bluuebunny/crossref_metadata_2025_split huggingface dataset:
A flexible formula for incorporating distributive concerns into cost-effectiveness analyses: priority weights
Authors: Haaland Ø.A. , Lindemark F. , Johansson K.A. 
Published: August 2019

ABSTRACTCost effectiveness analyses (CEAs) are widely used to evaluate the opportunity cost of health care investments. However, few functions that take equity concerns into account are available for such CEA methods, and these concerns are therefore at risk of being disregarded. Among the functions that have been developed, most focus on the distribution of health gains, as opposed to the distribution of lifetime health. This is despite the fact that there are good reasons to give higher priority to individuals and groups with a low health adjusted life expectancy. Also, an even distribution of health gains may imply an uneven distribution of lifetime health.We develop a systematic and explicit approach that allows for the inclusion of lifetime health concerns in CEAs, by creating a new priority weight function, PW=α+(t-γ)·C·e-β·(t-γ), where t is the health measure. PW has several desirable properties. First, it is continuous and smooth, ensuring that people with similar health characteristics are treated alike. Second, it is flexible regarding shape and outcome measure, so that a broad range of values may be modelled.Third, the coefficients have distinct roles. This allows for the easy manipulation of the PW’s shape. In order to demonstrate how PW may be applied, we use data from a previous study and estimated the coefficients of PW based on two approaches.The first considers the mean weights assigned by the respondents:PWmean=-0.42+(t+22.2)·0.27·e-0.031·(t+22.2).The second considers the median weights:PWmedian=0.79+(t+8.85)·0.17·e-0.053·(t+8.85).This illustrates that our framework allows for the estimation of PWs based on empirical data.
Efficient Prediction of Vitamin B Deficiencies via Machine-learning Using Routine Blood Test Results in Patients With Intense Psychiatric Episode
Authors: Tamune Hidetaka , Ukita Jumpei , Hamamoto Yu , Tanaka Hiroko , Narushima Kenji , Yamamoto Naoki 
Published: August 2019

AbstractBackgroundVitamin B deficiency is common worldwide and may lead to psychiatric symptoms; however, vitamin B deficiency epidemiology in patients with intense psychiatric episode has rarely been examined. Moreover, vitamin deficiency testing is costly and time-consuming, which has hampered effectively ruling out vitamin deficiency-induced intense psychiatric symptoms. In this study, we aimed to clarify the epidemiology of these deficiencies and efficiently predict them using machine-learning models from patient characteristics and routine blood test results that can be obtained within one hour.MethodsWe reviewed 497 consecutive patients deemed to be at imminent risk of seriously harming themselves or others over 2 years in a single psychiatric tertiary-care center. Machine-learning models (k-nearest neighbors, logistic regression, support vector machine, and random forest) were trained to predict each deficiency from age, sex, and 29 routine blood test results gathered in the period from September 2015 to December 2016. The models were validated using a dataset collected from January 2017 through August 2017.ResultsWe found that 112 (22.5%), 80 (16.1%), and 72 (14.5%) patients had vitamin B1, vitamin B12, and folate (vitamin B9) deficiency, respectively. Further, the machine-learning models were well generalized to predict deficiency in the future unseen data, especially using random forest; areas under the receiver operating characteristic curves for the validation dataset (i.e. the dataset not used for training the models) were 0.716, 0.599, and 0.796, respectively. The Gini importance of these vitamins provided further evidence of a relationship between these vitamins and the complete blood count, while also indicating a hitherto rarely considered, potential association between these vitamins and alkaline phosphatase (ALP) or thyroid stimulating hormone (TSH).DiscussionThis study demonstrates that machine-learning can efficiently predict some vitamin deficiencies in patients with active psychiatric symptoms, based on the largest cohort to date with intense psychiatric episode. The prediction method may expedite risk stratification and clinical decision-making regarding whether replacement therapy should be prescribed. Further research includes validating its external generalizability in other clinical situations and clarify whether interventions based on this method could improve patient care and cost-effectiveness.
Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-A
Authors: Touchette Jillienne C. , Moen Janna K. , Robinson Jenna M. , Lee Anna M. 
Published: August 2019

