bluuebunny/crossref_metadata_2025 huggingface dataset:
Obesity causes irreversible mitochondria failure in visceral adipose tissue despite successful anti-obesogenic lifestyle-based interventions
Authors: Gonzalez-Franquesa Alba , Gama-Perez Pau , Kulis Marta , Dahdah Norma , Moreno-Gomez Sonia , Latorre-Pellicer Ana , Fernández-Ruiz Rebeca , Aguilar-Mogas Antoni , Monelli Erika , Samino Sara , Miró Joan , Oemer Gregor , Duran Xavier , Sanchez-Rebordelo Estrella , Schneeberger Marc , Obach Merce , Montane Joel , Castellano Giancarlo , Chapaprieta Vicente , Navarro Lourdes , Prieto Ignacio , Castaño Carlos , Novials Anna , Gomis Ramon , Monsalve Maria , Claret Marc , Graupera Mariona , Soria Guadalupe , Vendrell Joan , Fernandez-Veledo Sonia , Enríquez Jose Antonio , Carracedo Angel , Perales José Carlos , Nogueiras Rubén , Herrero Laura , Keller Markus A. , Yanes Oscar , Sales-Pardo Marta , Guimerà Roger , Martín-Subero José Ignacio , Garcia-Roves Pablo M.
Published: July 2020

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most pathological features were successfully reverted, we observed a high degree of metabolic dysfunction irreversibility in visceral white adipose tissue, characterised by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and apparent global phenotypic recovery, obesity specifically triggered in visceral adipose a cascade of events progressing from mitochondrial metabolic and proteostatic defects to widespread cellular stress, which compromises its biosynthetic and recycling capacity. Our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in white adipose tissue, becoming a significant milestone in disease progression.
Long-range GABAergic inhibition modulates spatiotemporal dynamics of the output neurons in the olfactory bulb
Authors: Villar Pablo S. , Hu Ruilong , Araneda Ricardo C.
Published: July 2020

Local interneurons of the olfactory bulb (OB) are densely innervated by long-range GABAergic neurons from the basal forebrain (BF), suggesting that this top-down inhibition regulates early processing in the olfactory system. However, how GABAergic inputs modulate the OB output neurons, the mitral/tufted cells, is unknown. Here, in acute brain slices, we show that optogenetic activation of BF GABAergic inputs produced distinct local circuit effects that can influence the activity of mitral/tufted cells in the spatiotemporal domains. Activation of the GABAergic axons produced a fast disinhibition of mitral/tufted cells consistent with a rapid and synchronous release of GABA onto local interneurons in the glomerular and inframitral circuits of the OB, which also reduced the spike precision of mitral/tufted cells in response to simulated stimuli. In addition, BF GABAergic inhibition modulated local oscillations in a layer-specific manner. The intensity of locally evokedθoscillations was decreased upon activation of top-down inhibition in the glomerular circuit, while evokedγoscillations were reduced by inhibition of granule cells. Furthermore, BF GABAergic input reduced dendrodendritic inhibition in mitral/tufted cells. Together, these results suggest that long-range GABAergic neurons from the BF are well suited to influence temporal and spatial aspects of processing by OB circuits.
Errors in Predicting Muscle Fiber Lengths from Joint Kinematics Point to the Need to Include Tendon Tension in Computational Neuromuscular Models
Authors: Hagen Daniel A , Valero-Cuevas Francisco J
Published: July 2020

Accurate predictions of tendon forces must consider musculotendon mechanics; specifically muscle fiber lengths and velocities. These are either predicted explicitly by simulating musculoskeletal dynamics or approximated from measured limb kinematics. The latter is complicated by the fact that tendon lengths and pennation angles vary with both limb kinematicsandtendon tension. We now derive the error in kinematically-approximated muscle fiber lengths as a general equation of muscle geometry and tendon tension. This enables researchers to objectively evaluate this error’s significance—which can reach ~ 80% of the optimal muscle fiber length—with respect to the scientific or clinical question being asked. Although this equation provides a detailed functional relationship between muscle fiber lengths, joint kinematics and tendon tension, the parameters used to characterize musculotendon architecture aresubject- andmuscle-specific. This parametric uncertainty limits the accuracy ofanygeneric musculoskeletal model that hopes to explain subject-specific phenomena. Nevertheless, the existence of such a functional relationship has profound implications to biological proprioception. These results strongly suggest that tendon tension information (from Golgi tendon organs) is likely integrated with muscle fiber length information (from muscle spindles) at the spinal cord to produce useful estimates of limb configuration to enable effective control of movement.
Chronic high glyphosate exposure delays individual worker bee (Apis melliferaL.) development under field conditions
Authors: Odemer Richard , Alkassab Abdulrahim T. , Bischoff Gabriela , Frommberger Malte , Wernecke Anna , Wirtz Ina P. , Pistorius Jens , Odemer Franziska
Published: July 2020

