bluuebunny/crossref_metadata_2025_split huggingface dataset:
Working Memory Performance after Daily Caffeine Intake: Compromised Performance and Reduced Hippocampal Activity
Authors: Lin Yu-Shiuan , Weibel Janine , Landolt Hans-Peter , Santini Francesco , Slawik Helen , Borgwardt Stefan , Cajochen Christian , Reichert Carolin 
Published: April 2021

AbstractNeuroprotective effects of caffeine have been frequently reported in the context of disease and cognitive dysfunction as well as in epidemiological studies in humans. However, evidence on caffeine effects on neural and memory functions during daily intake in a healthy cognitive state remains scarce. This randomized double-blind placebo-controlled crossover study investigated working memory functions by N-back tasks and functional magnetic resonance imaging (fMRI) after daily caffeine intake compared to a placebo baseline and to acute caffeine withdrawal in 20 young healthy volunteers. Each volunteer was given 3 times 150 mg caffeine for 10 days in the daily caffeine condition, 3 times 150 mg mannitol for 10 days in the placebo condition, and 9-day caffeine plus 1-day mannitol in the acute withdrawal condition. During the 10thday, participants performed 4 N-back sessions (two loads each: 0- and 3-back) under controlled laboratory conditions. During the 4thsession of N-Back (i.e. at 5.5 h, 36.5 h and > 10 days after the last caffeine intake in the caffeine, withdrawal, and placebo condition, respectively) we assessed blood-oxygen-level-dependent (BOLD) activity. During the entire 10thday, in 0-back tasks, we observed longer reaction times (RTs) in the withdrawal compared to the placebo (Cohen’s d = 0.7) and caffeine condition (Cohen’s d = 0.6), but no significant effects of conditions on error rates. In contrast, in 3-back tasks (controlled for 0-back), the RTs in the caffeine condition were longer compared to placebo (Cohen’s d = 0.6) and withdrawal (Cohen’s d = 0.5). Error rates were higher during both caffeine and withdrawal conditions compared to placebo (Cohen’s d of both contrasts = 0.4). Whole-brain analyses on fMRI data did not reveal significant condition-dependent differences in activities between task loads. Across task loads, however, we observed a reduced hippocampal activation (Cohen’s d = −1.3) during the caffeine condition compared to placebo, while no significant difference in brain activities between withdrawal and placebo conditions. Taken together, the worse working memory function and the hippocampal hypoactivation implicate a potential detrimental effect of daily caffeine intake on neurocognitive functions of healthy adults. Moreover, they echo the hippocampal volumetric reduction reported previously in the same volunteers. Lastly, acute withdrawal from daily caffeine intake impairs both low-order cognitive processes and working memory performance. Taking earlier studies on acute caffeine effects into account, our findings indicate that daily caffeine intake elicits a dynamic change in cerebral activities during the course of repeated consumption, with unknown consequences in the long run.
Neuromodulation-induced burst firing in parvalbumin interneurons of the basolateral amygdala mediates transition between fear-associated network and behavioral states
Authors: Fu Xin , Teboul Eric , Maguire Jamie , Tasker Jeffrey G. 
Published: April 2021

AbstractPatterned coordination of network activity in the basolateral amygdala (BLA) is important for fear expression. Neuromodulatory systems play an essential role in regulating changes between behavioral states, however the mechanisms underlying the neuromodulatory control of BLA circuits that mediates transitions between brain and behavioral states remain largely unknown. We examined the role of neuromodulation of parvalbumin (PV)-expressing interneurons in the BLA in coordinating network and behavioral states using combined chemogenetics,ex vivopatch clamp recordings, andin vivoandex vivolocal field potential recordings. We show that Gq signaling, whether by the designer receptor, hM3D, α1A adrenoreceptors, or 5-HT2a serotonergic receptors, induces a previously undescribed, highly stereotyped bursting pattern of activity in BLA PV interneurons that generates synchronous bursts of inhibitory postsynaptic currents and phasic firing in the BLA principal neurons. The Gq activation in PV interneurons induced a transition from tonic to phasic firing in the BLA PV neurons and principal neurons and suppressed BLA gamma oscillations in slices and suppressed BLA gamma and potentiated theta powerin vivo. Gq activation in BLA PV interneurons also facilitated fear memory recall, consistent with previous reports of BLA gamma suppression and theta potentiation during conditioned fear expression. Thus, our data reveal a BLA parvalbumin neuron-specific Gq neuromodulatory mechanism that mediates the transition to a fear-associated network and behavioral state.
Gene editing in Farm Animals: A Step Change for Eliminating Epidemics on our Doorstep?
Authors: Leony Petersen Gertje Eta , Buntjer Jaap , Hely Fiona S. , Byrne Timothy John , Whitelaw Bruce , Doeschl-Wilson Andrea 
Published: April 2021

