bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Diphenyl Diselenide on Thiol Redox Homeostasis and Electrogenic Membrane Transport in Rotenone-Induced Parkinson’s Disease
Authors: Ologunagba Titilayo Ibironke , Olorundare Bunmi Olaoluwa , Iyanda Titilope , Adewole Adenike , Kade Ige Joseph 
Published: November 2022

ABSTRACTThe central role of oxidative stress in the etiology of Parkinsons disease defines a key therapeutic role for antioxidant compounds in the management of the disease. Redox-sensitive proteins such as the Na+/K+-ATPase have also been implicated as one of the targets of oxidative stress. The present study sought to investigate the role of diphenyl diselenide (DPDSe) in amelioration of disturbed redox homeostasis and modulation of enzyme activity caused by rotenone administration to Wistar albino rats. In determining the best route of rotenone administration, animals were grouped into four namely: control, oral, intraperitoneal (IP) and subcutanoeus (SC) and administered rotenone (3mg/kg) via oral, intraperitoneal (IP) and subcutaneous routes, with controls receiving the vehicle (2% DMSO + 98% normal saline (0.85%)). Having observed a more deleterious impact in the with he IP route, this mode of rotenone administration was selected along with oral administration of DPDSe (10mg/kg). this was done with four groups of animals namely: control, DPDSe, rotenone and DPDSe+rotenone. The effect of treatment was evaluated after seven days for total and non-protein thiol levels, lipid peroxidation and Na+/K+-ATPase activity. The result demonstrated the antioxidant potential of DPDSe in attenuating depletion of thiols, and lipid peroxidation caused by rotenone. It is apparent that DPDSe is a promising therapeutic agent in the management of PD, hence further investigations into its impact on different pathways is expedient in the search for an effective treatment for PD.HighlightsIntraperitoneal administration of rotenone gives a comparatively faster development of Parkinson’s disease features in rodentsRotenone mediates depletion of total and non-protein thiol levels in the pathogenesis of Parkinson’s diseaseDiphenyl diselenide significantly attenuates thiol depletion and lipid peroxidation mediated by rotenoneRotenone-mediated inactivation of Na+/K+-ATPase in Parkinson’s disease etiology may involve ATP depletion
System-wide mapping of neuropeptide-GPCR interactions inC. elegans
Authors: Beets Isabel , Zels Sven , Vandewyer Elke , Demeulemeester Jonas , Caers Jelle , Baytemur Esra , Schafer William R. , Vértes Petra E. , Mirabeau Olivier , Schoofs Liliane 
Published: November 2022

SummaryNeuropeptides are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many neuropeptides remain elusive, as our insight into neuropeptide-receptor interactions is limited and many peptide GPCRs in animal models and humans are still orphan receptors. Here we report a genome-wide neuropeptide-GPCR interaction map inC. elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into neuropeptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems inC. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network.HighlightsSystem-wide reverse pharmacology deorphanizes 68C. eleganspeptide GPCRsDiscovery of 461 peptide-GPCR pairs and additional ligands for characterized GPCRsNeuropeptides show specific and complex combinatorial receptor interactionsPeptide-GPCR pairs support long-range conservation and expansion of peptide systems
Chromosome fissions and fusions act as barriers to gene flow betweenBrenthisfritillary butterflies
Authors: Mackintosh Alexander , Vila Roger , Laetsch Dominik R. , Hayward Alex , Martin Simon H. , Lohse Konrad 
Published: November 2022

AbstractChromosome rearrangements are thought to promote reproductive isolation between incipient species. However, it is unclear how often, and under what conditions, fission and fusion rearrangements act as barriers to gene flow. Here we investigate speciation between two largely sympatric fritillary butterflies,Brenthis daphneand B. ino. We use a composite likelihood approach to infer the demographic history of these species from whole genome sequence data. We then compare chromosome-level genome assemblies of individuals from each species and identify a total of nine chromosome fissions and fusions. Finally, we fit a demographic model where effective population sizes and effective migration rate vary across the genome, allowing us to quantify the effects of chromosome rearrangements on reproductive isolation. We show that chromosomes involved in rearrangements experienced less effective migration since the onset of species divergence and that genomic regions near rearrangement points have a further reduction in effective migration rate. Our results suggest that the evolution of multiple rearrangements in theB. daphneandB. inopopulations, including alternative fusions of the same chromosomes, have resulted in a reduction in gene flow. While fission and fusion of chromosomes are unlikely to be the only processes that have led to speciation between these butterflies, this study shows that these rearrangements can directly promote reproductive isolation and may be involved in speciation when karyotypes evolve quickly.
Nucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state
Authors: Wang Lixin , Paudel B. Bishal , McKnight R. Anthony , Janes Kevin A. 
Published: November 2022