The ongoing debate about glyphosate-based herbicides (GBH) and their implications for beneficial arthropods give rise to controversy. This research was carried out to cover possible sublethal GBH effects on brood and colony development, adult survival, and overwintering success of honey bees (Apis melliferaL.) under field conditions. Residues in bee relevant matrices such as nectar, pollen and plants were measured in addition. To address these questions, we adopted four independent study approaches. For brood effects and survival, we orally exposed mini-hives housed in the “Kieler mating-nuc” system to sublethal concentrations of 4.8 mg glyphosate/kg (T1, low) and 137.6 mg glyphosate/kg (T2, high) over the period of one brood cycle (21 days). Brood development and colony conditions were assessed after a modified OECD method (No. 75). For adult survival, we weighed and labeled freshly emerged workers from exposed colonies and introduced them into non-contaminated mini-hives to monitor life span for 25 consecutive days. Results from these experiments showed a trivial effect of GBH on colony conditions and survival of individual workers, even though hatching weight was reduced in T2. The brood termination rate (BTR) in the T2 treatment, however, was more than doubled (49.84%) when compared to the control (22.11%) or T1 (20.69%). This was surprising as T2 colonies gained similar weight and similar numbers of bees per colony compared to the control, indicating equal performance. Obviously, the brood development in T2 was not “terminated” as expected by the OECD method terminology but rather “slowed down” for an unknown period of time. In light of these findings, we suggest that chronic high GBH exposure is capable of delaying worker brood development to a significant extent while no further detrimental effects seem to appear at the colony level. Against this background, we discuss additional results and possible consequences of GBH for honey bee health.
DIET INFLUENCES PERIPHERAL AMYLOID β METABOLISM: A ROLE FOR CIRCULATING INSULIN-LIKE GROWTH FACTOR I
Authors: Herrero-Labrador R. , Trueba-Saiz A. , Martinez-Rachadell L. , de Sevilla E. Fernandez , Diaz-Pacheco S. , Fernandez Ana F. , Torres Aleman I.
Published: July 2020

Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact on brain Aβ load, a major landmark of AD pathology. Overweight mice showed increased peripheral Aβ clearance by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. Since circulating insulin-like growth factor I (IGF-I) modulates brain Aβ clearance, and is increased in serum of overweight mice, we determined whether it affects peripheral Aβ clearance. We found that Aβ uptake by hepatocytes is stimulated by IGF-I. Moreover, mice with low serum IGF-I levels show reduced peripheral Aβ clearance. In the brain, IGF-I favored association of its receptor (IGF-IR) with Aβ precursor protein (APP), and at the same time stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly less activation of brain IGF-IR phosphorylation and APP/IGF-IR association was found in overweight mice as compared to lean controls. Collectively, these results indicate that diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ clearance probably because its brain entrance is reduced.
Evidence for reduced immune gene diversity and activity during the evolution of termites
Authors: He Shulin , Sieksmeyer Thorben , Che Yanli , Esparza Mora M. Alejandra , Stiblik Petr , Banasiak Ronald , Harrison Mark C. , Šobotník Jan , Wang Zongqing , Johnston Paul R. , McMahon Dino P.
Published: July 2020

The evolution of biological complexity is associated with the emergence of bespoke immune systems that maintain and protect organism integrity. Unlike the well studied immunity at the cell and individual level, little is known about the origins of immunity during the transition to eusociality, a major evolutionary transition comparable to the evolution of multicellular organisms from single-celled ancestors. We tackle this by characterizing the immune gene repertoire of 18 cockroach and termite species, spanning the spectrum of solitary, subsocial and eusocial lifestyles. We identified five significant immune gene family contractions and one immune gene family expansion along the spine of a time-calibrated phylogeny, correlating with key transitions in termite sociality. In cross-species comparisons of immune gene expression, we find that termites appear to have evolved a caste-specific social defense system at the expense of individual immune protection. Our study indicates that a major transition in organismal complexity entailed a fundamental reshaping of the immune system optimized for group over individual defense.
Severely ill COVID-19 patients display augmented functional properties in SARS-CoV-2-reactive CD8+T cells
Authors: Kusnadi Anthony , Ramírez-Suástegui Ciro , Fajardo Vicente , Chee Serena J , Meckiff Benjamin J , Simon Hayley , Pelosi Emanuela , Seumois Grégory , Ay Ferhat , Vijayanand Pandurangan , Ottensmeier Christian H
Published: July 2020

The molecular properties of CD8+T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+T cells from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+T cell response to SARS-CoV-2 was ‘exhausted’ or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the non-exhausted subsets from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+T cell memory responses in patients with severe COVID-19 illness. CD8+T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features. Cells with such features were mostly absent in SARS-CoV-2 responsive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+T cells responding to SARS-CoV-2.
Large genetic diversity and strong positive selection in F-box and GPCR genes among the wild isolates ofCaenorhabditis elegans
Authors: Ma Fuqiang , Lau Chun Yin , Zheng Chaogu
Published: July 2020