AbstractRecent breakthroughs in gene-editing technologies that can render individuals fully resistant to infections may offer unprecedented opportunities for controlling future epidemics. Yet, their potential for reducing disease spread are poorly understood as the necessary theoretical framework for estimating epidemiological effects arising from gene editing applications is currently lacking. Here, we develop semi-stochastic modelling approaches to investigate how the adoption of gene editing may affect infectious disease prevalence in farmed animal populations and the prospects and time-scale for disease elimination. We apply our models to the Porcine Reproductive and Respiratory Syndrome PRRS, one of the most persistent global livestock diseases to date. Whereas extensive control efforts have shown limited success, recent production of gene-edited pigs that are fully resistant to the PRRS virus have raised expectations for eliminating this deadly disease.Our models predict that disease elimination on a national scale would be difficult to achieve if gene editing was used as the only disease control. However, when complemented with vaccination, the introduction of 10% of genetically resistant animals in a fraction of herds could be sufficient for eliminating the disease within 3-6 years. Besides strategic distribution of genetically resistant animals, several other key determinants underpinning the epidemiological impact of gene-editing were identified.
When good mutations go bad: how population size can change the direction of natural selection
Authors: Raynes Yevgeniy , Burch Christina L. , Weinreich Daniel M. 
Published: April 2021

ABSTRACTClassical evolutionary theory holds that the efficiency, but not the direction, of natural selection depends on population size. In small populations, drift overwhelms selection, rendering all fitness-affecting mutations selectively neutral. Yet, beneficial mutations never become deleterious and deleterious mutations never become beneficial. Remarkably, several mutations, including in modifiers of recombination and mutation rate, have now been shown to be favored at some population sizes but disfavored at others, challenging established theory. Previously, we have designated this phenomenon sign inversion. Here we show that, unlike selected mutations in the classical framework, mutations susceptible to sign inversion confer both fitness costs and fitness benefits, that vary among their carriers. Furthermore, all such mutations can be classified based on whether their effects differ between or within mutant lineages. Using computer simulations, we demonstrate that both between-lineage and within-lineage variability can cause sign inversion and elucidate the common underlying mechanism. Our results confirm that variability in the sign of selective effects is necessary for sign inversion, which occurs because drift overwhelms selection on carriers bearing the cost and carriers enjoying the benefit at different population sizes.
Ruxolitinib versus Dexamethasone in Hospitalized Adults with Covid-19: multicenter matched-controlled study
Authors: Stanevich O.V. , Fomina D.S. , Bakulin I.G. , Galeev Sh. I. , Bakin E.A. , Belash V.A. , Kulikov A.N. , Lebedeva A.A. , Lioznov D.A. , Polushin Yu S. , Shlyk I.V. , Vorobyev E.A. , Vorobyeva S.V. , Surovceva T.V. , Bakulina N.V. , Lysenko M.A. , Moiseev I.S. 
Published: April 2021

