bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesolimbic opioid-dopamine interaction is disrupted in obesity but recovered by weight loss following bariatric surgery
Authors: Karlsson Henry K. , Tuominen Lauri , Helin Semi , Salminen Paulina , Nuutila Pirjo , Nummenmaa Lauri 
Published: December 2020

AbstractBackgroundObesity is a growing burden to health and economy worldwide. Obesity is associated with central μ-opioid receptor (MOR) downregulation, and the interaction between MOR and dopamine D2receptor (D2R) system in the ventral striatum is disrupted among obese subjects. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying subjects undergoing surgical weight loss (bariatric surgery) procedure.MethodsWe recruited 20 healthy non-obese (mean BMI 22) and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and D2R availability was measured using positron emission tomography (PET) with [11C]carfentanil and [11C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed to obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery.ResultsIn the control subjects, MOR and D2R availabilities were associated in the ventral striatum (r= .62) and dorsal caudate (r= .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r= .12) but unaltered association in dorsal caudate (r= .43). The association between MOR and D2R availabilities in the ventral striatum was recovered (r= .62) among obese subjects following the surgery-induced weight loss (mean total weight loss 22 %).ConclusionsBariatric surgery and concomitant weight loss recovers the interaction between MOR and D2R in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioural interventions for treating obesity.Clinical Trials RegistrationSleevePET2,NCT01373892,http://www.clinicaltrials.gov
APOE4 affects basal and NMDAR mediated protein synthesis in neurons by perturbing calcium homeostasis
Authors: Ramakrishna Sarayu , Jhaveri Vishwaja , Konings Sabine C , Chakraborty Sumita , Holst Bjørn , Schmid Benjamin , Gouras Gunnar K , Freude Kristine K , Muddashetty Ravi S 
Published: December 2020

AbstractApolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans – APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the pre-disposition for Alzheimer’s disease. The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4 induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons to APOE4 leads to a significant decrease in global protein synthesis. APOE4 treatment also abrogates the NMDA mediated translation response indicating an impairment of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure to APOE3 causes a short burst of calcium through NMDARs in neurons leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-VGCCs, thereby causing sustained translation inhibition through eEF2 phosphorylation, which in turn disrupts NMDAR response. Thus, we show that APOE4 affects basal and activity mediated protein synthesis response in neurons by affecting calcium homeostasis. We propose this as a possible mechanism to explain the synaptic dysfunction caused by APOE4.Highlights / SummaryAPOE3 treatment causes a short burst of calcium through NMDARs, leading to an acute increase in eEF2 phosphorylation which eventually recovers to basal levels.Global translation follows a similar temporal profile of initial inhibition followed by recovery in APOE3 treated neurons, thus unaffecting the NMDA mediated translation response.APOE4 treatment activates both NMDARs and L-VGCCs leading to a marked elevation in calcium levels, thus causing sustained increase in eEF2 phosphorylation as well as global translation inhibition.Hence, the NMDA mediated response is perturbed, potentially causing a stress-related phenotype in APOE4 treated neurons.Thus, different calcium signatures and sources lead to distinct temporal profiles of translation.
Identification of eight SARS-CoV-2 ORF7a deletion variants in 2,726 clinical specimens
Authors: Rosenthal Sun Hee , Kagan Ron M. , Gerasimova Anna , Anderson Ben , Grover David , Hua Michael , Liu Yan , Owen Renius , Lacbawan Felicitas 
Published: December 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF7a, the ortholog of SARS-CoV ORF7a, is a type I transmembrane protein and plays an important role in virus-host interactions. Deletion variants in ORF7a may influence virulence, but only a few such isolates have been reported. Here, we report 8 unique ORF7a deletion variants of 6 to 96 nucleotides in length identified from 2,726 clinical specimens collected in March of 2020.
Macrocybin, a mushroom natural triglyceride, reduces tumor growthin vitroandin vivothrough caveolin-mediated interference with the actin cytoskeleton
Authors: Vilariño Marcos , García-Sanmartín Josune , Ochoa-Callejero Laura , López-Rodríguez Alberto , Blanco-Urgoiti Jaime , Martínez Alfredo 
Published: December 2020