The F-box and chemosensory GPCR (csGPCR) gene families are greatly expanded in nematodes, including the model organismCaenorhabditis elegans, compared to insects and vertebrates. However, the intraspecific evolution of these two gene families in nematodes remain unexamined. In this study, we analyzed the genomic sequences of 330 recently sequenced wild isolates ofC. elegansusing a range of population genetics approaches. We found that F-box and csGPCR genes, especially theSrwfamily csGPCRs, showed much more diversity than other gene families. Population structure analysis and phylogenetic analysis divided the wild strains into eight non-Hawaiian and three Hawaiian subpopulations. Some Hawaiian strains appeared to be more ancestral than all other strains. F-box and csGPCR genes maintained a great amount of the ancestral variants in the Hawaiian subpopulation and their divergence among the non-Hawaiian subpopulations contributed significantly to population structure. F-box genes are mostly located at the chromosomal arms and high recombination rate correlates with their large polymorphism. Moreover, using both neutrality tests and Extended Haplotype Homozygosity analysis, we identified signatures of strong positive selection in the F-box and csGPCR genes among the wild isolates, especially in the non-Hawaiian population. Accumulation of high-frequency derived alleles in these genes was found in non-Hawaiian population, leading to divergence from the ancestral genotype. In summary, we found that F-box and csGPCR genes harbour a large pool of natural variants, which may be subjected to positive selection. These variants are mostly mapped to the substrate-recognition domains of F-box proteins and the extracellular and intracellular regions of csGPCRs, possibly resulting in advantages during adaptation by affecting protein degradation and the sensing of environmental cues, respectively.

Significance statement

The small nematodeCaenorhabditis eleganshas emerged as an important organism in studying the genetic mechanisms of evolution. F-box and chemosensory GPCR proteins are two of the largest gene families inC. elegans. However, their intraspecific evolution withinC. eleganswas not studied before. In this work, using the nonsynonymous SNV (single nucleotide variant) data of 330C. eleganswild isolates, we found that F-box and chemosensory GPCR genes showed larger polymorphisms and stronger positive selection than other genes. The large diversity is likely the result of rapid gene family expansion, high recombination rate, and gene flow. Analysis of subpopulation suggests that positive selection of these genes occurred most strongly in the non-Hawaiian population, which underwent a selective sweep possibly linked to human activities.
Aedes albopictus(Skuse) susceptibility status to agrochemical-insecticides used in durian plantating systems in southern Thailand
Authors: Ratisupakorn Sakda , Lorn Sokchan , Dada Nsa , Ngampongsai Aran , Chaivisit Pawit , Ritthison Wanapa , Tainchum Krajana
Published: July 2020

High rates of dengue, chikungunya, and zika morbidity occur in southern Thailand. The intensive application of insecticides in orchards could impact not only agricultural insect pests, but also non-target insects, such as mosquitoes, or non-target beneficial insects. In this study, the population density and insecticide susceptibility ofAedes albopictuspopulations to field application concentrations of four agrochemical insecticides – cypermethrin, chlorpyrifos, carbaryl, and imidacloprid were examined. Mosquito eggs were collected from durian cultivation sites in five provinces in southern Thailand and hatched and allowed to develop to the adult stage. The study sites were categorized into three groups based on insecticide application; intensive-application of insecticides (IA), less-application of insecticides (LA), and no application of insecticides (NA). Twenty ovitraps were deployed for at least three consecutive days at each study site to collect mosquito eggs and to determine theAe. albopictuspopulation density then WHO tube assays being used to determine the susceptibility of adult mosquitoes to selected insecticides. This study represents the first report of the agrochemical insecticide susceptibility status ofAe. albopictuscollected from durian orchards in southern Thailand. The study found that the populations ofAe. albopictuswere susceptible to chlorpyrifos, but showed reduced mortality following exposure to lambda-cyhalothrin, carbaryl, and imidacloprid which is suggestive of the existence of resistance. These findings provide new insights into mosquito insecticide resistance focusing onAe. albopictuspopulations and has important implications for mosquito and mosquito-borne disease control in Thailand as well as providing baseline data on which future studies can develop.
Loss of Cdk5rap2 triggers cellular senescence via β-catenin-mediated downregulation of WIP1
Authors: Wang Xidi , Sipila Patrick , Si Zizhen , Rosales Jesusa L. , Gao Xu , Lee Ki-Young
Published: July 2020

