bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced versus standard outpatient care of asthmatic children in Malawi: study protocol for a pilot randomised controlled trial
Authors: Rylance Sarah , Phiri Joseph , Grigg Jonathan , Jewell Chris , Jambo Kondwani , Mortimer Kevin 
Published: August 2020

AbstractBackgroundAsthma is the most common chronic disease in childhood and is a growing global concern. However, there are limited data regarding long-term asthma management in low-income countries (LIC), particularly for children.This study will assess the feasibility of recruitment and retention, the acceptability of an intervention and data collection methods, and baseline levels of asthma control and exacerbation rates in our target population of Malawian asthmatic children. Furthermore, we plan to; evaluate the effect of a package of enhanced asthma care, appropriate for a LIC, over a 3-month period; to describe clinical and airway inflammatory phenotypes; to identify clinical and laboratory features which might predict response to treatment in this population.MethodsWe will recruit 120 children aged 6-15 years, attending outpatient asthma follow-up at a tertiary government hospital in Malawi. Participants will be randomised, stratified by level of asthma control (Childhood Asthma Control Test (C-ACT) ≤19 or ≥20), to receive standard care in the hospital clinic, or an enhanced care package comprising; detailed clinical assessment (including pre- and post-bronchodilator spirometry, exercise challenge, exhaled nitric oxide (FeNO) measurement and sputum induction), optimisation of inhaled asthma treatment, and asthma education delivered by non-healthcare workers. Feasibility outcomes will include recruitment and retention rates, data completeness for study procedures, and baseline asthma control and exacerbation rates. The primary clinical outcome is asthma control, measured by C-ACT at 3 months, with adjustment for baseline measurement and intervention as covariates in a regression model. Secondary clinical outcomes at 3 months include; asthma exacerbations (requiring emergency health care use, treatment with oral corticosteroids or hospital admission), school absence, lung function and FeNO levels. Participants will be described by clinical and inflammatory phenotypes, with the latter categorised as eosinophilic or non-eosinophilic based on sputum cytology results and FeNO levels.DiscussionIt is important to assess whether global treatment guidelines for long-term asthma management are appropriate for low-income settings. This study will provide key feasibility data, including baseline clinical characteristics of asthmatic Malawian children, to inform assessment of an asthma care package in a low-income setting, which includes task-shifting to non-healthcare workers.Trial registrationPan African Clinical Trials Registry: PACTR201807211617031. Registered 09/07/18, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=3468
Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release
Authors: Jones Nathan T , Zahid Zarmeen , Grady Sean M , Sultan Ziyad W , Zheng Zhen , Banks Matthew I , Wenthur Cody J 
Published: August 2020

AbstractDespite observed correlations between acute glucocorticoid release, self-reported anxiety, and long-term treatment outcomes for human studies using psilocybin-assisted psychotherapy approaches, the mechanistic relationship between psychedelic-dependent stress and subsequent behavioral responses remains unclear. Using rodents, direct manipulation of stress-associated hormone responses can be achieved with established pharmacologic models for the assessment of antidepressant and anxiolytic therapeutics. Here, chronic oral corticosterone-induced suppression of the hypothalamic-pituitary-adrenal axis is used to assess the relevance of drug-induced glucocorticoid release on the acute, post-acute, and long-term effects of psilocybin in male C57BL/6J mice. In these studies, psilocybin-induced acute anxiogenesis was found to be correlated to post-acute anxiolysis in a dose-dependent manner. Psilocybin also displayed acute increases in plasma corticosterone, but a post-acute anxiolytic effect in the novelty suppressed feeding test. Both effects were lost when psilocybin was administered in animals pre-exposed to chronic oral corticosterone. A similar long-term interaction between chronic corticosterone and psilocybin administration was observed in an open field test occurring one week after drug administration. Psilocybin administration alone led to more time spent in the center of the arena, but animals spent less time in the center with chronic corticosterone exposure. Intriguingly, these interactive effects were absent in animals exposed to brief isoflurane anesthesia after drug treatment. Overall, these experiments identify acute glucocorticoid release as a relevant biological modifier for the post-acute and long-term behavioral effects of psilocybin in mice. Rodent studies are thus suggested as a tractable means to address neuroendocrine mechanisms supporting context-dependent psychedelic effects in mammalian species.
Attention capture outside the oculomotor range
Authors: Hanning Nina M. , Deubel Heiner 
Published: August 2020