AbstractThe prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating the neurocircuitries in this region in mediating the effects of sazetidine-A. Furthermore, sazetidine-A-induced reduction in alcohol consumption was mediated by non-α4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both α4 knock-out and wild-type mice. Finally, we found that in mice pre-treated with sazetidine-A, alcohol induced Fos transcript within Th-expressing but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A acts on non-α4 nAChRs to enhance the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-α4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs.
Placental neurosteroids shape cerebellar development and social behaviour
Authors: Vacher Claire-Marie , O’Reilly Jiaqi J. , Salzbank Jacquelyn , Lacaille Helene , Bakalar Dana , Sebaoui-Illoul Sonia , Liere Philippe , Clarkson-Paredes Cheryl , Sasaki Toru , Sathyanesan Aaron , Kawasawa Yuka Imamura , Popratiloff Anastas , Hashimoto-Torii Kazue , Gallo Vittorio , Schumacher Michael , Penn Anna A. 
Published: August 2019

ABSTRACTCompromised placental function or premature loss has been linked to diverse neurodevelopmental disorders 1,2. The placenta is the first functional foetal endocrine organ, but the direct impact of placental hormone loss on foetal brain in late gestation has not been empirically tested. Allopregnanolone (ALLO) is a non-glucocorticoid, progesterone derivative that acts as a positive modulator of GABA-A receptor activity3 with the potential to alter critical GABA-mediated developmental processes 4,5. To directly test the role of placental ALLO, we generated a novel mouse model in which the gene encoding the synthetic enzyme for ALLO (Akr1c14) is specifically deleted in trophoblasts using a tissue-specific Cre-Lox strategy. ALLO concentrations are significantly decreased in late gestation in placenta and brain when placental Akr1c14 is removed, indicating placenta as the primary gestational ALLO source. We now demonstrate that targeted placental ALLO loss leads to permanent changes in brain development in a sex- and regionally-specific manner. Placental ALLO insufficiency led to male-specific cerebellar white matter (WM) abnormalities characterized by excess myelination with increased myelin protein expression, similar to changes reported in boys with autism spectrum disorders (ASD)6,7. Behavioural testing of these mice revealed increased repetitive behaviour and sociability deficits, two hallmarks of ASD, only in male offspring with placental ALLO insufficiency. Notably, a strong positive correlation was seen between the cerebellar contents of myelin basic protein (MBP) and the severity of ASD-like behaviours. A single injection of ALLO during gestation was sufficient to rescue both cerebellar MBP levels and aberrant behaviours. This study reveals a new role for a placental hormone in shaping specific brain structures and behaviours, and suggests that identifying placental hormone insufficiency or preterm loss may offer novel therapeutic opportunities to prevent later neurobehavioural disorders.
A mathematical model of mitochondrial calcium-phosphate dissolution as a mechanism for persistent post-CSD vasoconstriction
Authors: Xu Shixin , Chang Joshua C. , Chow Carson C. , Huang Huaxiong 
Published: August 2019

AbstractCortical spreading depolarization (CSD) is the propagation of a relatively slow wave in cortical brain tissue that is linked to a number of pathological conditions such as stroke and migraine. Most of the existing literature investigates the dynamics of short term phenomena such as the depolarization and repolarization of membrane potentials or large ion shifts. Here, we focus on the clinically-relevant hour-long state of neurovascular malfunction in the wake of CSDs. This dysfunctional state involves widespread vasoconstriction and a general disruption of neurovascular coupling. We demonstrate, using a mathematical model, that dissolution of calcium that has aggregated within the mitochondria of vascular smooth muscle cells can drive an hour-long disruption. We determine the rate of calcium clearance as well as the dynamical implications on overall blood flow. Based on reaction stoichiometry, we quantify a possible impact of calcium phosphate dissolution on the maintenance of F0F1-ATP synthase activity.
Cell-substrate adhesion drives Scar/WAVE activation and phosphorylation, which controls pseudopod lifetime
Authors: Singh Shashi Prakash , Thomason Peter A. , Lilla Sergio , Schaks Matthias , Tang Qing , Goode Bruce L. , Machesky Laura M. , Rottner Klemens , Insall Robert H. 
Published: August 2019