Loss-of-function mutations in Cdk5rap2 is associated with the developmental disorders, primary microcephaly and primordial dwarfism, but the underlying molecular link remains obscure. Here, we show that Cdk5rap2 loss in BJ-5ta human fibroblasts triggers senescence that is associated with proliferation defect, which is manifested as small body size in Cdk5rap2an/anmice. In fibroblasts, Cdk5rap2 loss induces p53 Ser15 phosphorylation that correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses senescence in Cdk5rap2-depleted cells, linking senescence to WIP1 downregulation. Cdk5rap2 interacts with GSK3β, increasing inhibitory Ser9 phosphorylation in GSK3β, which phosphorylates and tags β-catenin for degradation. Thus, Cdk5rap2 loss decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing β-catenin that affects expression of NF-κB target genes, including WIP1. Consequently, Cdk5rap2 or β-catenin depletion downregulates WIP1. GSK3β Inhibition in Cdk5rap2-depleted cells restores β-catenin and WIP1 levels, reducing p53 Ser15 phosphorylation and preventing senescence. Conversely, WIP1 inhibition increases p53 Ser15 phosphorylation and senescence in Cdk5rap2-depleted cells lacking GSK3β activity. Senescence through GSK3β/β-catenin downregulation of WIP1 may contribute to the developmental disorders associated with Cdk5rap2 loss-of-function.
Assessment of endemic northern swamp deer (Rucervus duvaucelii duvaucelii) distribution and identification of priority conservation areas through modeling and field surveys across north India
Authors: Paul Shrutarshi , Sarkar Debanjan , Patil Abhilash , Ghosh Tista , Talukdar Gautam , Kumar Mukesh , Habib Bilal , Nigam Parag , Mohan Dhananjai , Pandav Bivash , Mondol Samrat
Published: July 2020

Recent declines in large herbivores have led to significant conservation efforts globally. However, the niche-specific megaherbivores residing outside protected areas face more imminent extinction threats. Swamp deer, the obligate grassland-dwelling endemic cervid is the most extinction-prone megaherbivore in the Indian subcontinent. Limited information on distribution and habitat status pose significant conservation and management challenges for the remaining fragmented populations in north, north-east and central India. To this end, we combined exhaustive field surveys and Maximum Entropy (MaxEnt) modeling to generate the most detailed distribution map for the northern swamp deer subspecies. We used primary data from more than 6000 km2field surveys and eight ecologically relevant covariates for model predictions. Grassland cover, annual mean temperature and distance from water were the major factors that predicted the species distribution. Models predicted swamp deer distribution in only ~3% of the entire landscape, covering both protected (~1.4%) as well as non-protected (~1.6%) areas. Our validation surveys in some of these predicted areas confirmed swamp deer presence and indicated ~85% model accuracy. Finally, we identified four ‘Priority Conservation Areas’ still retaining adequate grassland habitat and species presence that require immediate attention to ensure population connectivity across this landscape. These results highlight the importance of the marginalized grassland ecosystems of northern India that still retains high biodiversity. We suggest a swamp deer-centric conservation approach to protect these human-dominated habitats and emphasize in generating such information for other endemic, habitat-specialist species across the globe.
Activation of the pro-resolving receptors Fpr2/3 attenuate lipopolysaccharide-induced inflammatory microglial activation
Authors: Wickstead Edward S. , Elliott Bradley T. , Biggs Christopher , Getting Stephen J. , McArthur Simon
Published: July 2020

Neuroinflammation driven primarily by microglia directly contributes to neuronal death in many neurodegenerative diseases. Classical anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution, the active endogenous process whereby inflammation is terminated, may also be of benefit. A key driver of peripheral inflammatory resolution, formyl peptide receptors 2/3 (Fpr2/3), is expressed by microglia, but its therapeutic potential in neurodegeneration remains unclear. Here, we sought to provide a proof-of-principle that Fpr2/3 targeting could reverse inflammatory microglial activation induced by the potent bacterial inflammogen lipopolysaccharide (LPS). Stimulation of murine BV2 microglia with LPS triggered release of nitric oxide, TNFα and IL-10, upregulated surface expression of CD38 and CD40 and suppressed CD206, all of which were reduced by subsequent treatment with the Fpr2/3 ligand C43. Cellular exposure to LPS also stimulated NADPH oxidase and mitochondrial derived reactive oxygen species production, effects reversed by C43 treatment. Mechanistic studies showed C43 to act through p38 MAPK phosphorylation and reduction of LPS-induced NFκB nuclear translocation through prevention of IκBα degradation. Here, we provide proof-of-concept data indicating exploitation of the pro-resolving receptor Fpr2/3 as a promising therapeutic strategy in neuroinflammatory conditions.
COCOA: Coordinate covariation analysis of epigenetic heterogeneity
Authors: Lawson John T. , Smith Jason P. , Bekiranov Stefan , Garrett-Bakelman Francine E. , Sheffield Nathan C.
Published: July 2020

A key challenge in epigenetics is to determine the biological significance of epigenetic variation among individuals. Here, we present Coordinate Covariation Analysis (COCOA), a computational framework that uses covariation of epigenetic signals across individuals and a database of region sets to annotate epigenetic heterogeneity. COCOA is the first such tool for DNA methylation data and can also analyze any epigenetic signal with genomic coordinates. We demonstrate COCOA’s utility by analyzing DNA methylation, ATAC-seq, and multi-omic data in supervised and unsupervised analyses, showing that COCOA provides new understanding of inter-sample epigenetic variation. COCOA is available as a Bioconductor R package (http://bioconductor.org/packages/COCOA).
Using a GTR+Γ substitution model for dating sequence divergence when stationarity and time-reversibility assumptions are violated
Authors: Barba-Montoya Jose , Tao Qiqing , Kumar Sudhir
Published: July 2020

