bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delta-9-tetrahydrocannabinol and cannabidiol in psychosis: A balancing act of the principal phyto-cannabinoids on human brain and behavior?
Authors: Ganesh Suhas , Cortes-Briones Jose , Martin Ashley M. Schnakenberg , Skosnik Patrick D , D’Souza Deepak C , Ranganathan Mohini 
Published: May 2021

AbstractDelta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience investigations. In this double-blind randomized placebo-controlled counterbalanced human laboratory experiment, we examined the effects of three different dose ratios of CBD: THC (1:1, 2:1 and 3:1) on ‘neural noise’, an electrophysiological biomarker of psychosis known to be sensitive to cannabinoids as well as subjective and psychotomimetic effects. Interestingly, the lowest CBD:THC ratio (1:1) resulted in maximal attenuation of both THC induced psychotomimetic effects (PANSS positive - ATS = 7.83, df = 1, pcorr = 0.015) and neural noise (ATS = 8.83, df = 1, pcorr = 0.009) with an inverse-linear dose response relationship. Further, in line with previous studies, addition of CBD did not reduce the subjective experience of THC induced “high” (p > 0.05 for all CBD doses).These novel results demonstrate that CBD attenuates THC induced subjective and objective effects relevant to psychosis- but in a dose/ratio dependent manner. Given the increasing global trend of cannabis liberalization and application for medical indications, these results assume considerable significance given the potential dose related interactions of these key phyto-cannabinoids.
SARS-like coronaviruses in horseshoe bats (Rhinolophus spp.) in Russia, 2020
Authors: Alkhovsky Sergey V. , Lenshin Sergey V. , Romashin Alexey V. , Vishnevskaya Tatyana V. , Vyshemirsky Oleg I. , Bulycheva Yulia I. , Lvov Dmitry K. , Gitelman Asya K. 
Published: May 2021

AbstractWe found and genetically described two novel SARS-like coronaviruses in feces and oral swabs of the great (R. ferrumequinum) and the lesser (R. hipposideros) horseshoe bats in southern region of Russia. The viruses, named Khosta-1 and Khosta-2, together with related viruses from Bulgaria and Kenya, form a separate phylogenetic lineage. We found an evidence of recombination events in evolutionary history of Khosta-1, which involved the acquisition of structural proteins S, E, and M as well as nonstructural genes ORF3, ORF6, ORF7a, and ORF7b from a virus that is closely related to Kenyan isolate BtKY72. Examination of bats by RT-PCR revealed that 62,5% of great horseshoe bats in one of the caves were positive for Khosta-1 virus while its overall prevalence was 14%. The prevalence of Khosta-2 was 1,75%. Our results show that SARS-like coronaviruses circulate in horseshoe bats in the region and provide a new data on their genetic diversity.
Platelet expression and reactivity after BNT162b2 vaccine administration
Authors: Klug Melissa , Lazareva Olga , Kirmes Kilian , Rosenbaum Marc , Lukas Marina , Weidlich Simon , Spinner Christoph D. , von Scheidt Moritz , Gosetti Rosanna , Baumbach Jan , Ruland Jürgen , Condorelli Gianluigi , Laugwitz Karl-Ludwig , List Markus , Bernlochner Isabell , Bongiovanni Dario 
Published: May 2021

