bluuebunny/crossref_metadata_2025 huggingface dataset:
Apolipoprotein E genotype and MRI-detected brain alterations pertaining to neurodegeneration: A systematic review
Authors: Piersson Albert Dayor , Mohamad Mazlyfarina , Suppiah Subapriya , Rajab Nor Fadilah
Published: January 2021

Introduction

The effect of apolipoprotein E (APOE) genotype, particularly APOE ε4, the main genetic risk factor for late-onset Alzheimer’s disease (LOAD), has been widely explored in neuroimaging studies pertaining to older adults. The goal of this systematic review was to review the literature on the relationship between carriage of the APOE ε4 allele and grey matter (GM) changes across various age groups and its influence on neurodegeneration as evidenced by structural magnetic resonance imaging (MRI).

Methods

A search of the electronic databases Pubmed, Scopus, Ovid and Cochrane was carried out till March 2020. Only studies published in English were included. Risk of bias of each study was assessed using the modified Newcastle-Ottawa Scale.

Results

A total of 115 articles met the inclusion criteria. Methodological quality varied from poor to good. There is moderate evidence of reduced GM volume in the middle frontal gyrus, precuneus, hippocampus, hippocampal subfields, amygdala, parahippocampal gyrus, middle temporal lobe, whole temporal lobe, temporal pole, and posterior cingulate cortex in APOE ε4 carriers.

Conclusion

The present data supports the utility of the hippocampal GM volume to evaluate early structural neurodegenerative changes that occurs in APOE ε4 positive elderly individuals who are at increased risk of developing LOAD. Furthermore, the evidence supports serial measurements and comparison of hippocampal volume based on age group, to track the progression of neurodegeneration in APOE ε4 carriers. Additional longitudinal studies are necessary to confirm whether the combination of MRI-detected hippocampal atrophy with APOE ε4 carrier status, can better predict the development of LOAD in cognitively normal individuals.
An elongated COI fragment to discriminate botryllid species and as an improved ascidian DNA barcode
Authors: Salonna Marika , Gasparini Fabio , Huchon Dorothée , Montesanto Federica , Haddas-Sasson Michal , Ekins Merrick , McNamara Marissa , Mastrototaro Francesco , Gissi Carmela
Published: January 2021

Botryllids are colonial ascidians widely studied for their potential invasiveness and as model organisms, however the morphological description and discrimination of these species is very problematic, leading to frequent specimen misidentifications.

To facilitate species discrimination and detection of cryptic/new species, we developed new barcoding primers for the amplification of a COI fragment of about 860 bp (860-COI), which is an extension of the common Folmer’s barcode region. Our 860-COI was successfully amplified in 177 worldwide-sampled botryllid colonies. Combined with morphological analyses, 860-COI allowed not only discriminating known species, but also identifying undescribed and cryptic species, resurrecting old species currently in synonymy, and proposing the assignment of clade D of the model organismBotryllus schlosseritoBotryllus renierii. Importantly, within clade A ofB. schlosseri, 860-COI recognized at least two candidate species against only one recognized by the Folmer’s fragment, underlining the need of further genetic investigations on this clade. This result also suggests that the 860-COI could have a greater ability to diagnose cryptic/new species than the Folmer’s fragment at very short evolutionary distances, such as those observed within clade A. Finally, our new primers simplify the amplification of 860-COI even in non-botryllid ascidians, suggesting their wider usefulness in ascidians.
Invivo and systematic analysis of random multigenic deletions associated with human diseases during epithelial morphogenesis in Drosophila
Authors: Nagarajan Usha , Pakkiriswami Shanmugasundaram , Srinivasan Sandiya , Ramkumar Niveditha , Rajaraman Rajeswari , Thangaraj Kumarasamy
Published: January 2021

Random loss of multigenic loci on chromosomes, a crucial drive for evolution, occurs frequently in all living organisms. Analysis of such chromosomal disruption and understanding the consequences of their impact on the growth and development of multicellular organisms is challenging. In this report, we have addressed this issue using invivo mosaic analysis of deficiency lines in Drosophila. Genes on fly deficiency lines were compared with human orthologs for their implications in disease development during cytoskeletal processes and epithelial morphogenesis. The cytoskeletal phenotypes from the fly has been utilized to predict the function of human orthologs. In addition, as these Drosophila deficiency lines are equivalent to human microdeletions, based on the clonal behaviour and phenotypes generated, a systematic analysis has been carried out to establish the critical loci that correspond to Microdeletion Syndromes and Mendelian Disorders in humans. Further we have drawn the synteny that exists between these chromosomes and have identified critical region corresponding to defects. A few potential candidates that might have an implication in epithelial morphogenesis are also identified.
Neural relational inference to learn allosteric long-range interactions in proteins from molecular dynamics simulations
Authors: Zhu Jingxuan , Wang Juexin , Han Weiwei , Xu Dong
Published: January 2021

