bluuebunny/crossref_metadata_2025_split huggingface dataset:
Forecasting Seizure Risk over Days
Authors: Proix Timothée , Truccolo Wilson , Leguia Marc G. , King-Stephens David , Rao Vikram R. , Baud Maxime O. 
Published: October 2019

AbstractFor persons with epilepsy, much suffering stems from the apparent unpredictability of seizures. Historically, efforts to predict seizures have sought to detect changes in brain activity in the seconds to minutes preceding seizures (pre-ictal period), a timeframe that limits preventative interventions. Recently, converging evidence from studies using chronic intracranial electroencephalography revealed that brain activity in epilepsy has a robust cyclical structure over hours (circadian) and days (multidien). These cycles organize pro-ictal states, hours-to days-long periods of heightened seizure risk, raising the possibility of forecasting seizures over horizons longer than the pre-ictal period. Here, using cEEG from 18 subjects, we developed point-process generalized linear models incorporating cyclical variables at multiple time-scales to show that seizure risk can be forecasted accurately over days in most subjects. Personalized risk-stratification days in advance of seizures is unprecedented and may enable novel preventative strategies.
Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue
Authors: Aldiss Peter , Lewis Jo E , Lupini Irene , Bloor Ian , Chavoshinejad Ramyar , Boocock David , Miles Amanda K , Ebling Francis J P , Budge Helen , Symonds Michael E 
Published: October 2019

AbstractTherapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality (∼20°C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold-exposure and β3-adrenoreceptor agonism under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28°C to 20°C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in IWAT in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e. G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e. eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality.
Developing a xenograft model of human vasculature in the mouse ear pinna
Authors: Meehan Gavin R. , Scales Hannah E. , Osii Rowland , De Niz Mariana , Lawton Jennifer C. , Marti Matthias , Garside Paul , Craig Alister , Brewer James M. 
Published: October 2019

AbstractHumanised xenograft models allow for the analysis of human tissue within a physiological environmentin vivo. However, current models often rely on the angiogenesis and ingrowth of recipient vasculature to perfuse tissues, preventing analysis of biological processes and diseases involving human blood vessels. This limits the effectiveness of xenografts in replicating human physiology and may lead to issues with translating findings into human research.We have designed a xenograft model of human vasculature to address this issue. Human subcutaneous fat was culturedin vitroto promote blood vessel outgrowth prior to implantation into immunocompromised mice. We demonstrate that implants survived, retained human vasculature and anastomosed with the circulatory system of the recipient mouse. Significantly, by performing transplants into the ear pinna, this system enabled intravital observation of xenografts by multiphoton microscopy, allowing us to visualise the steps leading to vascular cytoadherence of erythrocytes infected with the human parasitePlasmodium falciparum.This model represents a useful tool for imaging the interactions that occur within human tissuesin vivoand permits visualization of blood flow and cellular recruitment in a system which is amenable to intervention for various studies in basic biology together with drug evaluation and mechanism of action studies.
DominantVibrio choleraephage exhibits lysis inhibition sensitive to disruption by a defensive phage satellite
Authors: Hays Stephanie G. , Seed Kimberley D. 
Published: October 2019