AbstractSARS-CoV-2 infection induces a coagulopathy characterized by platelet activation and a hypercoagulable state with an increased incidence of cardiovascular events. The viral spike protein S has been reported to enhance thrombosis formation, stimulate platelets to release pro-coagulant factors and promote the formation of platelet-leukocyte aggregates even in absence of the virus. Although SARS-CoV-2 vaccines induce spike protein overexpression to trigger SARS-CoV-2-specific immune protection, thrombocyte activity has not been investigated in this context. Here, we provide the first phenotypic platelet characterization of healthy human subjects undergoing BNT162b2 vaccination.Using mass cytometry, we analyzed the expression of constitutive transmembrane receptors, adhesion proteins and platelet activation markers in 12 healthy donors before and at five different timepoints within four weeks after the first BNT162b2 administration. We measured platelet reactivity by stimulating thrombocyte activation with thrombin receptor-activating peptide (TRAP). Activation marker expression (P-Selectin, LAMP-3, LAMP-1, CD40L and PAC-1) did not change after vaccination. All investigated constitutive transmembrane proteins showed similar expressions over time. Platelet reactivity was not altered after BNT162b2 administration. Activation marker expression was significantly lower compared to an independent cohort of mild symptomatic COVID-19 patients analyzed with the same platform.This study reveals that BNT162b2 administration does not alter platelet protein expression and reactivity.
The New Therapeutics in Alzheimer’s Disease Longitudinal Cohort study (NTAD): study protocol
Authors: Lanskey Juliette H , Kocagoncu Ece , Quin Andrew J , Cheng Yun-Ju , Karadag Melek , Pitt Jemma , Isaac John , Lowe Stephen , Perkinton Michael , Raymont Vanessa , Singh Krish D , Woolrich Mark , Nobre Anna C , Henson Richard N , Rowe James B 
Published: May 2021

ABSTRACTIntroductionWith the pressing need to develop treatments that slow or stop the progression of Alzheimer’s disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease.Methods and AnalysisThe New Therapeutics in Alzheimer’s disease study (NTAD) aims to identify a biomarker set from magneto/electro-encephalographic that is sensitive to disease and progression over one year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimer’s disease and 30 healthy controls aged between 50 and 85 years. Repeat measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and magnetic resonance imaging) of participants with Alzheimer’s disease or mild cognitive impairment will be taken at baseline and at one year. To assess reliability of magneto/electro-encephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimer’s disease will undergo repeat magneto/electro-encephalographic two weeks after baseline. Clinical and cognitive assessment will be repeated at 2 years. Linear mixed models of baseline and longitudinal change in neurophysiology are the primary analyses of interest, supported by Bayesian inference. Additional outputs will include relative effect sizes for physiological markers, atrophy and cognitive change and the respective numbers needed to treat each arm of simulated clinical trials of a future disease modifying therapy.Ethics and disseminationThe study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group.STRENGTHS AND LIMITATIONS OF THIS STUDYStrengthsNTAD is a longitudinal, multicentre study of magneto/electro-encephalographic measures of Alzheimer’s disease progressionNTAD assesses the test-retest reliability of magneto/electro-encephalographic parametersAll participants with early-stage Alzheimer’s disease or mild cognitive impairment will be amyloid-positiveLimitationsAttrition during follow up may limit inferencesRecruitment is from volunteer panels and clinical services that may not reflect national diversity of people affected by Alzheimer’s disease
Incorporating structural knowledge into unsupervised deep learning for two-photon imaging data
Authors: Eichin Florian , Hackenberg Maren , Broichhagen Caroline , Kilias Antje , Schmoranzer Jan , Bartos Marlene , Binder Harald 
Published: May 2021

AbstractLive imaging techniques, such as two-photon imaging, promise novel insights into cellular activity patterns at a high spatio-temporal resolution. While current deep learning approaches typically focus on specific supervised tasks in the analysis of such data, we investigate how structural knowledge can be incorporated into an unsupervised generative deep learning model directly at the level of the video frames. We exemplify the proposed approach with two-photon imaging data from hippocampal CA1 neurons in mice, where we account for spatial structure with convolutional neural network components, disentangle the neural activity of interest from the neuropil background signal with separate foreground and background encoders and model gradual temporal changes by imposing smoothness constraints. Taken together, our results illustrate how such architecture choices facilitate a modeling approach that combines the flexibility of deep learning with the benefits of domain knowledge, providing an interpretable, purely image-based model of activity signals from live imaging data.Teaser sentenceUsing a neural network architecture that reflects domain knowledge provides an interpretable model of live cell imaging data.
A combined lifestyle intervention induces a sensitization of the blood transcriptomic response to a nutrient challenge
Authors: Gehrmann Thies , Beekman Marian , Deelen Joris , Partridge Linda , van de Rest Ondine , Mei Leon , Raz Yotam , de Groot Lisette , van der Breggen Ruud , Reinders Marcel J. T. , van den Akker Erik B. , Slagboom P. Eline 
Published: May 2021