Protein allostery is a biological process facilitated by spatially long-range intra-protein communication, whereby ligand binding or amino acid mutation at a distant site affects the active site remotely. Molecular dynamics (MD) simulation provides a powerful computational approach to probe the allostery effect. However, current MD simulations cannot reach the time scales of whole allostery processes. The advent of deep learning made it possible to evaluate both spatially short and long-range communications for understanding allostery. For this purpose, we applied a neural relational inference (NRI) model based on a graph neural network (GNN), which adopts an encoder-decoder architecture to simultaneously infer latent interactions to probe protein allosteric processes as dynamic networks of interacting residues. From the MD trajectories, this model successfully learned the long-range interactions and pathways that can mediate the allosteric communications between the two distant binding sites in the Pin1, SOD1, and MEK1 systems.
Piezo2 mechanosensitive ion channel is located to sensory neurons and non-neuronal cells in rat peripheral sensory pathway: implications in pain
Authors: Shin Seung Min , Moehring Francie , Itson-Zoske Brandon , Fan Fan , Stucky Cheryl L. , Hogan Quinn H. , Yu Hongwei
Published: January 2021

Piezo2 mechanotransduction channel is a crucial mediator of sensory neurons for sensing and transducing touch, vibration, and proprioception. We here characterized Piezo2 expression and cell specificity in rat peripheral sensory pathway using a validated Piezo2 antibody. Immunohistochemistry using this antibody revealed Piezo2 expression in pan primary sensory neurons (PSNs) of dorsal rood ganglia (DRG) in naïve rats, which was actively transported along afferent axons to both central presynaptic terminals innervating the spinal dorsal horn (DH) and peripheral afferent terminals in skin. Piezo2 immunoreactivity (IR) was also detected in the postsynaptic neurons of the DH and in the motor neurons of the ventral horn, but not in spinal GFAP- and Iba1-positive glia. Notably, Piezo2-IR was clearly identified in peripheral non-neuronal cells, including perineuronal glia, Schwann cells in the sciatic nerve and surrounding cutaneous afferent endings, as well as in skin epidermal Merkel cells and melanocytes. Immunoblots showed increased Piezo2 in DRG ipsilateral to plantar injection of complete Freund’s adjuvant (CFA), and immunostaining revealed increased Piezo2-IR intensity in the DH ipsilateral to CFA injection. This elevation of DH Piezo2-IR was also evident in various neuropathic pain models and monosodium iodoacetate (MIA) knee osteoarthritis (OA) pain model, compared to controls. We conclude that 1) the pan neuronal profile of Piezo2 expression suggests that Piezo2 may function extend beyond simply touch/proprioception mediated by large-sized low-threshold mechanosensitive PSNs, 2) Piezo2 may have functional roles involving sensory processing in spinal cord, Schwann cells, and skin melanocytes, and 3) aberrant Piezo2 expression may contribute pain pathogenesis.
20-HETE-promoted cerebral blow flow autoregulation is associated with enhanced α-smooth muscle actin positive cerebrovascular pericyte contractility
Authors: Liu Yedan , Zhang Huawei , Yu Tina , Fang Xing , Ryu Jane J. , Zheng Baoying , Chen Zongbo , Roman Richard J. , Fan Fan
Published: January 2021

We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, N-Hydroxy-N′-(4-butyl-2-methylphenyl)-formamidine (HET0016) but restored with 20-HETE analog 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (WIT003). Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and rescued by WIT003. Lastly, HET0016 impaired well autoregulated CBF in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in CBF autoregulation.
Design considerations of a wearable electronic-skin for mental health and wellness: balancing biosignals and human factors
Authors: Khan Yasser , Mauriello Matthew L. , Nowruzi Parsa , Motani Akshara , Hon Grace , Vitale Nicholas , Li Jinxing , Kim Jayoung , Foudeh Amir , Duvio Dalton , Shols Erika , Chesnut Megan , Landay James , Liphardt Jan , Williams Leanne , Sudheimer Keith D. , Murmann Boris , Bao Zhenan , Paredes Pablo E.
Published: January 2021