ABSTRACTActivation of HER2/ErbB2 coincides with escape from ductal carcinoma in situ (DCIS) premalignancy and disrupts 3D organization of cultured breast-epithelial spheroids. The 3D phenotype is infrequent, however, and mechanisms for its incomplete penetrance have been elusive. Using inducible HER2/ErbB2–EGFR/ErbB1 heterodimers, we matched phenotype penetrance to the frequency of co-occurring transcriptomic changes and uncovered a reconfiguration in the karyopherin network regulating ErbB nucleocytoplasmic transport. Induction of the exportin CSE1L inhibits nuclear accumulation of ErbBs, whereas nuclear ErbBs silence the importin KPNA1 by inducing miR-205. When these negative feedbacks are incorporated into a validated systems model of nucleocytoplasmic transport, steady-state localization of ErbB cargo becomes ultrasensitive to initial CSE1L abundance. Erbb2-driven carcinomas with Cse1l deficiency outgrow less irregularly from mammary ducts, and NLS-attenuating mutants or variants of HER2 favor escape in 3D culture. We conclude here that adaptive nucleocytoplasmic relocalization of HER2 creates a systems-level molecular switch at the premalignant-to-malignant transition.
Breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation
Authors: Lei Pin-Ji , Pereira Ethel R. , Andersson Patrik , Amoozgar Zohreh , Van Wijnbergen Jan Willem , O’Melia Meghan , Zhou Hengbo , Chatterjee Sampurna , Ho William W. , Posada Jessica M. , Kumar Ashwin Srinivasan , Morita Satoru , Chung Charlie , Ergin Ilgin , Jones Dennis , Huang Peigen , Beyaz Semir , Padera Timothy P. 
Published: November 2022

SummaryTumor-draining lymph nodes are critical sites for generating tumor antigen-specific T cells and are associated with durable immune responses. However, lymph nodes are often the first site of metastasis and lymph node metastases portend worse outcomes. Through cross-species single cell gene expression analysis of breast cancer progression and metastasis to lymph nodes, we uncovered features that define the heterogeneity, plasticity, and immune evasion of cancer cells. Notably, a subpopulation of metastatic cancer cells in the lymph node were marked by high levels of MHC class II (MHC-II) gene expression both in mice and humans. Mechanistically, the IFN-γ and JAK/STAT signaling pathways mediate MHC-II expression in cancer cells. Ablation of IFNGR1/2 or CIITA, the transactivator of MHC-II, in cancer cells prevented tumor progression. Interestingly, MHC-II+ cancer cells lacked co-stimulatory molecule expression, engendered the expansion of regulatory T cells and blunted CD4+ effector T cells in the tumor-draining lymph nodes and favor tumor progression. Overall, our data suggests that cancer cell plasticity during breast cancer progression and metastasis to lymph nodes endows metastatic cells with the ability to avoid immune surveillance. These data provide the basis for new opportunities to therapeutically stimulate anti-cancer immune responses against local and systemic metastases.
Mouse behaviour on the trial-unique non-matching-to-location (TUNL) touchscreen task reflects a mixture of distinct working memory codes and response biases
Authors: Bennett Daniel , Nakamura Jay , Vinnakota Chitra , Sokolenko Elysia , Nithianantharajah Jess , van den Buuse Maarten , Jones Nigel C. , Sundram Suresh , Hill Rachel 
Published: November 2022

AbstractThe trial-unique non-matching to location (TUNL) touchscreen task shows promise as a translational assay of working memory deficits in disorders including autism, ADHD, and schizophrenia. Although it is commonly assumed that the TUNL task predominantly measures spatial working memory in rodents, this proposition has not previously been tested. In this project, we used computational modelling of behaviour from mice performing the TUNL task (totalN= 163 mice across three datasets; 158,843 total trials). Contrary to common assumptions, behaviour on the TUNL task did not exclusively reflect spatial working memory. Instead, choice behaviour was explained as a mixture of both retrospective (spatial) working memory and prospective working memory for an intended behavioural response, as well as animal-specific response biases. We suggest that these findings can be understood within a resource-rational cognitive framework, and propose several task-design principles that we predict will maximise spatial working memory and minimise alternative behavioural strategies.
Punishment Risk Task: Monitoring anxiogenic states during goal directed actions in mice
Authors: Parker Kyle E. , Arackal Joel S. , Hunter Sarah C. , Hammarsten Carl , McCall Jordan G. 
Published: November 2022