AbstractThe global population is growing older. As age is a primary risk factor of (multi)morbidity, there is a need for novel indicators to predict, track, treat and prevent the development of disease. Lifestyle interventions have shown promising results in improving the health of participants and reducing the risk for disease, but in the elderly population, such interventions often show less reliable or subtle effects on health outcomes. This is further complicated by a poor understanding of the homeodynamics and the molecular effects of lifestyle interventions, by which their effects of a lifestyle intervention remain obscured. In the Growing Old Together (GOTO) study, we examined the responses of 164 healthy, elderly men and women to a 13-week combined physical and dietary lifestyle intervention. In addition to collecting blood samples at a fasted state, we sampled blood also 30 minutes following a standardized meal. This allows us to investigate an intervention response not only in the traditional fasted state, but also in the blood metabolic and cellular responses to a nutrient challenge. We investigated the transcriptomic and metabolomic responses to this nutrient challenge, how these responses relate to each other, and how this response is affected by the lifestyle intervention.We find that the intervention has very little effect on the fasted blood transcriptome, but that the nutrient challenge induces a large translational inhibition, and an innate immune activation, which together comprise a cellular stress response that is stimulated by the intervention. A sex-specific analysis reveals that although the same set of genes respond in the same direction in both males and females, the magnitude of these effects differ, and are modulated differently by the intervention. On the other hand, the metabolomic response to the nutrient challenge is largely unaffected by the intervention, and the correlation between the metabolomic nutrient response and transcriptomic modules indicates that the change in transcriptomic response to the nutrient challenge is independent from a change in cellular metabolomic environment.This work constitutes a glance at the acute transcriptomic stress response to nutrient intake in blood, and how a lifestyle intervention affects this response in healthy elderly, and may lead to the development of novel biomarkers to capture the phenotypic flexibility of health.
Y recombination arrest and degeneration in the absence of sexual dimorphism
Authors: Lenormand Thomas , Roze Denis 
Published: May 2021

AbstractCurrent theory proposes degenerated sex chromosomes evolve via three successive steps: recombination arrest, which links male-beneficial alleles to the Y chromosome; degeneration of these regions due to the inefficacy of natural selection in the absence of recombination; and lastly, the evolution of dosage compensation to correct the resulting low expression of X-linked genes in males. Here we investigate new models of sex chromosome evolution incorporating the coevolution of cis- and trans-regulators of gene expression. We show that the early emergence of dosage compensation favors the maintenance of Y-linked inversions by creating sex-antagonistic regulatory effects. This is followed by inversion degeneration caused by regulatory divergence between the X and Y chromosomes. In stark contrast to the current theory, the whole process occurs without any selective pressure related to sexual dimorphism.One Sentence SummaryTurning sex chromosome theory on its head: early evolution of dosage compensation can maintain successively forming Y chromosome strata that undergo genetic degeneration.
The processing of semantic complexity and co-speech gestures in schizophrenia: a naturalistic, multimodal fMRI study
Authors: Cuevas Paulina , He Yifei , Steines Miriam , Straube Benjamin 
Published: May 2021