AbstractBackgroundSeveral anti-cytokine therapies were tested in the randomized trials in hospitalized patients with severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Both janus kinase (JAK) inhibitor, baricitinib, and dexamethasone demonstrated the reduction of mortality. In this matched control study we compared dexamethasone to another JAK inhibitor, ruxolitinib.MethodsThe study included 146 hospitalized patients with COVID-19 and oxygen support requirement. The control group was selected 1:1 from 1355 dexamethasone-treated patients and was matched by 29 clinical and laboratory parameters predicting survival.ResultsRuxolitinib treatment in the general cohort of patients was associated with equivalent to dexamethasone mortality rate: 9,6% (95% CI 4,6-14,6%) vs 13,0% (95% CI 7,5-18,5%, superiority p=0.35, non-inferiority p=0.0137), respectively. Time to discharge without oxygen support requirement was also not different between these groups: 13 vs 11 days (p=0.13). Subgroup analysis without adjustment for multiple comparisons demonstrated reduced mortality in ruxolitnib-treated patients with febrile fever (OR 0.33, 95%CI 0.11-1.00). Except higher incidence of grade 1 thrombocytopenia (37% vs 23%, p=0.042), ruxolitinib therapy was associated with better safety profile due to reduced rate of severe cardiovascular adverse events (6.8% vs 15%, p=0.025).ConclusionsRuxolitinib may be an alternative anti-cytokine therapy with comparable efficacy in patients with potential risks of steroid administration. Patients with febrile fever at admission may benefit from ruxolitinib administration.FundingRuxolitinib was obtained from Novartis through Managed Access Program (MAP).
Simulation of aerosol and droplet spread during upper airway and gastrointestinal endoscopy
Authors: Heymer Johannes , Dengler Florian , Krohn Alexander , Jaki Christina , Schilling Tobias , Müller-Schilling Martina , Kandulski Arne , Ott Matthias 
Published: April 2021

AbstractObjectiveAerosols and droplets are the main vectors in transmission of highly contagious SARS-Cov-2. Invasive diagnostic procedures like upper airway and gastrointestinal endoscopy have been declared as aerosol generating procedures. Protection of health care workers is crucial in times of COVID-19 pandemic.MethodsWe simulated aerosol and droplet spread during upper airway and gastrointestinal endoscopy with and without physico-mechanical barriers using a simulation model.ResultsA clear plastic drape as used for central venous access markedly reduced visualized aerosol and droplet spread during endoscopy.ConclusionA simple and cheap drape has the potential to reduce aerosol and droplet spread during endoscopy. In terms of health care worker protection, this may be important particularly in low- or moderate-income countries.
Transient dopamine neuron activity precedes and encodes the vigor of contralateral movements
Authors: Mendonça Marcelo D , da Silva Joaquim Alves , Hernandez Ledia F. , Castela Ivan , Obeso José , Costa Rui M 
Published: April 2021

AbstractDopamine neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement vigor, and loss of these neurons leads to bradykinesia in Parkinson’s disease. However, it remains unclear whether DANs encode a general motivation signal or modulate movement kinematics. We imaged activity of SNc DANs in mice trained in a novel operant task which relies on individual forelimb sequences. We uncovered that a similar proportion of SNc DANs increased their activity before ipsi-vs. contralateral sequences. However, the magnitude of this activity was higher for contralateral actions, and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-related DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal, and invigorate kinematic aspects of contralateral movements.TeaserTransient activity in substantia nigra compacta dopamine neurons encodes contralateral, but not ipsilateral action vigor.
Untargeted1H NMR Metabolomics and Pathway Analysis Reveals Dysregulated Proteostasis in Cyclophilin D (CypD)-deficient Mice Tissues
Authors: Adegbite YI , Adegbite OS , Ouyang Y , Sutton R , Criddle DN , Lian LY 
Published: April 2021

AbstractCyclophilin D (CypD) is a nuclear-encoded mitochondrial protein. Although best known as a regulator of the mitochondrial permeability transition pore (MPTP), it is also implicated in the regulation of cellular bioenergetics and extramitochondrial activities. In addition, being a peptidyl prolylcis-transisomerase (PPIase), deletion of CypD is likely to affect protein stability in the mitochondria; however, there is little direct evidence of this. In this study, untargeted1H NMR metabolomics, coupled with multivariate analysis, was used to describe simultaneous changes in the metabolic system of CypD-deficient mice liver, heart, and pancreas, with data from the serum to identify systematic changes. Metabolomics Pathway Analyses (MetPA) revealed commonly perturbed metabolites in the different mouse tissues lacking CypD, with significantly enriched pathways that are related to amino acid, glucose and purine metabolisms, and bioenergetics. Serum from CypD-deficient mice confirmed changes in tissue urea cycle, lipid metabolism and ketogenesis. Overall this study reveals the role of CypD in maintaining protein homeostasis, concurring with its biochemical property as a peptidyl-prolyl isomerase and also demonstrates the wider metabolic adaptations induced by the deletion of theppifgene, resulting in a CypD-deficient mice metabolome that is different from the wild-type system.
Burkholderia PglL enzymes are serine preferring oligosaccharidetransferases which target conserved proteins across the Burkholderia genus
Authors: Hayes Andrew J. , Lewis Jessica M. , Davies Mark R. , Scott Nichollas E. 
Published: April 2021