Chronic stress has been associated with a variety of pathophysiological risks including developing mental illness. Conversely, appropriate stress management, can be used to foster mental wellness proactively. Yet, there is no existing method that accurately and objectively monitors stress. With recent advances in electronic-skin (e-skin) and wearable technologies, it is possible to design devices that continuously measure physiological parameters linked to chronic stress and other mental health and wellness conditions. However, the design approach should be different from conventional wearables due to considerations like signal-to-noise ratio and the risk of stigmatization. Here, we present a multi-part study that combines user-centered design with engineering-centered data collection to inform future design efforts. To assess human factors, we conducted ann=24 participant design probe study that examined perceptions of an e-skin for mental health and wellness as well as preferred wear locations. We complement this with ann=10 andn=16 participant data collection study to measure physiological signals at several potential wear locations. By balancing human factors and biosignals, we conclude that the upper arm and forearm are optimal wear locations.
Effect of Adolescent Stress on Adult Morphine-Induced Behavioral Sensitization is Dependent Upon Genetic Background
Authors: Kamens Helen M. , Miller Carley N. , Caulfield Jasmine I. , Zeid Dana , Horton William J. , Silva Constanza , Sebastian Aswathy , Albert Istvan , Gould Thomas J. , Fishbein Diana , Grigson P. Sue , Cavigelli Sonia A.
Published: January 2021

1

Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence – a critical period of frontal lobe development – influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the prefrontal cortex compared to control mice. The specificity of the effects for C57BL/6J versus BALB/cJ mice provides evidence of a gene by environmental interaction influencing opioid behaviors. Long-term differences in stress reactivity or miRNA expression suggests two possible biological mechanisms to evaluate in future research.
A critical role of AREG for bleomycin-induced skin fibrosis
Authors: Zhang Mary Yinghua , Fang Shuyi , Gao Hongyu , Zhang Xiaoli , Gu Dongsheng , Liu Yunlong , Wan Jun , Xie Jingwu
Published: January 2021

We report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene.Aregexpression is upregulated ~10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis,Aregis up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice withAregknockout, and found thatAregdeficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in theAregnull mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.
Early detection of SARS-CoV-2 infection cases or outbreaks at nursing homes by targeted wastewater tracking
Authors: Davó Laura , Seguí Raimundo , Botija Pilar , Beltrán María José , Albert Eliseo , Torres Ignacio , López-Fernández Pablo Ángel , Ortí Rafael , Maestre Juan Francisco , Sánchez Gloria , Navarro David
Published: January 2021

Objectives

Near-source tracking of SARS-CoV-2 RNA in the sewage drains serving particular buildings may allow rapid identification of SARS-CoV-2 infection cases or local outbreaks. In this pilot study, we investigated whether this was the case for nursing homes (NH).

Methods

The study involved five NH (from A to E) affiliated to the Clínico-Malvarrosa Health Department, Valencia (Spain). These were nursing or mixed nursing/care homes of different sizes, altogether providing care for 472 residents attended by a staff of 309. Near-source sewage samples were screened for presence of SARS-CoV-2 RNA by RT-qPCR at least 5 days per week during the study period. SARS-CoV-2 RNA testing in nasopharyngeal swabs from residents and staff was performed with the TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Massachusetts, USA).

Results

SARS-CoV-2 RNA was detected in wastewater samples from four of the five NH. SARS-CoV-2 infection cases were documented in three of these four NH. Of the two NH without SARS-CoV-2 infection cases, no SARS-CoV-2 RNA was detected in sewer samples from one facility, while it was repeatedly detected in samples from the other. Presence of SARS-CoV-2 RNA in sewage preceded identification of isolated cases among residents or staff or outbreak declaration in two NH, with lag times ranging from 5 to 19 days.

Conclusion

Our study demonstrated that intermittent or persistent detection of SARS-CoV-2 RNA in NH sewers can provide an early warning of subsequent individual cases or outbreaks in these facilities.
Associations between indicators of socioeconomic position and DNA methylation: A systematic review
Authors: Cerutti Janine K. , Lussier Alexandre A. , Zhu Yiwen , Liu Jiaxuan , Dunn Erin C.
Published: January 2021

Socioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possible explanation is through an epigenetic process called DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity, gene expression, and therefore long-term health. To understand the evidence supporting a potential SEP-DNAm link, we performed a systematic review of published empirical findings on the association between SEP (from prenatal development to adulthood) and DNAm measured across the life course, with an eye toward evaluating how the timing, duration, and type of SEP exposure influenced DNAm. Across the 37 studies we identified, there was some evidence for the effect of SEP timing and duration on DNAm, with early-life SEP and persistently low SEP being particularly strong indicators of DNAm. Different indicators of SEP also had some unique associations with DNAm profiles, suggesting that SEP is not a singular concept, but rather that different aspects of the socioeconomic environment can shift DNAm patterns through distinct pathways. These differences with respect to SEP timing, duration, and type were notable because they were detected even among heterogenous study designs. Overall, findings from this review underscore the importance of analyzing SEP timing, duration, and type, given the complex relationship between SEP and DNAm across the lifespan. To guide future research, we highlight current limitations in the literature and propose recommendations for overcoming some of these challenges.
Simulating the impact of different vaccination policies on the COVID-19 pandemic in New York City
Authors: Yang Wan , Kandula Sasikiran , Shaman Jeffrey
Published: January 2021

Purpose

To analyze potential COVID-19 epidemic outcomes in New York City under different SARS-CoV-2 virus circulation scenarios and vaccine rollout policies from early Jan 2021 to end of June 2021.