AbstractMushrooms have been used for millennia as cancer remedies. Our goal was to screen several species from the rain forest of Costa Rica looking for new antitumor molecules. Mushroom extracts were screened using two human cell lines: A549 (lung adenocarcinoma) and NL20 (immortalized normal lung epithelium). Extracts able to kill tumor cells while preserving nontumor cells were considered “anticancer”. The mushroom with better properties wasMacrocybe titans. Positive extracts were fractionated further and tested for biological activity on the cell lines. The chemical structure of the active compound was partially elucidated through nuclear magnetic resonance, mass spectrometry, and other ancillary techniques. Chemical analysis showed that the active molecule was a triglyceride containing oleic acid, palmitic acid, and a more complex fatty acid with 2 double bonds. Synthesis of all possible triglycerides and biological testing identified the natural compound, which was named Macrocybin. A xenograft study showed that Macrocybin significantly reduces A549 tumor growth. In addition, Macrocybin treatment resulted in the upregulation of Caveolin-1 expression and the disassembly of the actin cytoskeleton in tumor cells (but not in normal cells). In conclusion, we have shown that Macrocybin constitutes a new biologically active compound that may be taken into consideration for cancer treatment.
No behavioral evidence for rhythmic facilitation of perceptual discrimination
Authors: Lin Wy Ming , Oetringer Djamari A. , Bakker-Marshall Iske , Emmerzaal Jill , Wilsch Anna , ElShafei Hesham A. , Rassi Elie , Haegens Saskia 
Published: December 2020

AbstractIt has been hypothesized that internal oscillations can synchronize (i.e., entrain) to external environmental rhythms, thereby facilitating perception and behavior. To date, evidence for the link between the phase of neural oscillations and behavior has been scarce and contradictory; moreover, it remains an open question whether the brain can use this tentative mechanism for active temporal prediction. In our present study, we conducted a series of auditory pitch discrimination tasks with 181 healthy participants in an effort to shed light on the proposed behavioral benefits of rhythmic cueing and entrainment. In the three versions of our task, we observed no perceptual benefit of purported entrainment: targets occurring in-phase with a rhythmic cue provided no perceptual benefits in terms of discrimination accuracy or reaction time when compared with targets occurring out-of-phase or targets occurring randomly, nor did we find performance differences for targets preceded by rhythmic vs. random cues. However, we found a surprising effect of cueing frequency on reaction time, in which participants showed faster responses to cue rhythms presented at higher frequencies. We therefore provide no evidence of entrainment, but instead a tentative effect of covert active sensing in which a faster external rhythm leads to a faster communication rate between motor and sensory cortices, allowing for sensory inputs to be sampled earlier in time.
The gut microbiome facilitates ecological adaptation in an invasive vertebrate
Authors: Wagener Carla , Mohanty Nitya Prakash , Measey John 
Published: December 2020

ABSTRACTGut microbial communities regulate host physiology and health of humans and laboratory animals. The functional significance of these collective bacterial genomes (i.e. the microbiome) to the adaptive potential of wildlife hosts is still unknown. Studies demonstrating convincing examples of microbial flexibility to environmental change so far lack the experimental approaches to demonstrate the effect on host physiology. Invasive species provide natural experiments to tease apart these host-microbe relationships. However, no studies have investigated how microbial symbionts might mediate responses of invasive hosts’ physiology to environmental change. In this study, we examine whether invasive gut microbiomes have significantly diverged in their ability to respond to novel environmental change (i.e. a dietary challenge) compared to native gut microbiomes by performing reciprocal faecal microbial transplant (FMT) experiments in native and invasive guttural toad (Sclerophrys gutturalis) populations. Subsequently, we determine how the microbiome regulates host physiological changes in response to a dietary challenge. We show that invasive gut microbiomes exhibit higher microbial compositional and predicted functional flexibility to novel dietary change, compared to native gut microbiomes. This increased microbial flexibility is coupled with significant flexibility in energy harvesting. Furthermore, our results indicate that overall invasive gut microbiomes significantly upregulate energy harvesting and physiological performance of hosts, compared to native microbiomes. Our study is the first identifying gut microbiota as the sole factor contributing to the adaptive physiology of a vertebrate using a unique study design. These findings provide novel insights into the key role of gut microbial symbionts in increasing the invasive potential of its vertebrate host.
Human liver microbiota modeling strategy at the early onset of fibrosis
Authors: Champion Camille , Neagoe Radu M. , Effernberger Maria , Sala Daniela T. , Servant Florence , Christensen Jeffrey E. , Arnoriaga-Rodriguez Maria , Amar Jacques , Lelouvier Benjamin , Gamboa Fabrice , Tilg Herbert , Federici Massimo , Fernández-Real Jose-Manuel , Loubes Jean Michel , Burcelin Rémy 
Published: December 2020