AbstractThe Scar/WAVE complex is the principal catalyst of pseudopod and lamellipod formation. Here we show that Scar/WAVE’s proline-rich domain is polyphosphorylated after the complex is activated. Treatments that stop activation block phosphorylation in bothDictyosteliumand mammalian cells. This implies that phosphorylation modulates pseudopods after they have been formed, rather than controlling whether a protrusion is initiated. Unexpectedly, activation-dependent phosphorylation is not promoted by chemotactic signalling, or by signal-dependent kinases such as ERKs, but is greatly stimulated by cell:substrate adhesion. Scar/WAVE that has been mutated to be either unphosphorylatable or phosphomimetic is activated normally, and rescues the phenotype ofscar−cells, demonstrating that phosphorylation is dispensible for activation and actin regulation. However, pseudopods and patches of Scar/WAVE complex recruitment last substantially longer in unphosphorylatable mutants, altering cell polarisation and the efficiency of migration. We conclude that pseudopod engagement with substratum is more important than extracellular signals at regulating Scar/WAVE’s activity, and that phosphorylation acts as a timer, restricting pseudopod lifetime by promoting Scar/WAVE turnover.
Development and application of eDNA-based tools for the conservation of white-clawed crayfish
Authors: Troth Christopher R. , Burian Alfred , Mauvisseau Quentin , Bulling Mark , Nightingale Jen , Mauvisseau Christophe , Sweet Michael J. 
Published: August 2019

AbstracteDNA-based methods represent non-invasive and cost-effective approaches for species monitoring and their application as a conservation tool has rapidly increased within the last decade. Currently, they are primarily used to determine the presence/absence of invasive, endangered or commercially important species, but they also hold potential to contribute to an improved understanding of the ecological interactions that drive species distribution. However, this next step of eDNA-based applications requires a thorough method development.We developed an eDNA assay for the white-clawed crayfish (Austropotamobius pallipes), a flagship species of conservation in the UK. Multiple subsequent in-situ and ex-situ validation tests aimed at improving method performance allowed us to apply eDNA-based surveys to evaluate interactions between white-clawed crayfish, crayfish plague and invasive signal crayfish.The assay performed well in terms of specificity (no detection of non-target DNA) and sensitivity, which was higher than more established traditional species survey methods. Quantification of species biomass was, however, less reliable.Comparison of eDNA sampling methods (precipitation vs. various filtration approaches) revealed that optimal sampling method differed across environments and might depend on inhibitor concentrations.Finally, we applied our methodology together with established assays for crayfish plague and the invasive signal crayfish and demonstrated their significant interactions in a UK river system.Our analysis highlights the importance of thorough methodological development of eDNA-based assays. Only a critical evaluation of methodological strengths and weaknesses will allow us to capitalise on the full potential of eDNA-based methods and use them as decision support tools in environmental monitoring and conservation practices.
Discovery of aPseudomonas aeruginosaType VI secretion system toxin targeting bacterial protein synthesis using a global genomics approach
Authors: Nolan Laura M. , Cain Amy K. , Manoli Eleni , Sainz-Polo Maria A. , Dougan Gordon , Mavridou Despoina A.I. , Albesa-Jové David , Parkhill Julian , Filloux Alain 
Published: August 2019