Motivation

As the number and diversity of species and genes grow in contemporary datasets, two common assumptions made in all molecular dating methods, namely the time-reversibility and stationarity of the substitution process, become untenable. No software tools for molecular dating allow researchers to relax these two assumptions in their data analyses. Frequently the same General Time Reversible (GTR) model across lineages along with a gamma (+Γ) distributed rates across sites is used in relaxed clock analyses, which assumes time-reversibility and stationarity of the substitution process. Many reports have quantified the impact of violations of these underlying assumptions on molecular phylogeny, but none have systematically analyzed their impact on divergence time estimates.

Results

We quantified the bias on time estimates that resulted from using the GTR+Γ model for the analysis of computer-simulated nucleotide sequence alignments that were evolved with non-stationary (NS) and non-reversible (NR) substitution models. We tested Bayesian and RelTime approaches that do not require a molecular clock for estimating divergence times. Divergence times obtained using a GTR+Γ model differed only slightly (∼3% on average) from the expected times for NR datasets, but the difference was larger for NS datasets (∼10% on average). The use of only a few calibrations reduced these biases considerably (∼5%). Confidence and credibility intervals from GTR+Γ analysis usually contained correct times. Therefore, the bias introduced by the use of the GTR+Γ model to analyze datasets, in which the time-reversibility and stationarity assumptions are violated, is likely not large and can be reduced by applying multiple calibrations.

Availability

All datasets are deposited in Figshare:https://doi.org/10.6084/m9.figshare.12594638.

Contact

s.kumar@temple.edu
Corticohippocampal Neuroenergetics and histomorphology in aluminium-induced neurotoxicity: Putative therapeutic roles of ascorbic acid and nicotine
Authors: Temitayo Gbadamosi Ismail , Olaiya Omotoso Gabriel
Published: July 2020

Alzheimer’s disease (AD) is the most common cause of dementia and is hallmarked by β-amyloid plaque and neurofibrillary tangles deposition in the central nervous system. The complex mechanism that underlies AD pathogenesis has made the development of a definitive cure futile. Exploring the possible therapeutic advantages of combining two neuromodulatory molecules with different mechanisms of neuroprotection is an interesting way of drug discovery. Ascorbic acid (AA), a potent antioxidant molecule, and nicotine (NIC), an allosteric modulator of nAChRs, have both been documented to independently proffer neuroprotection in experimental and clinical neurodegenerative cases. This study elucidated the putative therapeutic advantages of combining ascorbic acid and nicotine as a treatment regimen against the aluminium-induced Alzheimer-like corticohippocampal histopathology, anxiety, and perturbed neuroenergetics in rats induced with

Rats treated with 100 mg/kg aluminium chloride for 28 days presented with significantly increased stretch attend posture frequency and centre square entry. Aluminium significantly depleted the activities of glucose-6-phosphate dehydrogenase (G6PDH) while increasing lactate levels. Corticohippocampal histomorphology of these animals showed poor histoarchitecture, increased congophilic and argentophilic densities that were coupled with increased anti-NSE immunopositivity. Animals post-treated with NIC (10mg/kg) and AA (100mg/kg) for 28 days presented with reduced anxiety level and improved corticohippocampal histomorphology. AA normalized G6PDH and lactate levels while the congophilic density was reduced by NIC. Corticohippocampal argentophilic density anti-NSE immunopositivity were also normalized by AA+NIC.

The findings from this study have shown that a combination of ascorbic acid and nicotine effectively mitigated aluminium-induced corticohippocampal histopathology and perturbed neuroenergetics.
A data-driven method to identify frequency boundaries in multichannel electrophysiology data
Authors: Cohen Michael X
Published: July 2020

Background

Electrophysiological recordings of the brain often exhibit neural oscillations, defined as narrowband bumps that deviate from the background power spectrum. These narrowband dynamics are grouped into frequency ranges, and the study of how activities in these ranges are related to cognition and disease is a major part of the neuroscience corpus. Frequency ranges are nearly always defined according to integer boundaries, such as 4-8 Hz for the theta band and 8-12 Hz for the alpha band.

New method

A data-driven multivariate method is presented to identify empirical frequency boundaries based on clustering of spatiotemporal similarities across a range of frequencies. The method, termed gedBounds, identifies patterns in covariance matrices that maximally separate narrowband from broadband activity, and then identifies clusters in the correlation matrix of those spatial patterns over all frequencies, using the dbscan algorithm. Those clusters are empirically derived frequency bands, from which boundaries can be extracted.