AbstractTo understand the pathophysiological impact of liver microbiota on the early stages of fibrosis we identified the corresponding microbiota sequences and overcome the impact of different group size and patient origins with adapted statistical approaches. Liver samples with low liver fibrosis scores (F0, F1, F2) were collected from Romania(n=36), Austria(n=10), Italy(n=19), and Spain(n=17). The 16SrDNA gene was sequenced. We considered the frequency, sparsity, unbalanced sample size between cohorts to identify taxonomic profiles and statistical differences. Multivariate analyses, including adapted spectral clustering with L1-penalty fair-discriminant strategies, and predicted metagenomics were used to identify that 50 % of liver taxa were Enterobacteriaceae and Pseudomonadaceae. The Caulobacteraceae, Flavobacteriaceae and Propionibacteriaceae discriminated between F0 and F1. The preQ0 biosynthesis and pathways involving glucoryranose and glycogen degradation were negatively associated with liver fibrosis F1-F2 vs F0. Altogether, our results suggest a role of bacterial translocation to the liver in the progression of fibrosis. This statistical approach can identify microbial signatures and overcome issues regarding sample size differences, the impact of environment, and sets of analyses.
Revisiting the Out of Africa event with a novel Deep Learning approach
Authors: Montinaro Francesco , Pankratov Vasili , Yelmen Burak , Pagani Luca , Mondal Mayukh 
Published: December 2020

AbstractAnatomically modern humans evolved around 300 thousand years ago in Africa1. Modern humans started to appear in the fossil record outside of Africa about 100 thousand years ago though other hominins existed throughout Eurasia much earlier2–4. Recently, several researchers argued in favour of a single out of Africa event for modern humans based on whole-genome sequences analyses5–7. However, the single out of Africa model is in contrast with some of the findings from fossil records, which supports two out of Africa8,9, and uniparental data, which proposes back to Africa movement10,11. Here, we used a novel deep learning approach coupled with Approximate Bayesian Computation and Sequential Monte Carlo to revisit these hypotheses from the whole genome sequence perspective. Our results support the back to Africa model over other alternatives. We estimated that there are two successive splits between Africa and out of African populations happening around 60-80 thousand years ago and separated by 12-13 thousand years. One of the populations resulting from the more recent split has to a large extent replaced the older West African population while the other one has founded the out of Africa populations.
A new Petri Net Model of Working Memory to Predict the Root Causes of Attention Deficit Disorder Symptoms
Authors: Baghdadi Golnaz , Doustmohammadi Ali , Jamshidi Ainaz , Towhidkhah Farzad 
Published: December 2020

AbstractWorking memory is a system that helps us to store, retrieve, and manipulate information for a short period. The improper function of working memory is highly reported in people with attention deficit disorder. Attention deficit disorder is one of the most common disruptive behavioral disorders in children. Finding the actual reasons that may lead to inattentive symptoms is still an enigma for scientists. In this study, a model was proposed to show the flow of information through sensory, long-term, and working memory based on the Petri net approach. A new “selective updating” mechanism is also suggested. It is speculated that the central executive part of working memory uses this mechanism for updating the less important content with new incoming essential inputs. The analysis of the proposed model shows how an abnormality in the time setting or unexpected delays in information transmission may lead to some symptoms of inattention. These predictions about the possible causes of inattentive symptoms would be valuable for psychologists to find new possible treatments. This study also illustrates the great potential of Petri net approach for modeling and analysis of biological systems.
Zebrafish skeletal muscle cell cultures: Monolayer to three-dimensional tissue engineered collagen constructs
Authors: Vishnolia K.K , Martin N.R.W , Player D.J , Spikings E , Lewis M.P 
Published: December 2020

AbstractZebrafish (Danio rerio) are a commonly used model organism to study human muscular myopathies and dystrophies. To date, much of the work has been conductedin vivodue to limitations surrounding the consistent isolation and culture of zebrafish muscle progenitor cells (MPCs)in vitroand the lack of physiologically relevant models.Here we report a robust, repeatable, and cost-effective protocol for the isolation and culture of zebrafish MPCs in conventional monolayer (2D) and have successfully transferred these cells to 3D culture in collagen based three-dimensional (3D) tissue-engineered constructs. Zebrafish MPC’s cultured in 2D were consistently reported to be Desmin positive reflecting their muscle specificity, with those demonstrating Desmin positivity in the 3D cultures. In addition, mRNA expression of muscle markers specific for proliferation, differentiation and maturation measured from both monolayer and 3D cultures at appropriate developmental stages were found consistent with previously published from other speciesin vitro and in vivomuscle data.Collagen constructs seeded with zebrafish MPC’s were initially characterised for optimal seeding density, followed by macroscopic characterisation (three-fold contraction) of the matrix. Direct comparison between the morphological characteristics (proportion of cells) and gene expression profiles of cells cultured in collagen constructs revealed higher maturation and differentiation compared to monolayer cultures. In this regard, cells embedded in 3D collagen constructs revealed higher fusion index, Desmin positivity, hypertrophic growth, myotube maturity and myogenic mRNA expression when compared to in monolayer.In conclusion, these methods and models developed herein will facilitatein vitroexperiments, which would complementin vivozebrafish studies used to investigate the basic developmental, myopathies and dystrophies in skeletal muscle cells.
Resonating neurons stabilize heterogeneous grid-cell networks
Authors: Mittal Divyansh , Narayanan Rishikesh 
Published: December 2020