AbstractSchizophrenia is marked by aberrant processing of complex speech and gesture, which may contribute functionally to its impaired social communication. To date, extant neuroscientific studies of schizophrenia have largely investigated dysfunctional speech and gesture in isolation, and no prior research has examined how the two communicative channels may interact in more natural contexts. Here, we tested if patients with schizophrenia show aberrant neural processing of semantically complex story segments, and if speech-associated gestures (co-speech gestures) might modulate this effect. In a functional MRI study, we presented to 34 participants (16 patients and 18 matched-controls) an ecologically-valid retelling of a continuous story, performed via speech and spontaneous gestures. We split the entire story into ten-word segments, and measured the semantic complexity for each segment with idea density, a linguistic measure that is commonly used clinically to evaluate aberrant language dysfunction at semantic level. Per segment, the presence of numbers of gestures varied (n = 0, 1, +2). Our results suggest that, in comparison to controls, patients showed reduced activation for more complex segments in the bilateral middle frontal and inferior parietal regions. Importantly, this neural aberrance was reduced in segments presented with gestures. Thus, for the first time with a naturalistic multimodal stimulation paradigm, we show that gestures reduced group differences when processing a natural story, probably by facilitating the processing of semantically complex segments of the story in schizophrenia.
Highly basic clusters in the HSV-1 nuclear egress complex drive membrane budding by inducing lipid ordering
Authors: Thorsen Michael K. , Lai Alex , Lee Michelle W. , Hoogerheide David P. , Wong Gerard C. L. , Freed Jack H. , Heldwein Ekaterina E. 
Published: May 2021

AbstractDuring replication of herpesviruses, capsids escape from the nucleus into the cytoplasm by budding at the inner nuclear membrane. This unusual process is mediated by the viral nuclear egress complex (NEC) that deforms the membrane around the capsid by oligomerizing into a hexagonal, membrane-bound scaffold. Here, we found that highly basic membrane-proximal regions (MPRs) of the NEC alter lipid order by inserting into the lipid headgroups and also promote negative Gaussian curvature. We also find that the electrostatic interactions between the MPRs and the membranes are essential for membrane deformation. One of the MPRs is phosphorylated by a viral kinase during infection, and the corresponding phosphomimicking mutations block capsid nuclear egress. We show that the same phosphomimicking mutations disrupt the NEC/membrane interactions and inhibit NEC-mediated buddingin vitro, providing a biophysical explanation for thein-vivophenomenon. Our data suggest that the NEC generates negative membrane curvature by both lipid ordering and protein scaffolding and that phosphorylation acts as an “off” switch that inhibits the membrane-budding activity of the NEC to prevent capsid-less budding.
Fusion of single-cell transcriptome and DNA-binding data, for genomic network inference in cortical development
Authors: Bartlett Thomas 
Published: May 2021

AbstractBackgroundNetwork models are well-established as very useful computational-statistical tools in cell biology. However, a genomic network model based only on gene expression data can, by definition, only infer gene co-expression networks. Hence, in order to infer gene regulatory patterns, it is necessary to also include data related to binding of regulatory factors to DNA.ResultsWe propose a new dynamic genomic network model, for inferring patterns of genomic regulatory influence in dynamic processes such as development. Our model fuses experiment-specific gene expression data with publicly available DNA-binding data. The method we propose is computationally efficient, and can be applied to genome-wide data with tens of thousands of transcripts. Thus, our method is well suited for use as an exploratory tool for genome-wide data. We apply our method to data from human fetal cortical development, and our findings confirm genomic regulatory patterns which are recognised as being fundamental to neuronal development.ConclusionsOur method provides a mathematical/computational toolbox which, when coupled with targeted experiments, will reveal and confirm important new functional genomic regulatory processes in mammalian development.
ModEst - Precise estimation of genome size from NGS data
Authors: Pfenninger Markus , Schönnenbeck Philipp , Schell Tilman 
Published: May 2021

AbstractPrecise estimates of genome sizes are important parameters for both theoretical and practical biodiversity genomics. We present here a fast, easy-to-implement and precise method to estimate genome size from the number of bases sequenced and the mean sequence coverage. To estimate the latter, we take advantage of the fact that a precise estimation of the Poisson distribution parameter lambda is possible from truncated data, restricted to the part of the coverage distribution representing the true underlying distribution. With simulations we could show that reasonable genome size estimates can be gained even from low-coverage (10X), highly discontinuous genome drafts. Comparison of estimates from a wide range of taxa and sequencing strategies with flow-cytometry estimates of the same individuals showed a very good fit and suggested that both methods yield comparable, interchangeable results.
Presence of a SARS-COV-2 protein enhances Amyloid Formation of Serum Amyloid A
Authors: Jana Asis K. , Greenwood Augustus B. , Hansmann Ulrich H. E. 
Published: May 2021