Results

gedBounds recovers ground truth results in simulated data with high accuracy. The method was tested on EEG resting-state data from Parkinson’s patients and control, and several features of the frequency components differed between patients and controls.

Comparison with existing methods

The proposed method offers higher precision in defining subject-specific frequency boundaries compared to the current standard approach.

Conclusions

gedBounds can increase the precision and feature extraction of spectral dynamics in electrophysiology data.
Alpha and theta oscillations contribute to attribute regulation in dietary decision making under self-control
Authors: HajiHosseini Azadeh , Hutcherson Cendri A.
Published: July 2020

How do different cognitive self-regulation strategies alter attribute value construction (AVC) and evidence accumulation (EA)? We recorded EEG during food choices while participants responded naturally or regulated their choices by focusing on healthy eating or decreasing their desire for all food. Using a drift diffusion model (DDM), we predicted the time course of neural signals associated with AVC and EA. Results suggested that suppression of frontal and occipital alpha power matched model-predicted EA signals: it tracked the goal-relevance of tastiness and healthiness attributes, predicted individual differences in successful down-regulation of tastiness, and conformed to the DDM-predicted time course of EA. We also found an earlier rise in frontal and occipital theta power that represented food tastiness more strongly during regulation, and predicted a weaker influence of food tastiness on behaviour. Our findings suggest that different regulatory strategies may commonly recruit theta-mediated control processes to modulate the attribute influence on EA.
SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function
Authors: Winkler Emma S. , Bailey Adam L. , Kafai Natasha M. , Nair Sharmila , McCune Broc T. , Yu Jinsheng , Fox Julie M. , Chen Rita E. , Earnest James T. , Keeler Shamus P. , Ritter Jon H. , Kang Liang-I , Dort Sarah , Robichaud Annette , Head Richard , Holtzman Michael J. , Diamond Michael S.
Published: July 2020

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.
Examining the boundary sharpness coefficient as an index of cortical microstructure and its relationship to age and sex in autism spectrum disorder
Authors: Olafson Emily , Bedford Saashi , Devenyi Gabriel A. , Patel Raihaan , Tullo Stephanie , Park Min Tae M. , Parent Olivier , Anagnostou Evdokia , Baron-Cohen Simon , Bullmore Edward T. , Chura Lindsay R. , Craig Michael C. , Ecker Christine , Floris Dorothea L. , Holt Rosemary J. , Lenroot Rhoshel , Lerch Jason P. , Lombardo Michael V. , Murphy Declan G. M. , Raznahan Armin , Ruigrok Amber N. V. , Spencer Michael D. , Suckling John , Taylor Margot J. ,   MRC AIMS Consortium, Lai Meng-Chuan , Chakravarty M. Mallar
Published: July 2020

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multi-center magnetic resonance structural imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male) and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Increases were observed in different brain regions in males and females, with larger effect sizes in females. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. BSC correlated with ADOS-2 CSS in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared to cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.
Dosage-sensitive functions in embryonic development drove the survival of genes on sex-specific chromosomes in snakes, birds, and mammals
Authors: Bellott Daniel W. , Page David C.
Published: July 2020

Different ancestral autosomes independently evolved into sex chromosomes in snakes, birds, and mammals. In snakes and birds, females are ZW, while males are ZZ; in mammals, females are XX and males are XY. While X and Z chromosomes retain nearly all ancestral genes, sex-specific W and Y chromosomes suffered extensive genetic decay. In both birds and mammals, the genes that survived on sex-specific chromosomes are enriched for broadly expressed, dosage sensitive regulators of gene expression, subject to strong purifying selection. To gain deeper insight into the processes that govern survival on sex-specific chromosomes, we carried out a meta-analysis of survival across 41 species — three snakes, 24 birds and 14 mammals — doubling the number of ancestral genes under investigation and increasing our power to detect enrichments among survivors relative to non-survivors. Out of 2573 ancestral genes, representing an eighth of the ancestral amniote genome, only 322 survive on present-day sex-specific chromosomes. Survivors are enriched for dosage sensitive developmental processes, particularly development of the face. However, there was no enrichment for expression in sex-specific tissues, involvement in sex-determination or gonadogenesis pathways, or conserved sex-biased expression. Broad expression and dosage sensitivity contributed independently to gene survival, suggesting that pleiotropy imposes additional constraints on the evolution of dosage compensation. We propose that maintaining the viability of the heterogametic sex drove gene survival on amniote sex-specific chromosomes, and that subtle modulation of the expression of survivor genes and their autosomal orthologs has disproportionately large effects on development and disease.
Discovery of clinically approved drugs capable of inhibiting SARS-CoV-2in vitroinfection using a phenotypic screening strategy and network-analysis to predict their potential to treat covid-19
Authors: Sales-Medina Douglas Ferreira , Ferreira Ludmila Rodrigues Pinto , Romera Lavínia M. D. , Gonçalves Karolina Ribeiro , Guido Rafael V. C. , Courtemanche Gilles , Buckeridge Marcos S. , Durigon Édison L. , Moraes Carolina B. , Freitas-Junior Lucio H.
Published: July 2020

