bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vagus nerve stimulation (VNS)-induced layer-specific modulation of evoked responses in the sensory cortex of rats
Authors: Takahashi Hirokazu , Shiramatsu Tomoyo I. , Hitsuyu Rie , Ibayashi Kenji , Kawai Kensuke 
Published: June 2020

AbstractNeuromodulation achieved by vagus nerve stimulation (VNS) induces various neuropsychiatric effects whose underlying mechanisms of action remain poorly understood. Innervation of neuromodulators and a microcircuit structure in the cerebral cortex informed the hypothesis that VNS exerts layer-specific modulation in the sensory cortex and alters the balance between feedforward and feedback pathways. To test this hypothesis, we characterized laminar profiles of auditory-evoked potentials (AEPs) in the primary auditory cortex (A1) of anesthetized rats with an array of microelectrodes and investigated the effects of VNS on AEPs and stimulus specific adaptation (SSA). VNS predominantly increased the amplitudes of AEPs in superficial layers, but this effect diminished with depth. In addition, VNS exerted a stronger modulation of the neural responses to repeated stimuli than to deviant stimuli, resulting in decreased SSA across all layers of the A1. These results may provide new insights that the VNS-induced neuropsychiatric effects may be attributable to a sensory gain mechanism: VNS strengthens the ascending input in the sensory cortex and creates an imbalance in the strength of activities between superficial and deep cortical layers, where the feedfoward and feedback pathways predominantly originate, respectively.
Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross Species Potency Differences
Authors: Gerstenberger Brian S. , Banker Mary Ellen , Clark James D. , Dowty Martin E. , Fensome Andrew , Gifford Roger , Griffor Matthew C. , Hegen Martin , Hollingshead Brett D. , Knafels John D. , Lin Tsung H. , Smith James F. , Vajdos Felix F. 
Published: June 2020

AbstractTranslation of modulation of drug target activity to therapeutic effect is a critical aspect for all drug discovery programs. In this work we describe the profiling of a non-receptor tyrosine-protein kinase (TYK2) inhibitor which shows a functionally relevant potency shift between human and preclinical species (e.g. murine, dog, macaque) in both biochemical and cellular assays. Comparison of the structure and sequence homology of TYK2 between human and preclinical species within the ATP binding site highlights a single amino acid (I960 → V) responsible for the potency shift. Through TYK2 kinase domain mutants and a TYK2 980I knock-in mouse model, we demonstrate that this single amino acid change drives a functionally relevant potency difference that exists between human and all evaluated preclinical species, for a series of TYK2 inhibitors which target the ATP binding site.
Survey of drug resistance associated gene mutations in Mycobacterium tuberculosis, ESKAPE and other bacterial species
Authors: Ghosh Abhirupa , N. Saran , Saha Sudipto 
Published: June 2020

AbstractTuberculosis treatment includes broad-spectrum antibiotics such as rifampicin, streptomycin and fluoroquinolones, which are also used against other pathogenic bacteria. We developed Drug Resistance Associated Genes database (DRAGdb), a manually curated repository of mutational data of drug resistance associated genes (DRAGs) across ESKAPE (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens, and other bacteria with a special focus on Mycobacterium tuberculosis (MTB). Analysis of mutations in drug-resistant genes listed in DRAGdb suggested both homoplasy and pleiotropy to be associated with resistance. Homoplasy was observed in six genes namely gidB, gyrA, gyrB, rpoB, rpsL and rrs. For these genes, drug resistance-associated mutations at codon level were conserved in MTB, ESKAPE and many other bacteria. Pleiotropy was exemplified by a single nucleotide mutation that was associated with resistance to amikacin, gentamycin, rifampicin and vancomycin in Staphylococcus aureus. DRAGdb data also revealed that mutations in some genes such as pncA, inhA, katG and embA,B,C were specific to Mycobacterium species. For inhA and pncA, the mutations in the promoter region along with those in coding regions were associated with resistance to isoniazid and pyrazinamide respectively. In summary, the DRAGdb database is a compilation of all the major MTB drug resistance genes across bacterial species, which allows identification of homoplasy and pleiotropy phenomena of DRAGs.
Comorbidities of epilepsy in low and middle-income countries: systematic review and meta-analysis
Authors: Muhigwa Aline , Preux Pierre-Marie , Gérard Daniel , Marin Benoit , Boumediène Farid , Ntamwira Charles , Tsai Chung-Huang 
Published: June 2020