AbstractGlycosylation is increasingly recognised as a common protein modification within bacterial proteomes. While great strides have been made in identifying species that contain glycosylation systems, our understanding of the proteins and sites targeted by these enzymes is far more limited. Within this work we explore the conservation of glycoproteins andO-linked glycosylation sites across the pan-Burkholderiaglycoproteome. Using a multi-protease glycoproteomic approach we generate high-confidence glycoproteomes and associated glycosylation sites in two widely utilizedB. cenocepaciastrains, K56-2 and H111. This resource reveals glycosylation occurs exclusively at serine residues and that glycoproteins/glycosylation sites are highly conserved across 294 publicly availableB. cenocepaciagenomes. Consistent with this we demonstrate that the substitution of Serine for Threonine residues in a model protein results in a dramatic decrease in glycosylation efficiency by the oligosaccharidetransferase pglLBCeven when pglLBCis overexpressed. This preference for glycosylation at Serine residues is observed across at least 9Burkholderiaglycoproteomes supporting that Serine is the dominant residue targeted by pglL-mediated glycosylation across theBurkholderiagenus. Using population genomics we observe that pglL targeted glycosylated proteins are common acrossBurkholderiaspecies. Combined, this work demonstrates that PglL enzymes of the Burkholderia genus are Serine-preferring oligosaccharidetransferases that target conserved and shared protein substrates across theBurkholderiagenus.
Modular biosynthesis of plant hemicellulose and its impact on yeast cells
Authors: Robert Madalen , Waldhauer Julian , Stritt Fabian , Yang Bo , Pauly Markus , Voiniciuc Cătălin 
Published: April 2021

AbstractBackgroundThe carbohydrate polymers that encapsulate plants cells have benefited humans for centuries and have valuable biotechnological uses. In the past five years, exciting possibilities have emerged in the engineering of polysaccharide-based biomaterials. Despite impressive advances on bacterial cellulose-based hydrogels, comparatively little is known about how plant hemicelluloses can be reconstituted and modulated in cells suitable for biotechnological purposes.ResultsHere, we assembled cellulose synthase-like A (CSLA) enzymes using an optimizedPichia pastorisplatform to produce tunable heteromannan (HM) polysaccharides in yeast. By swapping the domains of plant mannan and glucomannan synthases, we engineered chimeric CSLA proteins that made β-1,4-linked mannan in quantities surpassing those of the native enzymes while minimizing the burden on yeast growth. Prolonged expression of a glucomannan synthase fromAmorphophallus konjacwas toxic to yeast cells: reducing biomass accumulation and ultimately leading to compromised cell viability. However, an engineered glucomannan synthase as well as CSLA pure mannan synthases and a CSLC glucan synthase did not inhibit growth. Interestingly,Pichiacell size could be increased or decreased depending on the composition of the CSLA protein sequence. HM yield and glucose incorporation could be further increased by co-expressing chimeric CSLA proteins with a MANNAN-SYNTHESIS-RELATED (MSR) co-factor fromArabidopsis thaliana.ConclusionThe results provide novel routes for the engineering of polysaccharide-based biomaterials that are needed for a sustainable bioeconomy. The characterization of chimeric cellulose synthase-like enzymes in yeast offers an exciting avenue to produce plant polysaccharides in a tunable manner. Furthermore, cells modified with non-toxic plant polysaccharides such as β-mannan offer a modular chassis to produce and encapsulate sensitive cargo such as therapeutic proteins.
Sox8 remodels the cranial ectoderm to generate the ear
Authors: Buzzi Ailin Leticia , Chen Jingchen , Thiery Alexandre , Delile Julien , Streit Andrea 
Published: April 2021

