bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence of selection in UCP1 gene region suggests local adaptation to irradiance rather than cold temperatures in savanna monkeys (Chlorocebus spp.)
Authors: Gagnon Christian M. , Svardal Hannes , Jasinska Anna J. , Cramer Jennifer Danzy , Freimer Nelson B. , Grobler J. Paul , Turner Trudy R. , Schmitt Christopher A. 
Published: July 2022

AbstractThe genus Chlorocebus is widely distributed throughout sub-Saharan Africa, and in the last 300 thousand years expanded from equatorial Africa into the southernmost latitudes of the continent. In these new environments, colder climate was a likely driver of natural selection. We investigated population-level genetic variation in the mitochondrial uncoupling protein 1 (UCP1) gene region – implicated in non-shivering thermogenesis within brown/beige adipocytes – in 73 wild savanna monkeys from three taxa representing this southern expansion (C. pygerythrus hilgerti, C. cynosuros, C. p. pygerythrus) ranging from Kenya to South Africa. We found 17 SNPs with extended haplotype homozygosity consistent with positive selective sweeps, 10 of which show no significant LD with each other. Phylogenetic generalized least squares modeling with ecological covariates suggest that most derived allele frequencies are significantly associated with solar irradiance and winter precipitation, rather than overall low temperatures. This selection and association with irradiance appears to be driven by a population isolate in the southern coastal belt of South Africa. We suggest that sunbathing behaviors common to savanna monkeys, in combination with strength of solar irradiance, may mediate adaptations to thermal stress via non-shivering thermogenesis among savanna monkeys. The variants we discovered all lie in non-coding regions, some with previously documented regulatory functions, calling for further validation and research.
Adaptive duplication and functional diversification of Protein kinase R contribute to the uniqueness of bat-virus interactions
Authors: Jacquet Stéphanie , Culbertson Michelle , Zang Chi , El Filali Adil , De La Myre Mory Clément , Pons Jean-Baptiste , Filippi-Codaccioni Ondine , Lauterbur M. Elise , Ngoubangoye Barthélémy , Duhayer Jeanne , Verez Clément , Park Chorong , Dahoui Clara , Carey Clayton M. , Brennan Greg , Enard David , Cimarelli Andrea , Rothenburg Stefan , Elde Nels C. , Pontier Dominique , Etienne Lucie 
Published: July 2022

AbstractSeveral bat species act as asymptomatic reservoirs for many viruses that are instead highly pathogenic in other mammals. Here, we have characterized the functional diversification of the Protein kinase R (PKR), a major antiviral innate defense system. Our data indicate that PKR has evolved under positive selection and has undergone repeated genomic duplications in bats, in contrast to all studied mammals that possess a single copy of the gene. Functional testing of the relationship between PKR and poxvirus antagonists revealed how an evolutionary conflict with ancient pathogenic poxviruses has shaped a specific bat host-virus interface. More importantly, we determined that duplicated PKRs of the Myotis species have undergone functional diversification allowing them to collectively escape from and enhance control of DNA and RNA viruses. These findings suggest that viral-driven adaptations in PKR contribute to modern virus-bat interactions and may account for bat specific immunity.
Linking impulsivity to activity levels in pre-supplementary motor area during sequential gambling
Authors: Lohse Allan , Løkkegaard Annemette , Siebner Hartwig R. , Meder David 
Published: July 2022

AbstractImpulsivity refers to the tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Since the pre-supplementary motor area (preSMA) has been implicated in inhibitory control, this region may also contribute to impulsivity. Here, we examined whether functional recruitment of preSMA may contribute to risky choice behavior (state impulsivity) during sequential gambling and its relation to self-reported trait impulsivity. To this end, we performed task-based functional MRI (fMRI) after low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the preSMA. We expected low-frequency rTMS to modulate task-related engagement of the preSMA and hereby, tune the tendency to make risky choices. 24 healthy volunteers (12 females, 19-52 years) received real or sham rTMS on separate days in counterbalanced order. Thereafter, participants performed a sequential gambling task with concurrently increasing stakes and risk during whole-brain fMRI. In the sham-rTMS session, self-reported trait impulsivity scaled positively with state impulsivity (riskier choice behavior) during gambling. The higher the trait-impulsivity, the lower was the task-related increase in preSMA activity with increasingly risky choices. Following real-rTMS, low-impulsivity participants increased their preference for risky choices, while the opposite was true for high-impulsivity participants resulting in an overall decoupling of trait impulsivity and state impulsivity during gambling. This rTMS-induced behavioral shift was mirrored in the rTMS-induced change in preSMA activation. These results provide converging evidence for a causal link between the level of task-related preSMA activity and the propensity for impulsive risk-taking behavior in the context of sequential gambling.Significance statementImpulsivity is a personal trait characterized by a tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. The pre-supplementary motor area (preSMA) has been implicated in inhibitory control. Here, we provide evidence that this region contributes to the implementation of general impulsive tendencies (trait impulsivity) into actual behavior (state impulsivity). When healthy volunteers performed a sequential gambling task, their choice behavior (i.e., state impulsivity) correlated positively with their impulsivity score (i.e, trait impulsivity). Additionally, participants with lower trait impulsivity showed a stronger increase in task-related activity of the preSMA with increasing risk. Both of these relationships were uncoupled after perturbing the preSMA with repetitive transcranial stimulation (rTMS).
Hippocampal grading provides higher Alzheimer’s Disease prediction accuracy than hippocampal volume
Authors: Morrison Cassandra , Dadar Mahsa , Shafiee Neda , Collins D. Louis ,   Alzheimer’s Disease Neuroimaging Initiative
Published: July 2022