AbstractEpilepsy is a major public health concern in low and middle-income countries (LMICs) and comorbidities aggravate the burden associated with the disease. The epidemiology of these comorbidities has not been well described, although, identifying the main comorbidities of epilepsy, and their relative importance, is crucial for improving the quality of care. Comorbidities were defined as disorders coexisting with or preceding epilepsy, or else compounded or directly attributed to epilepsy or to its treatment. A meta-analysis of the proportion of main comorbidities by subcontinent as well as overall was also conducted. Out of the 2,300 papers identified, 109 from 39 countries were included in this systematic review. Four groups of comorbidities were identified: parasitic and infectious diseases (44% of comorbid conditions), somatic comorbidities (37%), psychosocial (11%), as well as psychiatric comorbidities (8%). Heterogeneity was statistically significant for most variables then random effect models were used. The most frequently studied comorbidities were: neurocysticercosis (comorbid proportion: 23%, 95% CI: 18–29), head trauma (comorbid proportion: 9%, 95% CI: 5–15) malnutrition (comorbid proportion: 16%, 95% CI: 28–40), stroke (comorbid proportion: 1.3%, 95% CI: 0.2–7.0), and discrimination for education (comorbid proportion: 34%, 95% CI: 28–40). Many comorbidities of epilepsy were identified in LMICs, most of them being infectious.
Body weight algorithm predicts humane endpoint in an intracranial rat glioma model
Authors: Helgers Simeon O. A. , Talbot Steven R. , Riedesel Ann-Kristin , Wassermann Laura , Wu Zhiqun , Krauss Joachim K. , Häger Christine , Bleich André , Schwabe Kerstin 
Published: June 2020

AbstractHumane endpoint determination is fundamental in animal experimentation. Despite commonly accepted endpoint criteria for intracranial tumour models (20% body weight loss and deteriorated clinical score) some animals still die before being euthanized in current research. We here systematically evaluated other measures as surrogates for a more reliable humane endpoint determination. Adult male BDIX rats (n = 119) with intracranial glioma formation after BT4Ca cell-injection were used. Clinical score and body weight were assessed daily. One subgroup (n = 14) was assessed daily for species-specific (nesting, burrowing), motor (distance, coordination) and social behaviour. Another subgroup (n = 8) was implanted with a telemetric device for monitoring heart rate (variability), temperature and activity. Body weight and clinical score of all other rats were used for training (n = 34) and validation (n = 63) of an elaborate body weight course analysis algorithm for endpoint detection. BT4Ca cell-injection reliably induced fast-growing tumours. No behavioural or physiological parameter detected deteriorations of the clinical state earlier or more reliable than clinical scoring by experienced observers. However, the body weight course analysis algorithm predicted endpoints in 97% of animals without confounding observer-dependent factors. Clinical scoring together with the novel algorithm enables highly reliable and observer-independent endpoint determination in a rodent intracranial tumour model.
A Simple and Scalable Strategy for Analysis of Endogenous Protein Dynamics
Authors: Schwinn Marie K. , Steffen Leta S. , Zimmerman Kris , Wood Keith V. , Machleidt Thomas 
Published: June 2020