Summary/AbstractCanonical preclinical studies of anxiety-related behavioral states use exploration of novel spaces to test approach-avoidance conflicts such as the open field test, elevated plus maze, and light-dark box. However, these assays cannot evaluate complicated behaviors in which competing states of motivation result in anxiogenic behaviors. Furthermore, these assays can only test the approach-avoidance conflict once due to a reliance on spatial novelty. Here we demonstrate the punishment risk task (PRT) in male and female, group- and singly-housed mice, a model initially described in singly-housed male rats by Park and Moghaddam (2017). The task tests how probabilistic punishment affects reward-seeking behavior. In particular, it measures the delay to pursue a reward (sweetened food pellet) while the likelihood of punishment (foot shock) actively impinges reward-associated actions. Here, we found that mice show increased latency to respond to food reward cues in trials in which the probability of punishment is highest. Further, anxiolytic treatment with diazepam or propranolol block any increase in response latency, indicating the model’s potential to for study of anxiogenesis in mice. Elucidating how these competitive behavioral states are integral to adaptive behavior and change over time and experience to coordinate anxiogenesis should greatly benefit anxiety disorder research. Specifically, implementing this assay in mice will enable cell-type selective interrogation of these processes and further our understanding of the neural basis of anxiogenesis.
Unsupervised Clustering Applied to Electronic Health Record-derived Phenotypes in Patients with Heart Failure
Authors: Reza Nosheen , Yang Yifan , Bone William P. , Singhal Pankhuri , Verma Anurag , Denduluri Srinivas , Adusumalli Srinath , Ritchie Marylyn D. , Cappola Thomas P. 
Published: November 2022

ABSTRACTBackgroundHigh-dimensional electronic health records (EHR) data can be used to phenotype complex diseases. The aim of this study is to apply unsupervised clustering to EHR-based traits derived in a cohort of patients with heart failure (HF) from a large integrated health system.MethodsUsing the institutional EHR, we identified 8569 patients with HF and extracted 1263 EHR-based input features, including clinical, echocardiographic, and comorbidity data, prior to the time of HF diagnosis. Principal component analysis, Uniform Manifold Approximation and Projection, and spectral clustering were applied to the input features after sex stratification of the cohort. The optimal number of clusters for each sex-stratified group was selected by highest Silhouette score and by within-cluster and between-cluster sums of squares. Determinants of cluster assignment were evaluated.ResultsWe identified four clusters in each of the female-only (44%) and male-only (56%) cohorts. Sex-specific cohorts differed significantly by age of HF diagnosis, left ventricular chamber size, markers of renal and hepatic function, and comorbidity burden (all p<0.001). Left ventricular ejection fraction was not a strong driver of cluster assignment.ConclusionReadily available EHR data collected in the course of routine care can be leveraged to accurately classify patients into major phenotypic HF subtypes using data driven approaches.
Negligible peptidome diversity of SARS-CoV-2 and its higher taxonomic ranks
Authors: Chong Li Chuin , Khan Asif M. 
Published: November 2022

AbstractThe unprecedented increase in SARS-CoV-2 sequence data limits the application of alignment-dependent approaches to study viral diversity. Herein, we applied our recently published UNIQmin, an alignment-free tool to study the protein sequence diversity of SARS-CoV-2 (sub-species) and its higher taxonomic lineage ranks (species, genus, and family). Only less than 0.5% of the reported SARS-CoV-2 protein sequences are required to represent the inherent viral peptidome diversity, which only increases to a mere ∼2% at the family rank. This is expected to remain relatively the same even with further increases in the sequence data. The findings have important implications in the design of vaccines, drugs, and diagnostics, whereby the number of sequences required for consideration of such studies is drastically reduced, short-circuiting the discovery process, while still providing for a systematic evaluation and coverage of the pathogen diversity.
Evaluation of GABAAR-mediated inhibition in the human brain using TMS-evoked potentials
Authors: Šulcová Dominika , Salatino Adriana , Ivanoiu Adrian , Mouraux André 
Published: November 2022

AbstractGABAAreceptor (GABAAR) – mediated inhibition participates in the control of cortical excitability, and its impairment likely contributes to the pathologic excitability changes that have been associated with multiple neurological disorders. Therefore, there is a need for its direct evaluation in the human brain, and the combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) might represent the optimal tool. TMS-evoked brain potentials (TEPs) capture the spread of activity across the stimulated brain network, and since this process at least partially depends on the GABAAR-mediated inhibition, TEPs may constitute relevant biomarkers of local GABAAergic function.Here, we aimed to assess the effect of GABAARs activation using TEPs, and to identify TEP components that are sensitive to the state of GABAAergic inhibition. In 20 healthy subjects, we recorded TEPs evoked by sub- and supra-threshold stimulation of the primary motor cortex (M1), motor-evoked potentials (MEPs) and resting-state EEG (RS-EEG). GABAARs were activated (1) pharmacologically by oral administration of alprazolam compared to placebo within each subject, and (2) physiologically using a sub-threshold conditioning stimulus to characterize the effect of short-latency intracortical inhibition (SICI).In supra-threshold TEPs, alprazolam suppressed the amplitude of components N17, N100 and P180, and increased component N45. The pharmacological modulation of N17 correlated with the change observed in MEPs and with the alprazolam-induced increase of lower β-band RS-EEG. Only a reduction of N100 and P180 was found in sub-threshold TEPs. TEP SICI manifested as a reduction of N17, P60 and N100, and its effect on N17 correlated with the alprazolam-induced N17 suppression and β increase. Our results indicate that N17 of supra-threshold TEPs could serve as a non-invasive biomarker of local cortical excitability reflecting the state of GABAAR-mediated inhibition in the sensorimotor network. Furthermore, the alprazolam-induced increase of β-band oscillations possibly corresponds to the increased inhibitory neurotransmission within this network.
A mesocorticolimbic signature of pleasure in the human brain
Authors: Kragel Philip A. , Treadway Michael T. , Admon Roee , Pizzagalli Diego A. , Hahn Emma C. 
Published: November 2022