ABSTRACTNeurophysiological studies demonstrated that attentional orienting is performed by fronto-parietal brain areas which also play an important role in oculomotor control. Accordingly, several studies claimed that exogenous attention can only be allocated to where we can potentially make an eye movement, i.e. within the oculomotor range. We tested this assumption by assessing the disruptive effect of a salient distractor at locations within and beyond participants’ oculomotor range. Participants rotated their heads ~38° leftwards to prevent them from performing large rightward saccades. In this posture, participants fixated the screen center and focused their attention on a location on the left side of the screen, where they had to discriminate the orientation of a visual noise patch. While assessing visual orientation sensitivity – an established proxy of visual attention – at this endogenously attended location, we flashed a salient cue either at the attended location or at various locations inside or outside their oculomotor range. We found that whenever the salient cue occurred at a location other than the endogenously attended location, it withdrew visual attention and significantly disrupted endogenous attentional orienting. Crucially, this effect occurred regardless of whether the cue was presented within or beyond participants’ oculomotor range, demonstrating that exogenous events equally grab our attention both inside and outside the eyes reach. Since spatial exogenous attention was attracted unrestrictedly toward locations to which no saccade could be executed, the coupling of attention and eye movement control is less tight than, for example, the prominent “Premotor Theory of Attention” suggests. Rather, attention can be shifted freely over the entire visual range, independent of pathological and physiological limitations of the eye movement system.
Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes
Authors: Lim Chun Shen , Sozzi Vitina , Revill Peter A. , Brown Chris M. 
Published: August 2020

ABSTRACTHepatitis B virus (HBV) is a major human pathogen that causes liver diseases. The main HBV RNAs are unspliced transcripts that encode the key viral proteins. Recent studies show that some of the HBV spliced transcript isoforms are predictive of liver cancer, yet the roles of these spliced transcripts remain elusive. Furthermore, a total of 9 major HBV genotypes were isolated from discrete geographical regions of the world, it is likely that these genotypes may express a broad variety of spliced transcript isoforms. To systematically study the HBV splice variants, we transfected the human hepatoma cells Huh7 with 4 HBV genotypes (A2, B2, C2, and D3), followed by deep RNA-sequencing. We found that 12-25% of HBV RNAs were splice variants, which were reproducibly detected across independent biological replicates. This accounted for a total of 6 novel and 6 previously identified splice variants. In particular, 2 highly abundant novel splice variants, in which we called the putative splice variants 1 and 5 (pSP1 and pSP5), were specifically expressed at high levels in genotypes D3 and B2, respectively. In general, the HBV splicing profiles varied across the genotypes except for the known spliced pgRNAs SP1 and SP9, which were present in all 4 major genotypes. Counterintuitively, these singly spliced SP1 and SP9 had a suboptimal 5′ splice site, suggesting that splicing of HBV RNAs is tightly controlled by the viral post-transcriptional regulatory RNA element.IMPORTANCEHBV infection affects over 257 million people worldwide. HBV is a major cause of liver diseases including cancer and there is no cure. Some HBV RNAs are spliced variants and their roles are largely unclear, although some splice variants have been previously found to be associated with liver cancer. HBV exists as 9 genotypes worldwide with marked differences in replicative capacity and disease sequelae. Whether HBV splice variants vary for the different genotypes is yet to be investigated in depth. Here we sequenced RNAs from 4 major HBV genotypes using a cell culture system. We found 6 new and 6 previously known splice variants across these genotypes. Some novel splice variants were present at high levels, suggesting they could be functionally important. Interestingly, although HBV has adapted to human hosts for over 50,000 years, the most frequently spliced location shared little flanking sequence similarity with that of humans.
Diagnostic accuracy of B scan ultrasonography for posterior segment eye disorders in a tertiary care setting in Eastern India
Authors: Chaudhury Maheswar , Parida Bikash , Panigrahi Sandeep Kumar 
Published: August 2020