AbstractThe ability to analyze protein function in a native context is central to understanding cellular physiology. This study explores whether tagging endogenous proteins with a reporter is a scalable strategy for generating cell models that accurately quantitate protein dynamics. Specifically, it investigates whether CRISPR-mediated integration of the HiBiT luminescent peptide tag can easily be accomplished on a large-scale and whether integrated reporter faithfully represents target biology. For this purpose, a large set of proteins representing diverse structures and functions, some of which are known or potential drug targets, were targeted for tagging with HiBiT in multiple cell lines. Successful insertion was detected for 86% of the targets, as determined by luminescence-based plate assays, blotting, and imaging. In order to determine whether endogenously tagged proteins yield more representative models, cells expressing HiBiT protein fusions either from endogenous loci or plasmids were directly compared in functional assays. In the tested cases, only the edited lines were capable of accurately reproducing the anticipated biology. This study provides evidence that cell lines expressing HiBiT fusions from endogenous loci can be rapidly generated for many different proteins and that these cellular models provide insight into protein function that may be unobtainable using overexpression-based approaches.
Trends and causes of mortality in a population-based cohort of HIV-infected adults in Spain: comparison with the general population
Authors: Fontela Carmen , Aguinaga Aitziber , Moreno-Iribas Conchi , Repáraz Jesús , Rivero María , Gracia María , Floristán Yugo , Fresán Ujué , Miguel Ramón San , Ezpeleta Carmen , Castilla Jesús 
Published: June 2020

AbstractCombination antiretroviral therapy reduces mortality of HIV-infected persons. In Spain, where this therapy is widely available, we aim to evaluate mortality trends and causes of death in HIV-infected adults, and to estimate the excess mortality compared to the general population. From 1999 to 2018 mortality by causes was analyzed in a population-based cohort of adults aged 25 to 74 years diagnosed with HIV infection in Spain. Observed deaths and expected deaths according mortality in the general population of the same sex and age were compared using standardized mortality ratios (SMRs). HIV-infected people increased from 839 in 1999–2003 to 1059 in 2014–2018, median age increased from 37 to 47 years, the annual mortality rate decreased from 33.5 to 20.7 per 1000 person-years and the proportion of HIV-related deaths declined from 64% to 35%. HIV-related mortality declined from 21.4 to 7.3 (p < 0.001), while non-HIV-related mortality remained stable: 12.1 and 13.4 per 1000, respectively. Mortality decreased principally in persons diagnosed with AIDS-defining events. In the last decade, 2009–2018, mortality was still 8.1 times higher among HIV-infected people than in the general population, and even after excluding HIV-related deaths, remained 4.8 times higher. Excess mortality was observed in non-AIDS cancer (SMR = 3.7), cardiovascular disease (SMR = 4.2), respiratory diseases (SMR = 7.9), liver diseases (SMR = 8.8), drug abuse (SMR = 47), suicide (SMR = 5.3) and other external causes (SMR = 6). In conclusion, HIV-related mortality continued to decline, while non-HIV-related mortality remained stable. HIV-infected people maintained important excess mortality. Prevention of HIV infections in the population and promotion of healthy life styles in HIV-infected people must be a priority.
The Human Leukocyte Antigen Locus and Rheumatic Heart Disease Susceptibility in South Asians and Europeans
Authors: Auckland Kathryn , Mittal Balraj , Cairns Benjamin J. , Garg Naveen , Kumar Surendra , Mentzer Alexander J. , Kado Joseph , Perman Mai Ling , Steer Andrew C. , Hill Adrian V. S. , Parks Tom 
Published: June 2020

AbstractRheumatic heart disease (RHD), an autoinflammatory heart disease, was recently declared a global health priority by the World Health Organization. Here we report a genome-wide association study (GWAS) of RHD susceptibility in 1,163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1,459 Europeans (150 cases; 1,309 controls) from the UK Biobank study. We identify a novel susceptibility signal in the class III region of the human leukocyte antigen (HLA) complex in the South Asian dataset that clearly replicates in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51–2.18, P = 3.48×10−10). Importantly, this signal remains despite conditioning on the lead class I and class II variants (P = 0.00033). These findings suggest the class III region is a key determinant of RHD susceptibility offering important new insight into pathogenesis while partly explaining the inconsistency of earlier reports.
Diagnosis of NTM active infection in lymphadenopathy patients with anti-interferon-gamma auto-antibody using inhibitory ELISA vs. indirect ELISA
Authors: Nithichanon Arnone , Chetchotisakd Ploenchan , Matsumura Takayuki , Takahashi Yoshimasa , Ato Manabu , Sakagami Takuro , Lertmemongkolchai Ganjana 
Published: June 2020