ABSTRACTA marker for the severeness and disease progress of COVID-19 is overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis. In order to understand whether SAA amyloidosis could also be a long-term risk of SARS-COV-2 infections we have used long all-atom molecular dynamic simulations to study the effect of a SARS-COV-2 protein segment on SAA amyloid formation. Sampling over 40 µs we find that presence of the nine-residue segment SK9, located at the C-terminus of the Envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils. Our results therefore suggest that SAA amyloidosis and related pathologies may be a long-term risk of SARS-COV-2 infections.
Landscape-Based Mutational Sensitivity Cartography and Network Community Analysis of the SARS-CoV-2 Spike Protein Structures: Quantifying Functional Effects of the Circulating Variants
Authors: Verkhivker Gennady M. , Agajanian Steve , Oztas Deniz Yazar , Gupta Grace 
Published: May 2021

AbstractStructural and biochemical studies SARS-CoV-2 spike mutants with the enhanced infectivity have attracted significant attention and offered several mechanisms to explain the experimental data. In this study, we used an integrative computational approach to examine molecular mechanisms underlying functional effects of the D614G mutation by exploring atomistic modeling of the SARS-CoV-2 spike proteins as allosteric regulatory machines. We combined atomistic simulations, deep mutational scanning and sensitivity mapping together with the network-based community analysis to examine structures of the native and mutant SARS-CoV-2 spike proteins in different functional states. Conformational dynamics and analysis of collective motions in the SARS-CoV-2 spike proteins demonstrated that the D614 position anchors a key regulatory cluster that dictates functional transitions between open and closed states. Using mutational scanning and sensitivity analysis of the spike residues, we identified the evolution of stability hotspots in the SARS-CoV-2 spike structures of the mutant trimers. The results offer support to the reduced shedding mechanism of as a driver of the increased infectivity triggered by the D614G mutation. By employing the landscape-based network community analysis of the SARS-CoV-2 spike proteins, our results revealed that the D614G mutation can promote the increased number of stable communities in the open form by enhancing the stability of the inter-domain interactions. This study provides atomistic view of the interactions and stability hotspots in the SARS-CoV-2 spike proteins, offering a useful insight into the molecular mechanisms of the D614G mutation that can exert its functional effects through allosterically induced changes on stability of the residue interaction networks.
Humanized substitutions of Vmat1 in mice alter amygdala-dependent behaviors associated with the evolution of anxiety
Authors: Sato Daiki X. , Inoue Yukiko U. , Morimoto Yuki , Inoue Takayoshi , Kuga Nahoko , Sasaki Takuya , Ikegaya Yuji , Nomoto Kensaku , Kikusui Takefumi , Hattori Satoko , Sala Giovanni , Hagihara Hideo , Miyakawa Tsuyoshi , Kawata Masakado 
Published: May 2021

AbstractThe human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that affect monoamine uptake into synaptic vesicles. These substitutions are absent in all known mammals, suggesting their contributions to distinct aspects of human behavior modulated by monoaminergic transmission, such as emotion and cognition. To directly test the impact of these human-specific mutations, we introduced the humanized residues into mouse Vmat1 via CRISPR/Cas9-mediated genome editing and examined changes at the behavioral, neurophysiological and molecular levels. Behavioral tests revealed reduced anxiety-related traits of Vmat1Ile mice, consistent with human studies, and electrophysiological recordings showed altered oscillatory activity in the amygdala under anxiogenic conditions. Transcriptome analyses further identified amygdala-specific changes in the expression of genes involved in neurodevelopment and emotional regulation, which may corroborate the observed phenotypes. This knock-in mouse model hence provides compelling evidence that the mutations affecting monoaminergic signaling and amygdala circuits have contributed to the evolution of human socio-emotional behaviors.