SUMMARYThe Type VI secretion system (T6SS) is a bacterial weapon which delivers toxic effectors to kill competitors or subvert some of their key functions. Here we usetransposondirected insertion-sitesequencing (TraDIS) to identify T6SS toxins associated with the H1-T6SS, one of the three T6SS machines found inPseudomonas aeruginosa. This approach identified several putative toxin-immunity pairs, including Tse8-Tsi8. Full characterization of this protein pair demonstrated that Tse8 is delivered by the VgrG1a spike complex into prey cells where it targets the transamidosome, a multiprotein complex involved in protein synthesis in bacteria lacking either one or both of the asparagine or glutamine tRNA synthases. Our data suggests that Tse8 combines as a non-cognate component of the transamidosome complex, reducing fitness by limiting the ability of the cell to synthesize proteins. This is the first demonstration of a T6SS toxin affecting protein synthesis, expanding the range of cellular components targeted by this bacterial weapon. The success of the current study validates the use of our TraDIS approach as a tool to drastically expand the repertoire of T6SS toxins in any T6SS-encoding bacterium.
Cytosolic Adaptation to Mitochondrial Precursor Overaccumulation Stress Induces Progressive Muscle Wasting
Authors: Wang Xiaowen , Middleton Frank A. , Tawil Rabi , Chen Xin Jie 
Published: August 2019

AbstractMitochondrial dysfunction causes muscle wasting (or atrophy) in many diseases and probably also during aging. The underlying mechanism is unclear. Accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative stress are insufficient by themselves to intrinsically cause muscle wasting, raising the possibility that non-bioenergetic factors may contribute to mitochondria-induced muscle wasting. In this report, we show that chronic adaptation to mitochondria-induced proteostatic stress in the cytosol induces muscle wasting. We generated transgenic mice with unbalanced mitochondrial protein loading and import, by a two-fold increase in the expression of the nuclear-encoded mitochondrial carrier protein, Ant1. We found that the ANT1-transgenic mice progressively lose muscle mass. Skeletal muscle is severely atrophic in older mice without affecting the overall lifespan. Mechanistically, Ant1 overloading induces aggresome-like structures and the expression of small heat shock proteins in the cytosol. The data support mitochondrial Precursor Overaccumulation Stress (mPOS), a recently discovered cellular stress mechanism caused by the toxic accumulation of unimported mitochondrial precursors/preproteins. Importantly, the ANT1-transgenic muscles have a drastically remodeled transcriptome that appears to be trying to counteract mPOS, by repressing protein synthesis, and by stimulating proteasomal function, autophagy and lysosomal amplification. These anti-mPOS responses collectively reduce protein content, which is known to decrease myofiber size and muscle mass. Our work therefore revealed that a subtle imbalance between mitochondrial protein load and import is sufficient to induce mPOS in vivo, and that anti-mPOS adaptation is a robust mechanism of muscle wasting. This finding may help improve the understanding of how mitochondria contribute to muscle wasting. It could have direct implications for several human diseases associated with ANT1 overexpression, including Facioscapulohumeral Dystrophy (FSHD).One Sentence SummaryProteostatic adaptations to proteostatic stress in the cytosol caused by unbalanced mitochondrial protein loading and import lead to progressive muscle wasting.
quasitools: A Collection of Tools for Viral Quasispecies Analysis
Authors: Marinier Eric , Enns Eric , Tran Camy , Fogel Matthew , Peters Cole , Kidwai Ahmed , Ji Hezhao , Van Domselaar Gary 
Published: August 2019

AbstractSummaryquasitools is a collection of newly-developed, open-source tools for analyzing viral quasispcies data. The application suite includes tools with the ability to create consensus sequences, call nucleotide, codon, and amino acid variants, calculate the complexity of a quasispecies, and measure the genetic distance between two similar quasispecies. These tools may be run independently or in user-created workflows.AvailabilityThe quasitools suite is a freely available application licensed under the Apache License, Version 2.0. The source code, documentation, and file specifications are available at: https://phac-nml.github.io/quasitools/Contactgary.vandomselaar@canada.ca
Signaling gradients in surface dynamics as basis for planarian regeneration
Authors: Scheel Arnd , Stevens Angela , Tenbrock Christoph 
Published: August 2019