AbstractIntroductionOphthalmic ultrasound (USG) produces real time high resolution images of the eye and orbit. It can categorize and predict the location of pathology in the posterior chamber of eye very well. It is useful even in pre-operative evaluation and diagnosing posterior segment eye disorders. However, the diagnostic accuracy has usually not being studied thoroughly, with special emphasis to its probability of predicting posterior-segment eye disorders using B-scan USG.ObjectivesTo find out the prevalence and pattern of posterior segment disorders using B-scan ultrasonography, and to find its diagnostic accuracy.Materials and MethodsThe study was prospective in nature and conducted in the department of radiodiagnosis and ophthalmology of a tertiary care center of Eastern India. Patients referred to the radiology department for ruling out intra-ocular pathology using B-scan ophthalmic ultrasound were included in the study, irrespective of any age and gender. Data were captured on an excel sheet and analyzed using Stata 12.1 SE.ResultsThe mean age of 84 study participants was 37.4 ± 19.5 years, with maximum in between 40-50 years. Males were more (72.6%). 50% presented with low vision, and most commonly associated with cataract (45%). Prevalence of posterior segment eye disorders was 13.1%. Sensitivity and negative predictive values were 100%. Post-test probability was 95.5%. Accuracy was however very less (39.3%).ConclusionUsing B-scan ultrasonography for pre-operative assessment and confirmation of diagnosis increases the probability of detecting presence or absence of posterior segment pathology. Absence of posterior segment disorder using this is also very helpful in ruling out disease entirely. It also a very high sensitivity and hence can be used even in rural health centers.
Assembly and symmetry of the fungal E3BP-containing core of the Pyruvate Dehydrogenase Complex
Authors: Forsberg B. O. , Aibara S. , Howard R. J. , Mortezaei N. , Lindahl E. 
Published: August 2020

AbstractThe pyruvate dehydrogenase complex (PDC) is a central component of all aerobic respiration, connecting glycolysis to mitochondrial oxidation of pyruvate. Despite its central metabolic role, its precise composition and means of regulation remain unknown. To explain the variation in stoichiometry reported for the E3-recruiting protein X (PX) in the fungal PDC, we established cryo-EM reconstructions of the native and recombinant PDC from the filamentous fungus and model organismNeurospora crassa. We find that the PX C-terminal domain localizes interior to the E2 core. Critically, we show that two distinct arrangements of a trimeric oligomer exists, which both result in strict tetrahedral symmetry of the PDC core interior. Both oligomerization and volume occlusion of the PDC interior by PX appears to limit its binding stoichiometry, which explains the variety of stoichiometries found previously forS. cerevisiae. This also suggests that the PX oligomer stability and size are potential mechanisms to dynamically adjust PDC compostion in response to external cues. Moreover, we find that the site where PX binds is conserved within fungi but not mammals, suggesting that it could be therapeutically targeted. To this end, we also show that a PX knockout results in loss of activity through dysfunctional E3 recruitment, leading to severely impairedN. crassagrowth on sucrose. The fungal PDC is thus shown to be fundamentally similar to the mammalian PDC in function but subject to other conditions of possible regulation, conditioned by a steric restrictions imposed by the symmetry of the PDC and its components.
eIF2B extends lifespan through inhibition of the integrated stress response
Authors: Derisbourg Maxime , Wester Laura , Baddi Ruth , Denzel Martin S. 
Published: August 2020

AbstractProtein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The integrated stress response (ISR) is a conserved stress-signaling pathway that tunes mRNA translation via phosphorylation of the translation initiation factor eIF2. ISR activation and translation initiation are finely balanced by eIF2 kinases and by the eIF2 guanine nucleotide exchange factor eIF2B. However, the role of the ISR during aging remains unexplored. Using a genomic screen inCaenorhabditis elegans, we discovered a role of eIF2B and the eIF2 kinases in longevity. By limiting the ISR, these mutations enhanced protein homeostasis and increased lifespan. Consistently, full ISR inhibition using phosphorylation-defective eIF2α or pharmacological ISR inhibition prolonged lifespan. Lifespan extension through ISR inhibition occurred without changes in overall protein synthesis, and depended on enhanced translational efficiency of the kinase KIN-35. Evidently, lifespan is limited by the ISR and its inhibition may provide an intervention in aging.
Structure of the activated Roq1 resistosome directly recognizing the pathogen effector XopQ
Authors: Martin Raoul , Qi Tiancong , Zhang Haibo , Liu Furong , King Miles , Toth Claire , Nogales Eva , Staskawicz Brian J. 
Published: August 2020