Key findings

In anticipation of the potential arrival and dominance of the more infectious SARS-CoV-2 variant:

Mass-vaccination would be critical to mitigating epidemic severity (26-52% reduction in infections, hospitalizations, and deaths, compared to no vaccination, provided the new UK variant supplants currently circulating variants).

Prioritizing key risk groups for earlier vaccination would lead to greater reductions in hospitalizations and deaths than infections. Thus, in general this would be a good strategy.

Current vaccination prioritization policy is suboptimal. To avert more hospitalizations and deaths, mass-vaccination of all individuals 65 years or older should be done as soon as possible. For groups listed in the same phase, 65+ year-olds should be given first priority ahead of others.

Available vaccine doses should be given to the next priority groups as soon as possible without awaiting hesitant up-stream groups.

While efficacy of vaccination off-protocol is unknown, provided immune response following a first vaccine dose persists, delaying the 2nd vaccine dose by ∼1 month (i.e. administer the two doses 8 weeks apart) can substantially reduce infections, hospitalizations, and deaths compared to the 3-week apart regimen. Across all scenarios tested here, delaying the 2nd vaccine dose leads to the largest reduction in severe epidemic outcomes (e.g. hospitalizations and deaths). Therefore, to protect as many people as possible, this strategy should be considered if rapid increases in infections, hospitalization or deaths and/or shortages in vaccines were to occur.
Incentivizing Multiple Objectives in Active Surveillance for Urban Disease Vectors
Authors: Arevalo-Nieto Claudia , Sheen Justin , Condori-Luna Gianfranco , Condori-Pino Carlos , Shinnick Julianna , Peterson Jennifer K. , Castillo-Neyra Ricardo , Levy Michael Z.
Published: January 2021

Large-scale vector control campaigns have successfully reduced infectious disease incidence around the world. In addition to preventing new infections, these campaigns produce a wealth of information about the distribution and density of insect vectors, which can be incorporated into risk maps. These maps can effectively communicate risk map data to technicians on the ground, although encouraging them to use the data remains a challenge. We carried out a series of rolling trials in which we evaluated risk map use under different incentive schemes. Participants in the studies were trained field technicians tasked with house-to-house surveillance for insect vectors of Chagas disease in Arequipa, Peru. A novel incentive scheme based on poker best achieved a dual objective: to encourage technicians to preferentially visit higher-risk houses while surveilling evenly across the search zone. The poker incentive structure may be well-suited to improve entomological surveillance activities and other complex multi-objective tasks.
Comparative Effects of E-cigarette Aerosol on Periodontium
Authors: Xu Fangxi , Aboseria Eman , Janal Malvin N , Pushalkar Smruti , Bederoff Maria V , Vasconcelos Rebeca , Sapru Sakshi , Paul Bidisha , Queiroz Erica , Makwana Shreya , Solarewicz Julia , Guo Yuqi , Aguallo Deanna , Gomez Claudia , Shelly Donna , Aphinyanaphongs Yindalon , Gordon Terry , Corby Patricia , Kamer Angela R. , Li Xin , Saxena Deepak
Published: January 2021

Introduction

Tobacco use is one of the main causes of periodontitis. E-cigarettes are gaining in popularity, and studies are needed to better understand the impact of e-cigarettes on oral health. Objective: To perform a longitudinal study to evaluate the adverse effects of e-cigarettes on periodontal health.

Methods

Naïve e-cigarette users, cigarette smokers, and non-smokers were recruited using newspaper and social media. Demographics, age, gender, and ethnicity, were recorded. Participants were scheduled for two visits 6 months apart. At each visit, we collected data on the daily frequency puffs of an e-cigarette, the number of cigarettes smokes, and other parameters, such as alcohol consumption. Carbon monoxide levels, cotinine levels, salivary flow rate, probing depth, and bleeding on probing were determined at both baseline and follow-up visits. P-values less than 0.05 were considered statistically significant.