The disease caused by SARS-CoV2, covid-19, rapidly spreads worldwide, causing the greatest threat to global public health in the last 100 years. This scenario has become catastrophic as there are no approved vaccines to prevent the disease, and the main measures to contain the virus transmission are confinement and social distancing. One priority strategy is based on drug repurposing by pursuing antiviral chemotherapy that can control transmission and prevent complications associated with covid-19. With this aim, we performed a high content screening assay for the discovery of anti-SARS-CoV-2 compounds. From the 65 screened compounds, we have found four drugs capable to selectively inhibit SARS-CoV-2in vitroinfection: brequinar, abiraterone acetate, neomycin, and the extract ofHedera helix. Brequinar and abiraterone acetate had higher inhibition potency against SARS-CoV-2 than neomycin andHedera helixextract, respectively. Drugs with reported antiviral activity and in clinical trials for covid-19, chloroquine, ivermectin, and nitazoxanide, were also included in the screening, and the last two were found to be non-selective. We used a data mining approach to build drug-host molecules-biological function-disease networks to show in a holistic way how each compound is interconnected with host node molecules and virus infection, replication, inflammatory response, and cell apoptosis. In summary, the present manuscript identified four drugs with active inhibition effect on SARS-CoV-2in vitroinfection, and by network analysis, we provided new insights and starting points for the clinical evaluation and repurposing process to treat SARS-CoV-2 infection.

Summary sentence

Discovery of drug repurposing candidates, inhibitors of SARS-CoV-2 infectionin vitro, using a phenotypic screening strategy and network analysis.
Molecular analysis of binding region of an ACE2 as a receptor for SARS-CoV-2 between humans and mammals
Authors: Hayashi Takuma , Aboko Kaoru , Mandan Masaki , Yaegashi Nobuo , Konishi Ikuo
Published: July 2020

In June 2020, a second wave of coronavirus disease-2019 (COVID-19) infections raised concern in Beijing, where salmon sold a fresh fish wholesale market was suspected of being the source of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. It has raised questions in the press and elsewhere about the scientific basis of salmon as a source of infection. With the number of cases growing, the surface of a salmon chopping board in the market was examined for the presence of SARS-CoV-2 and a positive reaction was observed. Following these test results, there has been debate over whether salmon can be infected with SARS-CoV-2. To find assess this, we investigated the structural homology of angiotensin-converting enzyme 2 (ACE2), a host-side receptor for SARS-CoV-2, between humans and other species including salmon and mink. As a result, a high structural homology between ACE2 and mink, which has reportedly transmitted SARS-CoV-2 to humans, was confirmed. However, a non-high structural homology of ACE2 between salmon and humans was observed. Further experiments are needed to find the source of SARS-CoV-2 transmission to the salmon.
Synchronous and opponent thermosensors use flexible cross-inhibition to orchestrate thermal homeostasis
Authors: Hernandez-Nunez Luis , Chen Alicia , Budelli Gonzalo , Richter Vincent , Rist Anna , Thum Andreas S. , Klein Mason , Garrity Paul , Samuel Aravinthan D.T.
Published: July 2020

Body temperature homeostasis is an essential function that relies upon the integration of the outputs from multiple classes of cooling- and warming-responsive cells. The computations that integrate these diverse outputs to control body temperature are not understood. Here we discover a new set of Warming Cells (WCs), and show that the outputs of these WCs and previously described Cooling Cells (CCs1) are combined in a cross-inhibition computation to drive thermal homeostasis in larvalDrosophila. We find that WCs and CCs are opponent sensors that operate in synchrony above, below, and near the homeostatic set-point, with WCs consistently activated by warming and inhibited by cooling, and CCs the converse. Molecularly, these opponent sensors rely on overlapping combinations of Ionotropic Receptors to detect temperature changes: Ir68a, Ir93a, and Ir25a for WCs; Ir21a, Ir93a, and Ir25a for CCs. Using a combination of optogenetics, sensory receptor mutants, and quantitative behavioral analysis, we find that the larva uses flexible cross-inhibition of WC and CC outputs to locate and stay near the homeostatic set-point. Balanced cross-inhibition near the set-point suppresses any directed movement along temperature gradients. Above the set-point, WCs mediate avoidance to warming while cross-inhibiting avoidance to cooling. Below the set-point, CCs mediate avoidance to cooling while cross-inhibiting avoidance to warming. Our results demonstrate how flexible cross-inhibition between warming and cooling pathways can orchestrate homeostatic thermoregulation.
Ethanolamine improves colonic barrier functions and inflammatory immunoreactions via shifting microbiome dysbiosis
Authors: Zhou Jian , Xiong Xia , Wan Dan , Liu Hongnan , Shao Yirui , Wu Yuliang , Huang Xiali , Peng Chanfeng , Huang Pan , Zou Lijun , Yin Yulong
Published: July 2020