AbstractThe anti-interferon-gamma (IFN-gamma) autoantibody is a known cause of opportunistic non-tuberculous mycobacterial (NTM) infection in adults. Diagnosis of those patients is difficult due to the low sensitivity of bacterial culture, and because detection of the neutralizing autoantibody needs special laboratory devices. We conducted a retrospective review of indirect and inhibitory ELISA, both used for detection of anti-IFN-gamma auto-antibody in 102 patients with lymphadenopathies. We assessed hospital records of NTM isolation and/or diagnosis of NTM infection. The review revealed the compatible sensitivity and superior specificity and predictive values for inhibitory ELISA over against indirect ELISA—the latter achieving 100% specificity and positive predictive value for diagnosis of NTM infection in patients with lymphadenopathies. The results confirm functional assays that show plasma samples from NTM-infected patients with positive results by either indirect and/or inhibitory ELISA are IFN-gamma neutralizing autoantibodies. The inhibitory titer of anti-IFN-gamma auto-antibody can be used to distinguish patients with active from inactive NTM infection. Inhibitory ELISA is thus a practical, rapid, high performance tool for routine detection of anti-IFN-gamma autoantibody and NTM infection diagnosis before confirmation, enabling a timely therapeutic strategy for active infection treatment.
Repetitive, mild traumatic brain injury results in a progressive white matter pathology, cognitive deterioration, and a transient gut microbiota dysbiosis
Authors: Angoa-Pérez Mariana , Zagorac Branislava , Anneken John H. , Briggs Denise I. , Winters Andrew D. , Greenberg Jonathan M. , Ahmad Madison , Theis Kevin R. , Kuhn Donald M. 
Published: June 2020

AbstractTraumatic brain injury (TBI) is often accompanied by gastrointestinal and metabolic disruptions. These systemic manifestations suggest possible involvement of the gut microbiota in head injury outcomes. Although gut dysbiosis after single, severe TBI has been documented, the majority of head injuries are mild, such as those that occur in athletes and military personnel exposed to repetitive head impacts. Therefore, it is important to determine if repetitive, mild TBI (rmTBI) will also disrupt the gut microbiota. Male mice were exposed to mild head impacts daily for 20 days and assessed for cognitive behavior, neuropathology and disruptions in the gut microbiota at 0, 45 or 90 days after injury. Deficits in recognition memory were evident at the late post-injury points. Brains show an early increase in microglial activation at the 0-day time point that persisted until 90 days post-injury. This was compounded by substantial increases in astrocyte reactivity and phosphorylated tau at the 90-day time point. In contrast, changes in the microbial community were minor and transient, and very few differences were observed in mice exposed to rmTBI compared to controls. While the progressive emergence of white matter damage and cognitive alterations after rmTBI resembles the alterations observed in athletes and military personnel exposed to rmTBI, these changes could not be linked to systematic modifications in the gut microbiota.
Surface structure on diamond foils generated by spatially nonuniform laser irradiation
Authors: Kato Hiroki , Nagatomo Hideo , Nakai Mitsuo , Sakaiya Tatsuhiro , Terasaki Hidenori , Kondo Tadashi , Hironaka Yoichiro , Shimizu Katsuya , Shigemori Keisuke 
Published: June 2020

AbstractHere we report on the effects of material strength factors on the generation of surface structure due to nonuniform laser irradiation. The influence of material strength on the generation of perturbation on a diamond surface subjected to nonuniform laser irradiation was experimentally investigated. Our previous investigations suggested that stiffer and denser materials reduce surface perturbation due to spatially nonuniform laser irradiation, which was reproduced well by calculations with multi-dimensional hydrodynamic simulation code. In this work, we found that local fractures due to yield strength failure are generated by high degrees of irradiation non-uniformity. A characteristic crack-like surface structure was observed, which was not reproduced by the 2D simulation code calculations at all. The 2D simulations showed that the pressure at the diamond surface locally exceeds the Hugoniot elastic limit due to nonuniform irradiation, implying the potential for development of surface perturbations. We also measured the areal-density distribution of perturbations for single-crystal diamond and diamond with a thin high atomic number (high-Z) coating on its surface. The experimental results imply that the combination of a stiff material and thin high-Z coating can suppress the solid-strength effects caused by large irradiation non-uniformity. The knowledge given here is applicable to inertial confinement fusion target design, laser material processing, and universal problems involving solids and high-energy-density plasmas.
(Fe,Ni)2P allabogdanite can be an ambient pressure phase in iron meteorites
Authors: Litasov Konstantin D. , Bekker Tatyana B. , Sagatov Nursultan E. , Gavryushkin Pavel N. , Krinitsyn Pavel G. , Kuper Konstantin E. 
Published: June 2020