AbstractPlants and animals detect pathogen infection via intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) that directly or indirectly recognize pathogen effectors and activate an immune response. How effector sensing triggers NLR activation remains poorly understood. Here we describe the 3.8 Å resolution cryo-electron microscopy structure of the activated Roq1, an NLR native toNicotiana benthamianawith a Toll-like interleukin-1 receptor (TIR) domain, bound to theXanthomonaseffector XopQ. Roq1 directly binds to both the predicted active site and surface residues of XopQ while forming a tetrameric resistosome that brings together the TIR domains for downstream immune signaling. Our results suggest a mechanism for the direct recognition of effectors by NLRs leading to the oligomerization-dependent activation of a plant resistosome and signaling by the TIR domain.One Sentence SummaryVisualization of an activated plant immune receptor that triggers the immune response upon pathogen recognition.
Structural insights into the interaction of heme with protein tyrosine kinase JAK2
Authors: Schmalohr Benjamin Franz , Mustafa Al-Hassan M. , Krämer Oliver , Imhof Diana 
Published: August 2020

AbstractJanus kinase 2 (JAK2) is the most important signal transducing tyrosine kinase in erythropoietic precursor cells. Its malfunction drives several myeloproliferative disorders. Heme is a small metal ion-carrying molecule, which is incorporated into hemoglobin in erythroid precursor cells to transport oxygen. In addition, heme is a signaling molecule and regulator of various biochemical processes. Here we show that heme exposure leads to hyperphosphorylation of JAK2 in a myeloid cancer cell line. Two peptides identified in JAK2 represent heme-regulatory motifs and show low micromolar affinities for heme. These peptides map to the kinase domain of JAK2, which is essential for downstream signaling. We suggest these motifs to be the interaction sites of heme with JAK2, which drive the heme-induced hyperphosphorylation. The results presented herein may facilitate the development of heme-related pharmacological tools to combat myeloproliferative disorders.
Expression of neuronal Na+ leak channel, NALCN, provides for persistent invasion of metastasizing cancer cells
Authors: Iamshanova Oksana , Gordienko Dmitri , Folcher Antoine , Bokhobza Alexandre , Shapovalov George , Kannancheri-Puthooru Dheeraj , Mariot Pascal , Allant Laurent , Desruelles Emilie , Spriet Corentin , Diez Raquel , Oullier Thibauld , Marionneau-Lambot Séverine , Brisson Lucie , Geraci Sandra , Impheng Hathaichanok , Lehenkyi V’yacheslav , Haustrate Aurelien , Mihalache Adriana , Gosset Pierre , Chadet Stéphanie , Retif Stéphanie , Laube Maryline , Sobilo Julien , Lerondel Stéphanie , Villari Giulia , Serini Guido , Pla Alessandra Fiorio , Roger Sébastien , Fromont-Hankard Gaelle , Djamgoz Mustafa , Clezardin Philippe , Monteil Arnaud , Prevarskaya Natalia 
Published: August 2020

AbstractCytosolic Ca2+ oscillations provide signaling input to several effector systems of the cell. These include neuronal development, migration and networking. Although similar signaling events are hijacked by highly aggressive cancer cells, the complexity of the ‘neuron-like’ remodeling in metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques we show that strongly metastatic prostate cancer cells acquire specific Na+/Ca2+ signature required for persistent invasion. We identify the ‘neuronal’ Na+ leak channel, NALCN, at the hot spots of the Ca2+ wave initiation and invadopodia formation. Mechanistically, NALCN associates functionally with plasmalemmal and mitochondrial Na+/Ca2+ exchangers, reactive oxygen species and store-operated channels to generate intracellular Ca2+ oscillations. In turn, this stimulates the activity of protooncogene Src kinase co-localized with NALCN, actin remodeling and secretion of proteolytic enzymes, thus increasing an invasive potential of the cancer cells and metastatic lesions in vivo (accessed in pre-clinical models). Overall, our findings provide new insight into the signaling pathway specific for metastatic cells where NALCN plays the role of the persistent invasion “launcher and controller”.
Retention of Lumpy Skin Disease Virus inStomoxysSpp (Stomoxys Calsitrans, Stomoxys Sitiens, Stomoxys Indica) following intrathoracic inoculation, Diptera: Muscidae
Authors: Issimov Arman , Kutumbetov Lespek , Zhanabayev Assylbek , Kazhgaliyev Nurlybay , Nurgaliyev Birzhan , Zhubantayev Izimgali , Akhmetaliyeva Aliya , Shalmenov Malik , Kereyev Abzal , White Peter J. 
Published: August 2020