Ethanolamine(EA) often occurs at a relatively high concentration within the inflamed gut of IBD patients. To investigate the role of EA in colonic inflammation and host-microbiome dysbiosis, thirty-six ICR mice were treated with 3% DSS for a week to generate acute intestinal inflammation and then supplied with 0μM, 500μM (LowEA), and 3000 μM (HighEA) in drinking water for two weeks, after that,16s RNA sequencing was applied in characterizing the changes in colonic microbiota driven by different EA levels. An inflamed colonic organoid model via 3% DSS treatment was also established for further verification of these in vivo findings.EA significantly reduced proximal colonic crypt depth but increased distal colonic villus height in HighEA group. The protein and mRNA expression of occludin and Reg3β, BD1, BD2, and MUC2were significantly up-regulated in EA treated groups. EA decreased mucosal inflammation-related cytokines levels (IL1, IL6, IL17, TNFα, and INFγ) and increased the significantly increased concentration of sIgA. Serum aspartate aminotransferase and alanine aminotransferase were significantly down-regulated in the highEA group. EA increased the relative abundance ofBlautia, Roseburia, Lactobacillus, Faecalibaculum, Candidatus_Saccharimonas, Alloprevotella, andLachnoclostridum.and thus microbial metabolic pathways includingOxidative phosphorylation, Lipopolysaccharide biosynthesis, Arginine and proline metabolism, Folate biosynthesis, andBiotin metabolismwere more abundant in LowEA group than those in control. EA up-regulated the protein or mRNA expression of TLR4/MyD88 in colonic tissues and the DSS-treated colonic organoid model. This study firstly demonstrated that ethanolamine in altering host-microbiome dysbiosis, which may provide new insights into the role of dietary lipids in IBD.

Importance

Inflammatory bowel disease (IBD) affects ~3.1 million people in the USA and is increasing in incidence worldwide. IBD pathogenesis has been associated with gut microbiome dysbiosis characterized as a decrease in gut microbial diversity. Extensive works have demonstrated the roles of dietary fiber, short-chain fatty acids, and aromatic amino acids in altering the composition of gut microbiota to restore immune homeostasis and alleviate inflammation via diverse mechanisms in IBD. However, little is known about essential sphingolipids like ethanolamine (EA), an essential compound in the CDP-ethanolamine pathway for phosphatidylethanolamine (PE) in both intestinal cells and bacteria. PE synthesis deficiency can ultimately result in a loss of membrane integrity and metabolic disorders in IBD. Our results demonstrate that ethanolamine could improve colonic barrier functions and inflammatory immunoreactions via shifting microbiome dysbiosis, which provides new insights into the role of dietary lipids in IBD.
Caspofungin resistance inCandia aurisdue to mutations inFks1 with adjunctive role of chitin and key cell wall stress response pathway genes
Authors: Sharma Dipti , Paul Raees A. , Chakrabarti Arunaloke , Bhattacharya Sanjay , Soman Rajeev , Shankarnarayan Shamanth A , Chavan Dipali , Singh Shreya , Das Parijit , Kaur Harsimran , Ghosh Anup K , Rudramurthy Shivaprakash M
Published: July 2020

The emergence of echinocandin resistance inC. aurishas become a major concern. Point mutations in Fks1 subunit of β-D-glucan synthase is the primary mechanism in echinocandin resistance. However, resistant isolates with wild typeFks1 are not infrequent. We screened 199 clinicalC. aurisisolates from 30 centres across India for echinocandin resistance. The cohort also contained six sequential isolates from a liver transplant recipient. Eleven isolates (5.7%) from 11 patients, and those six serial isolates had elevated echinocandin minimum inhibitory concentrations (MIC). Three of these 17 isolates carried S639F mutation in hot spot 1 region ofFks1. A novelFks1 mutation, F635Y was identified in two resistant isolates, and a related F635L mutation was detected in four of the six sequential isolates. Resistant isolates (MIC≥2 mg/L) and those with intermediate caspofungin susceptibility (MIC, 1.0 mg/L) demonstrated higher induction of chitin synthase gene,Chs1 [resistant, 2.2(1.3-5.8); intermediate, 6(2.5-11.2)] compared to susceptible isolates [1.2(0.8-2), P<0.05]. However, the expression of theFks1subunit of β-1, 3-glucan synthase was higher only in intermediate group [3.4(2-8.5), P<0.01].HOG1 MAP kinase showed higher inducible expression in intermediate isolates, while those ofHSP90-like protein andCnaB were comparable in resistant and intermediate groups. In one isolate pan-echinocandin resistance mediated by S639F mutation coupled with high basal chitin content was noted. This study reports novel mutation F635Y/L inFks1inC. auris, contributing to echinocandin resistance and suggests the possible adjunctive roles of chitin synthase,Fks1, and cell wall-remodeling pathway gene upregulation in caspofungin resistance.