AbstractBackgroundFinding an early biomarker of Alzheimer’s disease (AD) is essential to develop and implement early treatments. Much research has focused on using hippocampal volume to measure neurodegeneration in aging and Alzheimer’s disease (AD). However, a new method to measure hippocampal change, known as hippocampal grading, has shown enhanced predictive power in older adults. It is unknown whether this method can capture hippocampal changes at each progressive stage of AD better than hippocampal volume. The goal of this study was to determine if hippocampal grading is more strongly associated with group differences between normal controls (NC), early MCI (eMCI), late (lMCI), and AD than hippocampal volume.MethodsData from 1666 Alzheimer’s Disease Neuroimaging Initiative older adults with baseline MRI scans were included in the first set of analyses (513 normal controls NC, 269 eMCI, 556 lMCI, and 328 AD). Sub-analyses were also completed using only those that were amyloid positive (N=834; 179 NC, 148 eMCI, 298 lMCI, and 209 AD). We compared seven different classification techniques to classify participants into their correct cohort using 10-fold cross-validation. The following classifiers were applied: support vector machines, decision trees, k-nearest neighbors, error-correcting output codes, binary Gaussian kernel, binary linear, and random forest. These multiple classifiers enable comparison to other research and examination of the most suitable classifier for Scoring by Nonlocal Image Patch Estimator (SNIPE) grading, SNIPE volume, and Freesurfer volume. This model was then validated in the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL).ResultsSNIPE grading provided the highest classification accuracy over SNIPE volume and Freesurfer volume for all classifications in both the full sample and amyloid positive sample. When classifying NC from AD, SNIPE grading provided an accuracy of 89% for the full sample and 87% for the amyloid positive group. Much lower accuracies of 65% and 46% were obtained when using Freesurfer in the full sample and amyloid positive sample, respectively. Similar accuracies were obtained in the AIBL validation cohort for SNIPE grading (NC vs AD: 90% classification accuracy).ConclusionThese findings suggest that SNIPE grading offers increased prediction accuracy compared to both SNIPE volume and Freesurfer volume. SNIPE grading offers promise as a means to classify between people with and without AD. Future research is needed to determine the predictive power of grading at detecting conversion to MCI and AD in amyloid positive cognitively normal older adults (i.e., early in the AD continuum).Key pointsHC grading may better classify different disease cohorts than HC volumeHigher prediction accuracy was obtained for HC grading than HC volumeHC grading offers promise as a method to detect declines in aging and Alzheimer’s
Brief intensive social gaze training normalizes functional brain connectivity in boys with fragile X syndrome
Authors: Saggar Manish , Bruno Jennifer L. , Hall Scott S. 
Published: July 2022

AbstractBoys with fragile X syndrome (FXS), the leading known genetic cause of autism spectrum disorder (ASD), demonstrate significant impairments in social gaze and associated weaknesses in communication, social interaction, and other areas of adaptive functioning. Little is known, however, concerning the impact of behavioral treatments for these behaviors on functional brain connectivity in this population. As part of a larger study, boys with FXS (mean age 13.23 +/- 2.31 years) and comparison boys with ASD (mean age 12.15 +/- 2.76 years) received resting-state magnetic resonance imaging scans prior to and following social gaze training administered by a trained behavior therapist in our laboratory. Network-agnostic connectome-based predictive modeling (CPM) of pre-treatment RSFC data revealed a set of positive (FXS > ASD) and negative (FXS < ASD) edges that differentiated the groups significantly and consistently across all folds of cross-validation. Following administration of the brief training, the FXS and ASD groups demonstrated normalization of connectivity differences. The divergence in the spatial pattern of normalization response, based on functional connectivity differences pre-treatment, suggests a unique pattern of response to treatment in the FXS and ASD groups. These results support using connectome-based predictive modeling as an outcome measure in clinical trials.
Impact of neuropsychiatric symptoms on limbic structures in age-related cognitive decline
Authors: Lucas Ronat , Van-Tien Hoang , Alexandru Hanganu ,   the ADNI
Published: July 2022

