demonstrate that our approach yields high-fidelity results and achieves state-of-the-art performance without the requirement for manual curation of the tracker output data. To demonstrate the robustness of our supervision-free cell tracking pipeline, we retrieve cell cycle durations and their extended inter- and intra-generational family relationships, for up to eight generations, and up to fourth cousin relationships. The extracted lineage tree dataset represents approximately two orders of magnitude more data, and longer-range dependencies, than in previous studies of cell cycle heritability. Our results extend the range of observed correlations and suggest that strong heritable cell cycling is present. We envisage that our approach could be extended with additional live-cell reporters to provide a detailed quantitative characterisation of biochemical and mechanical origins to cycling heterogeneity in cell populations.
Semi-processive hyperglycosylation of adhesin by bacterial proteinN-glycosyltransferases
Authors: Yakovlieva Liubov , Ramírez-Palacios Carlos , Marrink Siewert J. , Walvoort Marthe T.C.
Published: September 2020

Processivity is an important feature of enzyme families such as DNA polymerases, polysaccharide synthases and protein kinases, to ensure high fidelity in biopolymer synthesis and modification. Here we reveal processive character in the family of cytoplasmic proteinN-glycosyltransferases (NGTs). Through various activity assays, intact protein mass spectrometry and proteomics analysis, we established that NGTs from non-typeableHaemophilus influenzaeandActinobacillus pleuropneumoniaemodify an adhesin protein fragment in a semi-processive manner. Molecular modeling studies suggest that the processivity arises from the shallow substrate binding groove in NGT, that promotes the sliding of the adhesin over the surface to allow further glycosylations without temporary dissociation. We hypothesize that the processive character of these bacterial protein glycosyltransferases is the mechanism to ensure multisite glycosylation of adhesinsin vivo, thereby creating the densely glycosylated proteins necessary for bacterial self-aggregation and adherence to human cells, as a first step towards infection.
High fat worsens olanzapine induced metabolic abnormalities in rats
Authors: Jamaluddin Sahara Juita , Nilugal Kiran C. , Kulkarni Nagaraj M. , Fattepur Santosh , Abdullah Ibrahim , Ugandar Rajan Ethiraj
Published: September 2020

Purpose

Olanzapine is widely prescribed in the treatment of schizophrenia and various psychiatric illnesses. Schizophrenia patients have been reported to eat a diet that contain higher in fat and lower in fiber. High dietary fat intake can predispose to the development of metabolic abnormalities and exacerbate hepatic changes. The aim of the paper is to investigate the effect of olanzapine and high fat diet on blood glucose, lipid profile and the liver in rats.

Design/methodology/approach

Twenty-four healthy male Sprague Dawley rats were divided into following groups: group I was given normal diet, group II was given high fat diet, group III was given high fat diet and olanzapine (5 mg/kg/day intraperitoneally twice daily) and group IV was given normal diet and olanzapine (at same dose). After 30 days, the blood samples were collected to assess levels of blood glucose and total lipid profile. Also, liver specimens were processed for histological study by using light microscope.

Findings

Group III showed significant increase in weight, blood glucose (p < 0.05), total cholesterol (p < 0.05), low-density lipoprotein-cholesterol (p < 0.05) and decrease in high-density lipoprotein-cholesterol (p < 0.05) when compared to group II. While group III revealed several histological changes including, dilatation and congestion of central veins and blood sinusoids as well some hepatocytes appeared damaged and were replaced by inflammatory cellular infiltrate.

Originality/value

These results suggest that olanzapine and high fat diet greatly increased the blood glucose, total cholesterol, LDL-C and considerable decreased HDL-C as well as mild inflammatory changes