AbstractWe introduce and analyze a mathematical model for the regeneration of planarian flatworms. This system of differential equations incorporates dynamics of head and tail cells which express positional control genes that in turn translate into localized signals that guide stem cell differentiation. Orientation and positional information is encoded in the dynamics of a long rangewnt-related signaling gradient. We motivate our model in relation to experimental data and demonstrate how it correctly reproduces cut and graft experiments. In particular, our system improves on previous models by preserving polarity in regeneration, over orders of magnitude in body size during cutting experiments and growth phases. Our model relies on tristability in cell density dynamics, between head, trunk, and tail. In addition, key to polarity preservation in regeneration, our system includes sensitivity of cell differentiation to gradients ofwnt-related signals relative to the tissue surface. This process is particularly relevant in a small tissue layer close to wounds during their healing, and modeled here in a robust fashion through dynamic boundary conditions.
Is Vagus Nerve Stimulation Brain Washing?
Authors: Cheng Kevin P. , Brodnick Sarah K. , Blanz Stephan L. , Zeng Weifeng , Kegel Jack , Pisaniello Jane A. , Ness Jared P. , Ross Erika , Nicolai Evan N. , Settell Megan L. , Trevathan James K. , Poore Samuel O. , Suminski Aaron J. , Williams Justin C. , Ludwig Kip A. 
Published: August 2019

AbstractVagal nerve stimulation (VNS) is an FDA approved treatment method for intractable epilepsy, treatment resistant depression, cluster headaches and migraine with over 100,000 patients having received vagal nerve implants to date. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood and an area of active research. In parallel, the glymphatic and meningeal lymphatic systems have recently been proposed and experimentally validated to explain how the brain maintains a healthy homeostasis without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins from the interstitium. Of note, clearance is sensitive to adrenergic signaling, and a primary driver of CSF influx into the parenchyma appears to be cerebral arterial pulsations and respiration. As VNS has well-documented effects on cardiovascular and respiratory physiology as well as brain adrenergic signaling, we hypothesized that VNS delivered at clinically derived parameters would increase CSF influx in the brain. To test this hypothesis, we injected a low molecular weight (3 kD) lysine-fixable fluorescent tracer (TxRed) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following VNS. We found that the clinical VNS group showed a significant increase in CSF dye penetrance as compared to the naïve control and sham groups. This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.One Sentence SummaryCervical vagus nerve stimulation using clinically derived parameters enhances movement of cerebrospinal fluid into the brain parenchyma presenting a previously unreported effect of vagus nerve stimulation with potential clinical utility.
Profiling of presynaptic mRNAs reveals a role for axonal PUMILIOs in associative memory formation
Authors: Arey Rachel , Kaletsky Rachel , Murphy Coleen T. 
Published: August 2019

AbstractPresynaptic protein synthesis is important in the adult central nervous system; however, the set of mRNAs localized to presynaptic areas has yet to be identified in any organism. We differentially labeled somatic and synaptic compartments nervous system-wide in adult C. elegans and isolated synaptic regions for deep sequencing. Analysis of the synaptic transcriptome reveals that synaptic transcripts are predicted to have specialized functions in neurons. Differential expression analysis identified 543 genes enriched in synaptic regions relative to somatic regions, with synaptic functions conserved in higher organisms. We find that mRNAs for pumilio RNA-binding proteins are abundant in synaptic regions, which we confirmed through high-sensitivity in situ hybridization. We identified a new role for the PUM2 orthologs puf-7/8 as repressors of memory formation through regulation of the mitochondrial dynamics regulator, mff-1. Identification of presynaptic mRNAs provides insight into mechanisms that regulate synaptic function and behavior.