AbstractLumpy skin disease (LSD) is an emerging disease in cattle in Kazakhstan and the means of transmission remains uncertain. In the current study, acquisition of Lumpy Skin Disease Virus (LSDV) byStomoxysspecies following intrathoracic inoculation was demonstrated under laboratory conditions. Flies were injected with a virulent LSDV strain into the thorax region to bypass the midgut barrier. The fate of pathogen in the hemolymph of the flies was further examined using PCR and Virus isolation tests. LSDV was isolated from all threeStomoxysspecies immediately and up to 24h post intrathoracic inoculation while virus DNA was detectable up to 7d post intrathoracic inoculation.
Sero-Prevalence and Associated Risk Factors of Bovine Brucellosis in Sendafa, Oromia Special Zone Surrounding Addis Ababa, Ethiopia
Authors: Bifo Hadji , Gugsa Getachew , Kifleyohannes Tsegabirhan , Abebe Engidaw , Ahmed Meselu 
Published: August 2020

AbstractBovine brucellosis is an infectious bacterial disease caused by members of genus Brucella, affecting both animals and humans, and resulting in a serious economic loss in animal production sector and deterioration of public health. This cross-sectional study was conducted from November 2014 to April 2015 to determine the sero-prevalence and associated risk factors of bovine brucellosis in Sendafa, Oromia special Zone, Ethiopia. A total of 503 blood samples were collected using simple random sampling technique from dairy cattle of above 6 months of age with no history of previous vaccination against brucellosis. All sera samples were demonstrated using both Rose Bengal Plate Test for screening and Compliment Fixation Test for confirmation. Accordingly, the overall sero-prevalence of bovine brucellosis in this area was 0.40%. The result showed that the sero-prevalence of bovine brucellosis in the study area was not statistically significant with all proposed risk factors. Thus, the study revealed the absence of significant statistical variation in the sero-prevalence of bovine brucellosis in different age, sex groups, breeding method and history of previous abortions (P>0.05). No reactors were observed in male animals. Sero-prevalence of 0.40% was observed in animals without previous history of abortion. Moreover, information was gathered on individual animal and farm-level risk factors and other farm characteristics using a questionnaire. The awareness among the society was poor, so the positive animals can be a potential hazard to animals and humans in the study area. Therefore, public education should be done in order to improve the awareness of people on bovine brucellosis and its public health impact with due consideration on the safely consumption of food of animal origin.
Integrating Non-Spiking Interneurons in Spiking Neural Networks
Authors: Strohmer Beck , Stagsted Rasmus Karnøe , Manoonpong Poramate , Larsen Leon Bonde 
Published: August 2020

AbstractResearchers working with neural networks have historically focused on either non-spiking neurons tractable for running on computers or more biologically plausible spiking neurons typically requiring special hardware. However, in nature homogeneous networks of neurons do not exist. Instead, spiking and non-spiking neurons cooperate, each bringing a different set of advantages. A well researched biological example of such a mixed network is the sensorimotor pathway, responsible for mapping sensory inputs to behavioral changes. This pathway is also well researched in robotics where it is applied to achieve closed-loop operation of legged robots by adapting amplitude, frequency, and phase of the motor output. In this paper we investigate how spiking and non-spiking neurons can be combined to create a sensorimotor neuron pathway capable of shaping network output based on analog input. We propose sub-threshold operation of an existing spiking neuron model to create a non-spiking neuron able to interpret analog information and communicate with spiking neurons. The validity of this methodology is confirmed through a simulation of a closed-loop amplitude regulating network. Additionally, we show that non-spiking neurons can effectively manipulate post-synaptic spiking neurons in an event-based architecture. The ability to work with mixed networks provides an opportunity for researchers to investigate new network architectures for adaptive controllers, potentially improving locomotion strategies of legged robots.