AbstractPleasure is a fundamental driver of human behavior, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula, and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translational parity. However, whether activation observed across these regions reflects a common, generalizable code for pleasure driven by opioidergic mechanisms remains unclear. Here we use pattern recognition techniques to develop a human functional magnetic resonance imaging signature of mesocorticolimbic activity unique to states of pleasure. In independent validation tests, we find this signature has high sensitivity to pleasant tastes and positive affect evoked by humor. The signature is spatially coextensive with mu-opioid receptor gene expression, and its response is attenuated by the opioid antagonist naloxone. These findings provide evidence of a basis for pleasure derived from primary and secondary rewards in humans that is distributed across brain systems, and suggest that similar mechanisms underlie hedonic impact across mammalian species.
Single cell CRISPR base editor engineering and transcriptional characterization of cancer mutations
Authors: Kim Heon Seok , Grimes Susan M. , Sathe Anuja , Lau Billy T. , Ji Hanlee P. 
Published: November 2022

ABSTRACTWe developed a multiplexed single cell technology to genome engineer mutations, directly delineate their genotype among individual cells and determine each mutation’s transcriptional phenotype. This approach uses CRISPR base editors to introduce predesignated variants into a target gene. Long-read sequencing of the target gene’s transcript identifies the engineered mutations among individual cells. Simultaneously, we analyzed the transcriptome profile from the same set of cells by short-read sequencing. By integrating the two types of data, we determined the mutations’ genotype and expression phenotype at single cell resolution. Using cell lines, we engineered and evaluated the phenotype of more than 100TP53mutations. Based on the single cell gene expression, we classified the mutations as having a functionally significant phenotype versus the wild-type state. We validated these results on a subset of mutations using isolated clones analyzed with RNA-seq. Overall, we successfully demonstrated single cell mutation engineering and phenotypic assessment.
Developing an automated skeletal phenotyping pipeline to leverage biobank-level medical imaging databases
Authors: Cataldo-Ramirez Chelsea C. , Haddad David , Amenta Nina , Weaver Timothy D. 
Published: November 2022

AbstractObjectivesCollecting skeletal measurements from medical imaging databases remains a tedious task, limiting the research utility of biobank-level data. Here we present an automated phenotyping pipeline for obtaining skeletal measurements from DXA scans and compare its performance to manually collected measurements.Materials and MethodsA pipeline that extends and modifies the Advanced Normalization Tools (ANTs) framework was developed on 341 whole-body DXA scans of UK Biobank South Asian participants. A set of 10 measurements throughout the skeleton was automatically obtained via this process, and the performance of the method was tested on 20 additional DXA images by calculating percent error and concordance correlation coefficients (CCC) for manual and automated measurements. Stature was then regressed on the automated femoral and tibia lengths and compared to published stature regressions to further assess the reliability of the automated measurements.ResultsBased on percent error and CCC, the performance of the automated measurements falls into three categories: poor (sacral and acetabular breadths), variable (trunk length, upper thoracic breadth, and innominate height), and high (maximum pelvic aperture breadth, bi-iliac breadth, femoral maximum length, and tibia length). Stature regression plots indicate that the automated measurements reflect realistic body proportions and appear consistent with published data reflecting these relationships in South Asian populations.DiscussionBased on the performance of this pipeline, a subset of measurements can be reliably extracted from DXA scans, greatly expanding the utility of biobank-level data for biological anthropologists and medical researchers.
Axon guidance pathways modulate neurotoxicity of ALS-associated UBQLN2
Authors: Kim Sang Hwa , Nichols Kye D. , Anderson Eric N. , Liu Yining , Ramesh Nandini , Jia Weiyan , Kuerbis Connor J. , Scalf Mark , Smith Lloyd M. , Pandey Udai Bhan , Tibbetts Randal S. 
Published: November 2022

AbstractMutations in the ubiquitin (Ub) chaperoneUbiquilin 2 (UBQLN2)cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage ofUnc-5or its coreceptorDcc/frazzleddiminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALSalleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALSknockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALSalleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.