AbstractThe vertebrate inner ear arises from a pool of progenitors with the potential to contribute to all the sense organs and cranial ganglia in the head. Here we explore the molecular mechanisms that control ear specification from these precursors. Using a multi-omics approach combined with loss-of-function experiments we identify a core transcriptional circuit that imparts ear identity, along with the first genome-wide characterization of non-coding elements that integrate this information. This analysis places the transcription factor Sox8 at the top of the ear determination network. Introducing Sox8 into cranial ectoderm not only converts non-ear cells into ear progenitors, but also activates the cellular programs for ear morphogenesis and neurogenesis. Thus, Sox8 has the unique ability to remodel transcriptional networks in the cranial ectoderm towards ear identity.
Identification of druggable host targets needed for SARS-CoV-2 infection by combined pharmacological evaluation and cellular network directed prioritization both in vitro and in vivo
Authors: Patten J.J. , Keiser Patrick T. , Gysi Deisy , Menichetti Giulia , Mori Hiroyuki , Donahue Callie J. , Gan Xiao , Valle Italo do , Geoghegan-Barek Kathleen , Anantpadma Manu , Boytz RuthMabel , Berrigan Jacob L. , Hulsey-Stubbs Sarah , Ayazika Tess , O’Leary Colin , Jalloh Sallieu , Wagner Florence , Ayehunie Seyoum , Elledge Stephen J. , Anderson Deborah , Loscalzo Joseph , Zitnik Marinka , Gummuluru Suryaram , Namchuk Mark N. , Barabási Albert-László , Davey Robert A. 
Published: April 2021

AbstractIdentification of host factors contributing to replication of viruses and resulting disease progression remains a promising approach for development of new therapeutics. Here, we evaluated 6710 clinical and preclinical compounds targeting 2183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target and cell interactome networking produced cellular networks important for infection. This analysis revealed 389 small molecules, >12 scaffold classes and 813 host targets with micromolar to low nanomolar activities. From these classes, representatives were extensively evaluated for mechanism of action in stable and primary human cell models, and additionally against Beta and Delta SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of novel host factor dependencies and treatments for viral diseases.
Energy Penalties Enhance Flexible Receptor Docking in a Model Cavity
Authors: Kamenik Anna S. , Singh Isha , Lak Parnian , Balius Trent E. , Liedl Klaus R. , Shoichet Brian K. 
Published: April 2021

AbstractProtein flexibility remains a major challenge in library docking due to difficulties in sampling conformational ensembles with accurate probabilities. Here we use the model cavity site of T4 Lysozyme L99A to test flexible receptor docking with energy penalties from molecular dynamics (MD) simulations. Crystallography with larger and smaller ligands indicates that this cavity can adopt three major conformations, open, intermediate, and closed. Since smaller ligands typically bind better to the cavity site, we anticipate an energy penalty for cavity opening. To estimate its magnitude, we calculate conformational preferences from MD simulations. We find that including a penalty term is essential for retrospective ligand enrichment, otherwise high-energy states dominate the docking. We then prospectively docked a library of over 900,000 compounds for new molecules binding to each conformational state. Absent a penalty term, the open conformation dominated the docking results; inclusion of this term led to a balanced sampling of ligands against each state. High ranked molecules were experimentally tested by Tm-upshift and X-ray crystallography. From 33 selected molecules, we identified 18 new ligands and determined 13 crystal structures. Most interesting were those bound to the open cavity, where the buried site opens to bulk solvent. Here, highly unusual ligands for this cavity had been predicted, including large ligands with polar tails; these were confirmed both by binding and by crystallography. In docking, incorporating protein flexibility with thermodynamic weightings may thus access new ligand chemotypes. The MD approach to accessing and, crucially, weighting such alternative states may find general applicability.Significance StatementThe dynamic nature of biomolecules is typically neglected in docking screens for ligand discovery. Key to benefitting from various receptor conformations is not only structural but also thermodynamic information. Here we test a general approach that uses conformational preferences from enhanced and conventional MD simulations to account for the cost of transitions to high energy states. Including this information as a conformational penalty term in a docking scoring function, we perform retrospective and prospective screens and experimentally confirm novel ligands with Tm-upshift and X-ray crystallography.