Results

We screened 159 subjects and recruited 140 subjects. One-hundred-one subjects (31 cigarette smokers, 32 e-cigarette smokers, and 38 non-smokers) completed every assessment in both visits. The retention and compliance rate of subjects was 84.1%. The use of social media and craigslist was significant in recruiting e-cigarette subjects. Ethnicity and race differed between cohorts, as did average age in the male subjects. Carbon monoxide and salivary cotinine levels were highest among cigarette smokers. Bleeding on probing and average probing depths similarly increased over time in all three cohorts. Increase in the rates of severe periodontal disease were significantly higher in cigarette smokers and e-cigarette users than non-smokers. Confounding factors were subjects’ age as most of the e-cigarette group were much younger than cigarette smokers.

Conclusion

Among the recruited participants, periodontal severity status after 6 month was significantly worse in cigarette smokers and e-cigarette smokers than non-smokers. This study design and protocol will assist in future larger studies on e-cigarette and oral health.
ORFLine: a bioinformatic pipeline to prioritise small open reading frames identifies candidate secreted small proteins from lymphocytes
Authors: Hu Fengyuan , Lu Jia , Munoz Manuel D. , Saveliev Alexander , Turner Martin
Published: January 2021

The annotation of small open reading frames (smORFs) of less than 100 codons (<300 nucleotides) is challenging due to the large number of such sequences in the genome. The recent development of next generation sequence and ribosome profiling enables identification of actively translated smORFs. In this study, we developed a computational pipeline, which we have named ORFLine, that stringently identifies smORFs and classifies them according to their position within transcripts. We identified a total of 5744 unique smORFs in datasets from mouse B and T lymphocytes and systematically characterized them using ORFLine. We further searched smORFs for the presence of a signal peptide, which predicted known secreted chemokines as well as novel micropeptides. Five novel micropeptides show evidence of secretion and are therefore candidate mediators of immunoregulatory functions.
A combined computational fluid dynamics and MRI Arterial Spin Labeling modeling strategy to quantify patient-specific cerebral hemodynamics in cerebrovascular occlusive disease
Authors: Schollenberger Jonas , Osborne Nicholas Harold , Hernandez-Garcia Luis , Figueroa C. Alberto
Published: January 2021

Cerebral hemodynamics in the presence of cerebrovascular occlusive disease (CVOD) are influenced by the anatomy of the intracranial arteries, the degree of stenosis, the patency of collateral pathways, and the condition of the cerebral microvasculature. Accurate characterization of cerebral hemodynamics is a challenging problem. In this work, we present a strategy to quantify cerebral hemodynamics using computational fluid dynamics (CFD) in combination with arterial spin labeling MRI (ASL). First, we calibrated patient-specific CFD outflow boundary conditions using ASL-derived flow splits in the Circle of Willis. Following, we validated the calibrated CFD model by evaluating the fractional blood supply from the main neck arteries to the vascular territories using Lagrangian particle tracking and comparing the results against vessel-selective ASL (VS-ASL). Finally, cerebral hemodynamics were assessed in two patients with CVOD and a healthy control subject. We demonstrated that the calibrated CFD model accurately reproduced the fractional blood supply to the vascular territories, as obtained from VS-ASL. The two patients revealed significant differences in pressure drop over the stenosis, collateral flow, and resistance of the distal vasculature, despite similar degrees of clinical stenosis severity. Our results demonstrated the advantages of a patient-specific CFD analysis for assessing the hemodynamic impact of stenosis.
Spiking recurrent neural networks represent task-relevant neural sequences in rule-dependent computation
Authors: Xue Xiaohe , Halassa Michael M. , Chen Zhe S.
Published: January 2021

Prefrontal cortical neurons play in important roles in performing rule-dependent tasks and working memory-based decision making. Motivated by experimental data, we develop an excitatory-inhibitory spiking recurrent neural network (SRNN) to perform a rule-dependent two-alternative forced choice (2AFC) task. We imposed several important biological constraints onto the SRNN, and adapted the spike frequency adaptation (SFA) and SuperSpike gradient methods to update the network parameters. These proposed strategies enabled us to train the SRNN efficiently and overcome the vanishing gradient problem during error back propagation through time. The trained SRNN produced rule-specific tuning in single-unit representations, showing rule-dependent population dynamics that strongly resemble experimentally observed data in rodent and monkey. Under varying test conditions, we further manipulated the parameters or configuration in computer simulation setups and investigated the impacts of rule-coding error, delay duration, weight connectivity and sparsity, and excitation/inhibition (E/I) balance on both task performance and neural representations. Overall, our modeling study provides a computational framework to understand neuronal representations at a fine timescale during working memory and cognitive control.