ABSTRACTA central theme that governs the functional design of biological networks is their ability to sustain stable function despite widespread parametric variability. Here, we investigated the impact of distinct forms of biological heterogeneities on the stability of a two-dimensional continuous attractor network (CAN) implicated in grid-patterned activity generation. We show that increasing degrees of biological heterogeneities progressively disrupted the emergence of grid- patterned activity and resulted in progressively large perturbations in low-frequency neural activity. We postulated that targeted suppression of low-frequency perturbations could ameliorate heterogeneity-induced disruptions of grid-patterned activity. To test this, we introduced intrinsic resonance, a physiological mechanism to suppress low-frequency activity, either by adding an additional high-pass filter (phenomenological) or by incorporating a slow negative feedback loop (mechanistic) into our model neurons. Strikingly, CAN models with resonating neurons were resilient to the incorporation of heterogeneities and exhibited stable grid-patterned firing. We found CAN networks with mechanistic resonators to be more effective in targeted suppression of low-frequency activity, with the slow kinetics of the negative feedback loop essential in stabilizing these networks. As low-frequency perturbations (1/fnoise) are pervasive across biological systems, our analyses suggest a universal role for mechanisms that suppress low- frequency activity in stabilizing heterogeneous biological networks.
Differences in neuronal numbers, morphology and developmental apoptosis in mice nigra provide experimental evidence of ontogenic origin of vulnerability to Parkinson’s disease
Authors: Vidyadhara D J , Yarreiphang Haorei , Raju Trichur R , Alladi Phalguni Anand 
Published: December 2020

AbstractParkinson disease (PD) prevalence varies by ethnicity. In an earlier study we replicated the reduced vulnerability to PD in an admixed population, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6J, MPTP-resistant CD-1 and their F1 crossbreds. In the present study we investigated if the differences have a developmental origin. Substantia nigra was evaluated at postnatal days 2 (P2), P6, P10, P14, P18, and P22. C57BL/6J mice had smaller nigra and fewer dopaminergic neurons than the CD-1 and crossbreds at P2, which persisted through development. A significant increase in numbers and nigral volume was observed across strains till P14. A drastic decline thereafter was specific to C57BL/6J. CD-1 and crossbreds retained their numbers from P14 to stabilize with supernumerary neurons at adulthood. The neuronal size increased gradually to attain adult morphology at P10 in the resistant strains, vis-à-vis at P22 in C57BL/6J. Accordingly, in comparison to C57BL/6J, the nigra of CD-1 and reciprocal crossbreds possessed cyto-morphological features of resilience, since birth. The considerably lesser dopaminergic neuronal loss in the CD-1 and crossbreds seen at P2, P14 and thereafter was complemented by attenuated developmental cell death. The differences in programmed cell death were confirmed by reduced TUNEL labelling, AIF and caspase-3 expression. GDNF expression aligned with the cell death pattern at P2 and P14 in both nigra and striatum. Earlier maturity of nigra and its neurons appear to be better features that reflect as MPTP-resistance at adulthood. Thus variable MPTP-vulnerability in mice and also differential susceptibility to PD in humans may arise early during nigral development.
Generation of a new Tbx6-inducible reporter mouse line to trace presomitic mesoderm derivatives throughout development and in adults
Authors: Yvernogeau Laurent , Klaus Anna , van Rooijen Carina , Robin Catherine 
Published: December 2020

ABSTRACTThe presomitic mesoderm (PSM) is initially an unsegmented structure localized on each side of the neural tube of the developing embryo, which progressively segments to form the somites. The somites will segregate and partition to generate the dorsal dermomyotome and the ventral sclerotome. Endothelial and myogenic cells of both the trunk and limbs are derived from the somites. There is a lack of efficient reporter mouse models to label and trace the PSM derivatives, despite their crucial contribution to many developmental processes. In this study, we generated a tamoxifen inducible transgenic Tbx6 mouse line, Tg(Tbx6_Cre/ERT2)/ROSA-eYFP, to tag and follow PSM-derivatives from early embryonic stages until adulthood. After induction, endothelial and myogenic cells can be easily identified within the trunk and limbs with proper expression patterns. Since our Tg(Tbx6_Cre/ERT2)/ROSA-eYFP model allows to permanently label the PSM-derived cells, their progeny can be studied at long-term, opening the possibility to perform lineage tracing of stem cells upon aging.