AbstractObjectivesNeuropsychiatric symptoms (NPS) are known to increase the risk of cognitive decline in aging. Several studies have investigated the brain substrates of these symptoms, reporting a broad involvement of the limbic regions.ParticipantsUsing the Alzheimer’s Disease Neuroimaging Initiative database, we investigated 223 participants with normal cognition, 367 with mild cognitive impairment (MCI) and 175 with Alzheimer’s disease (AD).MeasurementsNeuropsychiatric symptoms were assessed with the Neuropsychiatric Inventory and MRIs were processed with FreeSurfer. We used a general linear model (FreeSurfer) and multivariate analysis of covariance (IBM SPSS software) to establish the associations between the severity of neuropsychiatric symptoms and morphometry in cortical and subcortical structures in each clinical group.ResultsThe results outlined significant associations between cortical and subcortical structures and neuropsychiatric symptoms. In cognitively normal participants, only a positive association between nighttime behaviors and bilateral caudate nuclei volumes was found. In patients with MCI, agitation, depression, apathy and nighttime behaviors were respectively negatively associated with (i) left precentral and inferior frontal and inferior parietal volumes; (ii) left fusiform volume and area; (iii) right precentral thickness, left frontopolar area and bilateral ventral diencephalon volumes; (iv) right lingual thickness, whereas depression and nighttime behaviors were also respectively positively associated with right ventral diencephalon volume; and left temporal volume and area. In patients with Alzheimer’s disease, broader association were outlined between NPS severity and cortical structures notably agitation, apathy, irritability and nighttime behaviors outlined respectively positive associations with : (i) volumes in the right temporal regions and with surface area in the frontal region; (ii) the cortical thickness of the right pericalcarine region; (iii) volumes in the frontal, temporal and parietal regions; (iv) volume of the right cuneus region; whereas depression and apathy were also respectively negatively associated with the cortical thickness of the left parietal superior region; and cortical volume and area of the parietal regions.ConclusionsThese results showed that NPS have broad association patterns with associative brain structures and few associations with limbic structures. These associations were also dependent on the clinical stage of cognitive impairment.
Chronic fatigue, depression and anxiety symptoms in Long COVID are strongly predicted by neuroimmune and neuro-oxidative pathways which are caused by the inflammation during acute infection
Authors: Al-Hakeim Hussein Kadhem , Al-Rubaye Haneen Tahseen , Almulla Abbas F. , Al-Hadrawi Dhurgham Shihab , Maes Michael 
Published: July 2022

AbstractBackgroundLong-term coronavirus disease 2019 (Long COVID) is associated with physio-somatic (chronic fatigue syndrome and somatic symptoms) and affective (depression and anxiety) symptoms. The severity of the Long COVID physio-affective phenome is largely predicted by peak body temperature (BT) and lowered oxygen saturation (SpO2) during the acute infectious phase. This study aims to delineate whether the association of BT and SpO2 during the acute phase and the Long COVID physio-affective phenome is mediated by neurotoxicity (NT) resulting from activated immune-inflammatory and oxidative stress pathways.MethodsWe recruited 86 patients with Long COVID (3-4 months after the acute phase) and 39 healthy controls and assessed serum C-reactive protein (CRP), caspase-1, interleukin (IL)-1β, IL-18, IL-10, myeloperoxidase (MPO), advanced oxidation protein products (AOPP), total antioxidant capacity (TAC), and calcium (Ca), as well as peak BT and SpO2 during the acute phase.ResultsCluster analysis revealed that a significant part (34.9%) of Long COVID patients (n=30) show a highly elevated NT index computed based on IL-1β, IL-18, Caspase-1, CRP, MPO and AOPP. Partial Least Squares analysis showed that 61.6% of the variance in the physio-affective phenome of Long COVID is explained by the NT index, lowered Ca, peak BT/SpO2 in the acute phase, and prior vaccinations with Astra-Zeneca or Pfizer. The most important predictors of the physio-affective phenome are Ca, CRP, IL-1β, AOPP and MPO.ConclusionThe infectious-immune-inflammatory core of acute COVID-19 strongly predicts the development of physio-affective symptoms 3-4 months later, and these effects are partly mediated by neuro-immune and neuro-oxidative pathways.
RT-LAMP-CRISPR-Cas13a technology as a promising diagnostic tool for the SARS-CoV-2 virus
Authors: Ortiz-Cartagena Concha , Fernández-García Laura , Blasco Lucia , Pacios Olga , Bleriot Inés , López María , Cantón Rafael , Tomás María 
Published: July 2022