Author Summary

Working memory and decision making are fundamental cognitive functions of the brain, but the circuit mechanisms of these brain functions remain incompletely understood. Neuroscientists have trained animals (rodents or monkeys) to perform various cognitive tasks while simultaneously recording the neural activity from specific neural circuits. To complement the experimental investigations, computational modeling may provide an alternative way to examine the neural representations of neuronal assemblies during task behaviors. Here we develop and train a spiking recurrent neural network (SRNN) consisting of balanced excitatory and inhibitory neurons to perform the rule-dependent working memory tasks Our computer simulations produce qualitatively similar results as the experimental findings. Moreover, the imposed biological constraints on the trained network provide additional channel to investigate cell type-specific population responses, cortical connectivity and robustness. Our work provides a computational platform to investigate neural representations and dynamics of cortical circuits a fine timescale during complex cognitive tasks.
A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases and prostate cancer progression
Authors: Magraner-Pardo Lorena , Laskowski Roman A. , Pons Tirso , Thornton Janet M.
Published: January 2021

DNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have dire consequences as damaged DNA can result in cells turning cancerous. Here we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein-protein interaction interfaces. We show that somatic variants are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in theATM, BRCA1andBRCA2genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.
DDX24, a D-E-A-D box RNA helicase, is required for muscle fiber organization and anterior pole specification essential for head regeneration in planarians
Authors: Sarkar Souradeep R. , Dubey Vinay Kumar , Jahagirdar Anusha , Lakshmanan Vairavan , Haroon Mohamed Mohamed , Sowndarya Sai , Sowdhamini Ramanathan , Palakodeti Dasaradhi
Published: January 2021

Planarians have a remarkable ability to undergo whole-body regeneration. The timely establishment of polarity at the wound site followed by the specification of the organizing centers- the anterior pole and the posterior pole, are indispensable for successful regeneration. In planarians, polarity, pole, and positional-information determinants are predominantly expressed by muscles. The molecular toolkit that enables this functionality of planarian muscles however remains poorly understood. Here we report that SMED_DDX24, a D-E-A-D Box RNA helicase and the homolog of human DDX24, is critical for planarian head regeneration. DDX24 is enriched in muscles and its knockdown leads to defective muscle-fiber organization and failure to re-specify anterior pole/organizer. Overall, loss of DDX24 manifests into gross misregulation of many well-characterized positional-control genes and patterning-control genes, necessary for organogenesis and tissue positioning and tissue patterning. In addition, wound-induced Wnt signalling was also upregulated inddx24RNAi animals. Canonical WNT-βCATENIN signalling is known to suppress head identity throughout bilateria, including planarians. Modulating this Wnt activity byβ-catenin-1RNAi, the effector molecule of this pathway, partially rescues theddx24RNAi phenotype, implying that a high Wnt environment inddx24knockdown animals likely impedes their normal head regeneration. Furthermore, at a sub-cellular level, RNA helicases are known to regulate muscle mass and function by regulating their translational landscape.ddx24knockdown leads to the downregulation of large subunit ribosomal RNA and the 80S ribosome peak, implying its role in ribosome biogenesis and thereby influencing the translational output. This aspect seems to be an evolutionarily conserved role of DDX24. In summary, our work demonstrates the role of a D-E-A-D box RNA helicase in whole-body regeneration through muscle fiber organization, and pole and positional-information re-specification, likely mediated through translation regulation.
Survey of peridomestic mammal susceptibility to SARS-CoV-2 infection
Authors: Bosco-Lauth Angela M. , Root J. Jeffrey , Porter Stephanie M. , Walker Audrey E. , Guilbert Lauren , Hawvermale Daphne , Pepper Aimee , Maison Rachel M. , Hartwig Airn E. , Gordy Paul , Bielefeldt-Ohmann Helle , Bowen Richard A.
Published: January 2021

Wild animals have been implicated as the origin of SARS-CoV-2, but it is largely unknown how the virus affects most wildlife species and if wildlife could ultimately serve as a reservoir for maintaining the virus outside the human population. Here we show that several common peridomestic species, including deer mice, bushy-tailed woodrats, and striped skunks, are susceptible to infection and can shed the virus in respiratory secretions. In contrast, we demonstrate that cottontail rabbits, fox squirrels, Wyoming ground squirrels, black-tailed prairie dogs, house mice, and racoons are not susceptible to SARS-CoV-2 infection. Our work expands upon the existing knowledge base of susceptible species and provides evidence that human-wildlife interactions could result in continued transmission of SARS-CoV-2.
Experimental evidence for the benefits of higher X-ray energies for macromolecular crystallography
Authors: Storm S. L. S. , Axford D. , Owen R. L.
Published: January 2021