AbstractBacteriophages and their bacterial hosts are locked in a dynamic evolutionary arms race. Phage satellites, selfish genomic islands which exploit both host bacterium and target phage, further complicate the evolutionary fray. One such tripartite system involves the etiological agent of the diarrheal disease cholera –Vibrio cholerae, the predominant phage isolated from cholera patients – ICP1, and a phage satellite – PLE. When ICP1 infectsV. choleraeharboring the integrated PLE genome, PLE accelerates host lysis, spreading the PLE while completely blocking phage production protectingV. choleraeat the population level. Here we identify a single PLE gene,lidI, sufficient to mediate accelerated lysis during ICP1 infection and demonstrate that LidI functions through disrupting lysis inhibition – an understudied outcome of phage infection when phages vastly outnumber their hosts. This work identifies ICP1-encoded holin and antiholin genesteaAandarrArespectively, that mediate this first example of lysis inhibition outside the T-even coliphages. Throughlysisinhibitiondisruption, LidI is sufficient to limit the number of progeny phage produced from an infection. Consequently, this disruption bottlenecks ICP1 evolution as probed by recombination and CRISPR-Cas targeting assays. These studies link novel characterization of the classic phenomenon of lysis inhibition with a conserved protein in a dominant phage satellite, highlighting the importance of lysis timing during infection and parasitization, as well as providing insight into the populations, relationships, and evolution of bacteria, phages, and phage satellites in nature.ImportanceWith increasing awareness of microbiota impacting human health comes intensified examination of, not only bacteria and the bacteriophages that prey upon them, but also the mobile genetic elements (MGEs) that mediate interactions between them. Research is unveiling evolutionary strategies dependent on sensing the milieu: quorum sensing impacts phage infection, phage teamwork overcomes bacterial defenses, and abortive infections sacrifice single cells protecting populations. Yet, the first discovered environmental sensing by phages, known as lysis inhibition (LIN), has only been studied in the limited context of T-even coliphages. Here we characterize LIN in the etiological agent of the diarrheal disease cholera,Vibrio cholerae, infected by a phage ubiquitous in clinical samples. Further, we show that a specific MGE, the phage satellite PLE, collapses LIN with a conserved protein during its anti-phage program. The insights gleaned from this work add to our expanding understanding of microbial fitness in natural contexts beyond the canonical bacterial genome and into the realm of antagonistic evolution driven by phages and satellites.
Mindfulness meditation alters neural activity underpinning working memory during tactile distraction
Authors: Wang Michael Yufeng , Freedman Gabrielle , Raj Kavya , Fitzgibbon Bernadette Mary , Sullivan Caley , Tan Wei-Lin , Van Dam Nicholas , Fitzgerald Paul B , Bailey Neil W 
Published: October 2019

AbstractEvidence suggests that mindfulness meditation (MM) improves selective attention and reduces distractibility by enhancing top-down neural modulation. Altered P300 and alpha neural activity from MM have been identified and may reflect the neural changes that underpin these improvements. Given the proposed role of alpha activity in supressing processing of task-irrelevant information, it is theorised that altered alpha activity may underlie increased availability of neural resources in meditators. The present study investigated attentional function in meditators using a cross-modal study design, examining the P300 during working memory (WM) and alpha activity during concurrent distracting tactile stimuli. Thirty-three meditators and 27 healthy controls participated in the study. Meditators showed a more frontal distribution of P300 neural activity following WM stimuli (p = 0.005, η² = 0.060) and more modulation of alpha activity at parietal-occipital regions between single (tactile stimulation only) and dual task demands (tactile stimulation plus WM task) (p < 0.001, η² = 0.065). Additionally, meditators performed more accurately than controls (p = 0.038, η² = 0.067). The altered distribution of neural activity concurrent with improved WM performance suggests greater attentional resources dedicated to task related functions such as WM in meditators. Thus, meditation-related neural changes are likely multi-faceted involving both altered distribution and also amplitudes of brain activity, enhancing attentional processes depending on task requirements.
Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics
Authors: Durham Natasha D. , Agrawal Aditi , Waltari Eric , Croote Derek , Zanini Fabio , Davidson Edgar , Fouch Mallorie , Smith Olivia , Carabajal Esteban , Pak John E. , Doranz Benjamin J. , Robinson Makeda , Sanz Ana M. , Albornoz Ludwig L. , Rosso Fernando , Einav Shirit , Quake Stephen R. , McCutcheon Krista M. , Goo Leslie 
Published: October 2019

AbstractEliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To delineate bNAb targets, we characterized 28 monoclonal antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies revealed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against flaviviruses with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested a memory origin and divergent somatic hypermutation pathways for these bNAbs, and a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a novel epitope that can be exploited for vaccine design.
OncogenicGata1causes stage-specific megakaryocyte differentiation delay
Authors: Juban Gaëtan , Sakakini Nathalie , Chagraoui Hedia , Cheng Qian , Soady Kelly , Stoilova Bilyana , Garnett Catherine , Waithe Dominic , Doondeea Jess , Usukhbayar Batchimeg , Karkoulia Elena , Alexiou Maria , Strouboulis John , Morrissey Edward , Roberts Irene , Porcher Catherine , Vyas Paresh 
Published: October 2019

AbstractThe megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively in hemopoiesis. GATA1s causes an arrest late in erythroid differentiationin vivo, and even more profoundly in ES-cell derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41himegakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of cell cycle and reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focussed to understand the oncogenic action of GATA1s.Scientific CategoryHaematopoiesis and Stem CellsKey PointsGATA1s-induced stage-specific differentiation delay increases immature megakaryocytesin vivoandin vitro, during development.Differentiation delay is associated with increased numbers of cells in S-phase and reduced apoptosis.
A simple model for the evolution of temperature-dependent sex determination explains the temperature sensitivity of embryonic mortality in imperiled reptiles
Authors: Lawson Lauren , Rollinson Njal 
Published: October 2019

AbstractA common reptile conservation strategy involves artificial incubation of embryos and release of hatchlings or juveniles into wild populations. Temperature-dependent sex determination (TSD) occurs in most chelonians, permitting conservation managers to bias sex ratios towards females by incubating embryos at high temperatures, ultimately allowing the introduction of more egg-bearing individuals into populations. Here, we revisit classic sex allocation theory and hypothesize that TSD evolved in some reptile groups (specifically, chelonians and crocodilians) because male fitness is more sensitive to condition (general health, vigor) than female fitness. It follows that males benefit more than females from incubation environments that confer high-quality phenotypes, and hence high-condition individuals. We predict that female-producing temperatures, which comprise relatively high incubation temperatures in chelonians and crocodilians, are relatively stressful for embryos and subsequent life stages. We synthesize data from 28 studies to investigate how constant temperature incubation affects embryonic mortality in chelonians with TSD. We find several lines of evidence suggesting that female-producing temperatures, especially relatively warm temperatures, are more stressful than male-producing temperatures, and we find some evidence that pivotal temperatures (TPiv, the temperature that produces a 1:1 sex ratio) exhibit a correlated evolution with embryonic thermal tolerance. If patterns of temperature-sensitive embryonic mortality are also indicative of chronic thermal stress that occurs post hatching, then conservation programs may benefit from incubating eggs close to species-specific TPivs, thus avoiding high-temperature incubation. Indeed, our models predict that, on average, a sex ratio of more than 75% females can generally be achieved by incubating eggs only 1°C above TPiv. Of equal importance, we provide insight into the enigmatic evolution of TSD in chelonians, by providing support to the hypothesis that TSD evolution is related to the quality of the phenotype conferred by incubation temperature, with males produced in high-quality incubation environments.Lay summaryWe analyze data on embryonic mortality under constant-temperature incubation for 15 species of chelonians with temperature-dependent sex determination (TSD). Mortality is lowest near species-specific pivotal temperatures (Tpiv) but increases rapidly above TPiv, consistent with a theory that explains the adaptive significance of TSD. Conservation managers should incubate embryos near TPiv.
Secretin release after Roux-en-Y Gastric Bypass reveals a population of glucose-sensitive S-cells in distal small intestine
Authors: Modvig Ida M. , Andersen Daniel B. , Grunddal Kaare V. , Kuhre Rune E. , Martinussen Christoffer , Christiansen Charlotte B. , Ørskov Cathrine , Larraufie Pierre , Kay Richard , Reimann Frank , Gribble Fiona M. , Hartmann Bolette , Bojsen-Møller Kirstine N. , Madsbad Sten , Wewer Albrechtsen Nicolai J. , Holst Jens J. 
Published: October 2019

AbstractObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S-cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the post-operative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release.MethodsA specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA-sequencing, mass-spectrometry andin situhybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation.ResultsPlasma postprandial secretin was more than doubled in humans after RYGB (P<0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased secretion of secretin in a sodium-glucose co-transporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P<0.05) from the perfused rat pancreas but affected neither insulin (P=0.2) nor glucagon (P=0.97) secretion. When administered to ratsin vivo, insulin secretion was attenuated and glucagon secretion increased (P=0.04), while blood glucose peak time was delayed (from 15 min to 45 min) and gastric emptying time prolonged (P=0.004).ConclusionGlucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S-cells warrants further studies.
Microfluidic trapping of vesicles reveals membrane-tension dependent FtsZ cytoskeletal re-organisation
Authors: Ganzinger Kristina A. , Merino-Salomón Adrián , García-Soriano Daniela A. , Nelson Butterfield A. , Litschel Thomas , Siedler Frank , Schwille Petra 
Published: October 2019

AbstractThe geometry of reaction compartments can affect the outcome of chemical reactions. Synthetic biology commonly uses giant unilamellar vesicles (GUVs) to generate cell-sized, membrane-bound reaction compartments. However, these liposomes are always spherical due to surface area minimization. Here, we have developed a microfluidic chip to trap and reversibly deform GUVs into rod- or cigar-like shapes, including a constriction site in the trap mimicking the membrane furrow in cell division. When we introduce into these GUVs the bacterial tubulin homologue FtsZ, the primary protein of the bacterial Z ring, we find that FtsZ organization changes from dynamic rings to elongated filaments upon GUV deformation, and that these FtsZ filaments align preferentially with the short GUV axis, in particular at the membrane neck. In contrast, pulsing Min oscillations in GUVs remained largely unaffected. We conclude that microfluidic traps are a useful tool for deforming GUVs into non-spherical membrane shapes, akin to those seen in cell division, and for investigating the effect of confinement geometry on biochemical reactions, such as protein filament self-organization.
Repurposing theStreptococcus mutansCRISPR-Cas9 System to Understand Essential Gene Function
Authors: Shields RC , Walker AR , Maricic N , Chakraborty B , Underhill SAM , Burne RA 
Published: October 2019

AbstractA recent genome-wide screen identified ∼300 essential or growth-supporting genes in the dental caries pathogenStreptococcus mutans. To be able to study these genes, we built a CRISPR interference tool around the Cas9 nuclease (Cas9Smu) encoded in theS. mutansUA159 genome. Using a xylose-inducible dead Cas9Smuwith a constitutively active single-guide RNA (sgRNA), we observed titratable repression of GFP fluorescence that compared favorably to that ofStreptococcus pyogenesdCas9 (Cas9Spy). We then investigated sgRNA specificity and proto-spacer adjacent motif (PAM) requirements. Interference by sgRNAs did not occur with double or triple base-pair mutations, or if single base-pair mutations were in the 3’ end of the sgRNA. Bioinformatic analysis of >450S. mutansgenomes allied within vivoassays revealed a similar PAM recognition sequence as the Cas9Spy. Next, we created a comprehensive library of sgRNA plasmids that were directed at essential and growth-supporting genes. We discovered growth defects for 77% of the CRISPRi strains expressing sgRNAs. Phenotypes of CRISPRi strains, across several biological pathways, were assessed using fluorescence microscopy. A variety of cell structure anomalies were observed, including segregational instability of the chromosome, enlarged cells, and ovococci-to-rod shape transitions. CRISPRi was also employed to observe how silencing of cell wall glycopolysaccharide biosynthesis (rhamnose-glucose polysaccharide, RGP) affected both cell division and pathogenesis in a wax worm model. The CRISPRi tool and sgRNA library are valuable resources for characterizing essential genes inS. mutans, some of which could prove to be promising therapeutic targets.