AbstractAt the end of 2019, the new coronavirus, SARS-CoV-2, began a pandemic that persists to date and which has caused more than 6.2 million deaths. In the last couple of years, researchers have made great efforts to develop a diagnostic technique that maintains high levels of sensitivity and specificity, since an accurate and early diagnosis is required to minimize the prevalence of SARS-CoV-2 infection. In this context, CRISPR-Cas systems are proposed as promising tools for development in diagnostic techniques due to their high specificity, highlighting that Cas13 endonuclease discriminates single nucleotide changes and displays a collateral activity against single stranded RNA molecules. With the aim of improve the sensitivity of the diagnosis, this technology is usually combined with isothermal pre-amplification reactions (SHERLOCK, DETECTR). Basing on this, we have developed an RT-LAMP-CRISPR-Cas13a for SARS-CoV-2 virus detection in nasopharyngeal samples without using RNA extraction kit that exhibited 100 % specificity and 83 % sensitivity, as well as a positive predictive value of 100 % and a negative predictive value of 100%, 81%, 79.1% and 66.7 % in <20 Ct, 20-30 Ct, >30 Ct and total Ct values, respectively.ImportanceDuring Covid19 crisis has driven the development innovative molecular diagnose including the CRISPR-Cas technology. This work we have performed a protocol working with RNA-extraction kit free samples, places RT-LAMP-CRISPR-Cas13a technology at the top of rapid and specific diagnostic methods for COVID19 due to the high levels of specificity (100%), sensitivity (83%), PPV (100%) and NPV (81% in high loads viral) obtained in clinical samples.
Enhanced hippocampal LTP but typical NMDA receptor and AMPA receptor function in a novel rat model of CDKL5 deficiency disorder
Authors: de Oliveira L Simões , O’Leary HE , Nawaz S. , Loureiro R , Davenport EC , Baxter P. , Dando OR , Perkins E. , Booker SA , Hardingham GE , Cousin MA , Chattarji S , Benke TA , Wyllie DJA , Kind PC 
Published: July 2022

AbstractMutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a novel Cdkl5 KO rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function underlie the enhanced LTP we observe in the hippocampus of Cdkl5 KO rats. We tested this hypothesis using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. We show that NMDA receptor function and subunit expression are unaltered throughout development, and Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 KO rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability in Cdkl5 KO rats and supported by typical expression of pre-synaptic proteins in synaptosome preparations. Together these data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits might contribute to the altered plasticity.
Human genetic adaptation related to cellular zinc homeostasis
Authors: Roca-Umbert Ana , Garcia-Calleja Jorge , Vogel-González Marina , Fierro-Villegas Alejandro , Ill-Raga Gerard , Herrera-Fernández Víctor , Bosnjak Anja , Muntané Gerard , Gutiérrez Esteban , Campelo Felix , Vicente Rubén , Bosch Elena 
Published: July 2022

AbstractSLC30A9encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.Author SummaryContrasting continental signatures of positive natural selection have been previously found in the humanSLC30A9gene encoding the protein ZnT9, which transports zinc across cell membranes. Here we investigate the genetic variants that have been targeted by natural selection in the surrounding region of this gene and which molecular and whole-body changes may have brought about. We found that two majorSLC30A9variant combinations (haplotypes) that are extremely frequent in Africa and East Asia, respectively, are expressed differentially. These two haplotypes also differ at one site that creates an amino acid difference at ZnT9; the version most often found outside Africa avoiding zinc overload in the endoplasmic reticulum and mitochondria and directly influencing mitochondrial activity. Moreover, we found that this substitution, which is known to be associated with greater susceptibility to several neuropsychiatric disorders, is present in the Denisova and displays accompanying patterns of variation that could be suggestive of adaptive introgression. Since mitochondria play an important role in skeletal muscle energy metabolism, we speculate that adaptation to cold may have driven this selection event outside Africa, while also impacting predisposition to neuropsychiatric disorders in modern humans.
Structural Modeling of Peptide Toxin - Ion Channel Interactions using RosettaDock
Authors: Mateos Diego Lopez , Yarov-Yarovoy Vladimir 
Published: July 2022

SUMMARYVoltage-gated ion channels play essential physiological roles in action potential generation and propagation. Peptidic toxins from animal venoms target ion channels and provide useful scaffolds for the rational design of novel channel modulators with enhanced potency and subtype selectivity. Despite recent progress in obtaining experimental structures of peptide toxin – ion channel complexes, structural determination of peptide toxins bound to ion channels in physiologically important states remains challenging. Here we describe an application of RosettaDock approach to structural modeling of peptide toxins interactions with ion channels. We tested this approach on 10 structures of peptide toxinion channel complexes and demonstrated that it can sample near-native structures in all tested cases. Our approach will be useful for improving understanding of the molecular mechanism of natural peptide toxin modulation of ion channel gating and for the structural modeling of novel peptide-based ion channel modulators.