AbstractAn orthorhombic modification of (Fe,Ni)2P, allabogdanite, found in iron meteorites was considered to be thermodynamically stable at pressures above 8 GPa and temperatures of 1673 K according to the results of recent static high-pressure and high-temperature experiments. A hexagonal polymorphic modification of (Fe,Ni)2P, barringerite, was considered to be stable at ambient conditions. Experimental investigation through the solid-state synthesis supported by ab initio calculations was carried out to clarify the stability fields of (Fe,Ni)2P polymorphs. Both experimental and theoretical studies show that Fe2P-allabogdanite is a low-temperature phase stable at ambient conditions up to a temperature of at least 773 K and, therefore, is not necessarily associated with high pressures. This is consistent with the textural relationships of allabogdanite in iron meteorites.
A Study of Rainfall-Runoff Movement Process on High and Steep Slopes Affected by Double Turbulence Sources
Authors: Li Xinghua , Gao Jianen , Guo Zihao , Yin Yan , Zhang Xingchen , Sun Pengcheng , Gao Zhe 
Published: June 2020

AbstractTo increase the available land area, a large-scale land remediation campaign was carried out in the loess hilly and gully area. A large number of high and steep slopes have been produced in the construction of road engineering and water conservancy engineering, and these slopes will cause serious soil erosion under rainfall conditions. Because rainfall runoff is simultaneously affected by slope, bed surface and rainfall, the runoff movement characteristics are complex. It is difficult to consider all influencing factors in the existing models, especially for steep slopes. In this study, artificial rainfall experiments were conducted to study the rainfall-runoff hydraulic processes under different rainfall intensities and slope gradients, and a modified method was proposed to model the key hydraulic parameters (i.e., equilibrium time, water surface line, and runoff processes) on steep slopes. The results showed that (1) For steep slopes (a 70° slope compared to a 5° slope), the runoff generation time, confluence time and equilibrium time of the slope decreased significantly. At the same time, the single width runoff of the steep slope had a power function relationship with the rainfall intensity and gradient. (2) The runoff patterns of steep slopes were different from those on gentle slopes and runoff patterns were more likely to change. The Reynolds number and Froude number for slope flow changed slowly when the slope was less than the critical gradient and increased significantly when the slope exceeded the critical gradient. (3) Based on the analysis of the “double turbulent model theory of thin-layer flow on a high-steep slope”, combined with the dispersed motion wave model, a modified method for calculating the hydrodynamic factors of rainfall runoff was proposed. Then, this method was verified with indoor and outdoor experiments. The research results not only have theoretical significance, but also provide a more accurate calculation method for the design of high and steep slopes involved in land treatment engineering, road engineering and water conservancy engineering.
Neulich bei Coliquio
Authors: Gerke Stephan 
Published: June 2020

ZusammenfassungAnhand eines Interviews von Natalie Grams wird die aktuelle Studienlage kurz beleuchtet. Es wird diskutiert, ob die wenig eindrucksvollen Studienergebnisse, die deutlich hinter dem „gefühlten Behandlungserfolgen“ in den homöopathischen Praxen zurückbleiben, nicht auch Resultat der aktuellen Methodenvielfalt in der Homöopathie sind. Aphoristisch werden einige Verschreibungen, die der Autor bei diversen Seminaren erlebte, beschrieben. Es wird dringend an die homöopathische Gemeinschaft appelliert, die nach Meinung des Autors längst überfällige Diskussion um die Validität und die Validierbarkeit der verschiedenen homöopathischen Methoden zu führen.