X-ray induced radiation damage is a limiting factor for the macromolecular crystallographer and data must often be merged from many crystals to yield complete datasets for structure solution of challenging samples. Increasing the X-ray energy beyond the typical 10-15 keV range promises to provide an extension of crystal lifetime via an increase in diffraction efficiency. To date however hardware limitations have negated any possible gains. Through the first use of a Cadmium Telluride Eiger2 detector and a beamline optimised for high energy data collection, we show that at higher energies fewer crystals will be required to obtain complete data, as the diffracted intensity per unit dose increases by a factor of more than 3 between 12.4 and 25 keV. Additionally, those higher energy data provide more information, evidenced by an increase in high-resolution limit of up to 0.3 Å, pointing to a high energy future for synchrotron-based macromolecular crystallography.
High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity
Authors: Choi Ryan , Zhou Mowei , Shek Roger , Wilson Jesse W. , Tillery Logan , Craig Justin K. , Salukhe Indraneel A. , Hickson Sarah E. , Kumar Neeraj , James Rhema M. , Buchko Garry W , Wu Ruilian , Huff Sydney , Nguyen Tu-Trinh , Hurst Brett L. , Cherry Sara , Barrett Lynn K. , Hyde Jennifer L. , Van Voorhis Wesley C.
Published: January 2021

SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1-20 μM range in vitro. Furthermore, Exebryl-1, a β-amyloid anti-aggregation molecule for Alzheimer’s therapy, was shown to have antiviral activity between 10 to 66 μM, in VERO, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.

Author summary

Drugs to treat COVID-19 are urgently needed. To address this, we searched libraries of drugs and drug-like molecules for inhibitors of an essential enzyme of the virus that causes COVID-19, SARS-CoV-2 nonstructural protein (nsp)15. We found several molecules that inhibited the nsp15 enzyme function and one was shown to be active in inhibiting the SARS-CoV-2 virus. This demonstrates that searching for SARS-CoV-2 nsp15 inhibitors can lead inhibitors of SARS-CoV-2, and thus therapeutics for COVID-19. We are currently working to see if these inhibitors could be turned into a drug to treat COVID-19.
A brief report of sleep and circadian rhythm quotas in a population of dog owners in North Carolina, USA
Authors: Patel Ujas A. , Gruen Margaret E. , Samson David R.
Published: January 2021

Objectives

To characterize sleep and circadian rhythms of a sample population of healthy, dog-owning adults from North Carolina, USA.

Methods

Actigraphy was used to analyze sleep-wake patterns in forty-two dog owners from the Raleigh area in North Carolina. Sleep quotas, including sleep duration, efficiency, and fragmentation were measured alongside a Non-parametric Circadian Rhythms Analysis (NPCRA) to quantify strength, consistency, and fragmentation of rhythms.

Results

Compared to females, males demonstrated later sleep onset and sleep end (p<0.01), greater wake after sleep onset and sleep fragmentation (P<0.001), and lower sleep efficiency (p<0.001). The NPCRA revealed comparable relative amplitude (strength) and interdaily stability (consistency), yet less intra-daily variability (fragmentation), than previously reported post-industrial samples.

Conclusions

This study adds to the current data available on sleep and circadian rhythms in discrete human populations and highlights the need for more research characterizing cross-cultural sleep and circadian rhythmicity.
Molecular determinants underlying DS2 activity at δ-containing GABAAreceptors
Authors: Falk-Petersen Christina B. , Rostrup Frederik , Löffler Rebekka , Buchleithner Stine , Harpsøe Kasper , Gloriam David E. , Frølund Bente , Wellendorph Petrine
Published: January 2021

Delta selective compound 2 (DS2) is one of the most widely used tools to study selective actions mediated by δ subunit-containing GABAAreceptors. DS2 was discovered over 10 years ago, but despite great efforts, the precise molecular site of action has remained elusive.

Using a combination of computational modeling, site-directed mutagenesis and cell-based pharmacological assays, we probed three potential binding sites for DS2 and analogs at α4β1δ receptors: an α4(+)δ(-)interface site in the extracellular domain (ECD), equivalent to the diazepam binding site in αβγ2receptors, and two sites in the transmembrane domain (TMD); one in the α4(+)β1(-)and one in the α4(-)β1(+)interface, with the α4(-)β1(+)site corresponding to the binding site for etomidate and a recently disclosed low-affinity binding site for diazepam. We show that mutations in the ECD site did not abrogate DS2 modulation. However, mutations in the TMD α4(+)β1(-)interface, either α4(S303L) of the α4(+)-side or β1(I289Q) of the β1(-)-side, convincingly disrupted the positive allosteric modulation by DS2. This was consistently demonstrated both in an assay measuring membrane potential changes and by whole-cell patchclamp electrophysiology and rationalized by docking studies. Importantly, general sensitivity to modulators was not compromised in the mutated receptors. This study sheds important light on the long-sought molecular recognition site for DS2, refutes the misconception that the selectivity of DS2 for δ-containing receptors is caused by a direct interaction with the δ-subunit, and instead points towards a functional selectivity of DS2 and its analogs via a surprisingly well-conserved binding pocket in the TMD.

Significance statement

δ-Containing GABAAreceptors represent potential drug targets for the treatment of several neurological conditions with aberrant tonic inhibition. Yet, no drugs are currently in clinical use. With the identification of the molecular determinants responsible for positive modulation by the know compound DS2, the ground is laid for design of ligands that selectively target δ-containing GABAAreceptor subtypes, for better understanding of tonic inhibition, and, ultimately, for rational development of novel drugs.
RGS14 modulates locomotor behavior and ERK signaling induced by environmental novelty and cocaine within discrete limbic structures
Authors: Foster Stephanie L. , Lustberg Daniel J. , Harbin Nicholas H. , Bramlett Sara N. , Hepler John R. , Weinshenker David
Published: January 2021

Rationale

In rodents, exposure to novel environments or psychostimulants promotes locomotor activity. Indeed, locomotor reactivity to novelty strongly predicts behavioral responses to psychostimulants in animal models of addiction. RGS14 is a plasticity restricting protein with unique functional domains that enable it to suppress ERK-dependent signaling as well as regulate G protein activity. Although recent studies show that RGS14 is expressed in multiple limbic regions implicated in psychostimulant- and novelty-induced hyperlocomotion, its function has been studied almost entirely in the context of hippocampal physiology and hippocampusdependent behaviors.

Objective

We sought to determine whether RGS14 modulates novelty- and psychostimulant-induced locomotion and neuronal activity.

Methods

We assessedRgs14knockout (RGS14 KO) mice and wild-type (WT) littermate controls using novelty-induced locomotion (NIL) and cocaine-induced locomotion (CIL) behavioral tests with subsequent quantification of c-fos and phosphorylated ERK (pERK) induction in limbic regions that express RGS14.

Results

Compared to WT controls, RGS14 KO mice exhibited attenuated locomotor responses in the NIL test, driven by avoidance of the center of the novel environment. By contrast, RGS14 KO mice demonstrated augmented peripheral locomotion in the CIL test conducted in either a familiar or novel environment. The absence of RGS14 enhanced induction of c-fos and pERK in the central amygdala and hippocampus (areas CA1 and CA2) when cocaine was administered in a novel environment.

Conclusions

RGS14 regulates novelty- and psychostimulant-induced hyperlocomotion, particularly with respect to thigmotaxis. Further, our findings suggest RGS14 may reduce neuronal activity in discrete limbic subregions by inhibiting ERK-dependent signaling and transcription.
Plasma biomarkers of Alzheimer’s disease predict cognitive decline and could improve clinical trials in the cognitively unimpaired elderly
Authors: Cullen Nicholas C. , Leuzy Antoine , Janelidze Shorena , Palmqvist Sebastian , Svenningsson Anna L. , Stomrud Erik , Dage Jeffrey L. , Mattsson-Carlgren Niklas , Hansson Oskar
Published: January 2021

Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly indviduals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ±1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in the cognition (Pre-Alzheimer’s Clinical Composite; R2=0.14, 95% CI [0.12-0.17]; P<0.0001) and subsequent AD dementia (AUC=0.82, 95% CI [0.77-0.91], P<0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54-81]; P<0.001) with cognition as trial endpoint, and by 63% (95% CI [53-70], P<0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.
A discursive analysis of compliance, resistance and escalation to threats in sexually exploitative interactions between offenders and male children
Authors: Seymour‐Smith Sarah , Kloess Juliane A.
Published: January 2021

There is a notable scarcity of empirical studies focusing on online sexual grooming using real world, naturally occurring data. Limited research with real victims (as opposed to decoys) has indicated that more overt forceful threats are employed by offenders in such interaction; however, they tell us little about how these threats are built up and managed by both parties. Furthermore, the majority of research focuses on female victims, with limited attention paid to male victims. The current study presents a discursive psychology analysis of chat logs between one offender (posing as a teenage girl) and five male victims under the age of 16 years, in order to explore how victims attempt to resist such manoeuvres in situ, and how offenders manage such resistance. The sexualized nature evidenced in our data contrasts with other findings which suggest that boys are not sexually solicited and that interactions with boys are less aggressive and forceful. Our findings demonstrate for the first time how an offender escalated his issuing of threats following victims’ resistance and non‐compliance to requests. Turning points that appeared odd in the online interactions suggest that they may be used to encourage children to be more reflective about any further engagement.