Miracle-dz/UniFAR-FTUs huggingface dataset:
Host Polymorphisms in TLR9 and IL10 Are Associated With the Outcomes of Experimental Haemophilus ducreyi Infection in Human Volunteers.

BACKGROUND In humans inoculated with Haemophilus ducreyi, there are host effects on the possible clinical outcomes-pustule formation versus spontaneous resolution of infection. However, the immunogenetic factors that influence these outcomes are unknown. Here we examined the role of 14 single-nucleotide polymorphisms (SNPs) in 7 selected pathogen-recognition pathways and cytokine genes on the gradated outcomes of experimental infection. METHODS DNAs from 105 volunteers infected with H. ducreyi at 3 sites were genotyped for SNPs, using real-time polymerase chain reaction. The participants were classified into 2 cohorts, by race, and into 4 groups, based on whether they formed 0, 1, 2, or 3 pustules. χ(2) tests for trend and logistic regression analyses were performed on the data. RESULTS In European Americans, the most significant findings were a protective association of the TLR9 +2848 GG genotype and a risk-enhancing association of the TLR9 TA haplotype with pustule formation; logistic regression showed a trend toward protection for the TLR9 +2848 GG genotype. In African Americans, logistic regression showed a protective effect for the IL10 -2849 AA genotype and a risk-enhancing effect for the IL10 AAC haplotype. CONCLUSIONS Variations in TLR9 and IL10 are associated with the outcome of H. ducreyi infection.
Rotavirus Strain Trends During the Postlicensure Vaccine Era: United States, 2008-2013.

BACKGROUND Group A rotaviruses (RVA) are a significant cause of pediatric gastroenteritis worldwide. The New Vaccine Surveillance Network (NVSN) has conducted active surveillance for RVA at pediatric hospitals and emergency departments at 3-7 geographically diverse sites in the United States since 2006. METHODS Over 6 consecutive years, from 2008 to 2013, 1523 samples from NVSN sites that were tested positive by a Rotaclone enzyme immunoassay were submitted to the Centers for Disease Control and Prevention for genotyping. RESULTS In the 2009, 2010, and 2011 seasons, genotype G3P[8] was the predominant genotype throughout the network, with a 46%-84% prevalence. In the 2012 season, G12P[8] replaced G3P[8] as the most common genotype, with a 70% prevalence, and this trend persisted in 2013 (68.0% prevalence). Vaccine (RotaTeq; Rotarix) strains were detected in 0.6%-3.4% of genotyped samples each season. Uncommon and unusual strains (eg, G8P[4], G3P[24], G2P[8], G3P[4], G3P[6], G24P[14], G4P[6], and G9P[4]) were detected sporadically over the study period. Year, study site, and race were found to be significant predictors of genotype. CONCLUSIONS Continued active surveillance is needed to monitor RVA genotypes in the United States and to detect potential changes since vaccine licensure.
Salmonella typhimurium PtsJ is a novel MocR‐like transcriptional repressor involved in regulating the vitamin B6 salvage pathway

The vitamin B6 salvage pathway, involving pyridoxine 5′‐phosphate oxidase (PNPOx) and pyridoxal kinase (PLK), recycles B6 vitamers from nutrients and protein turnover to produce pyridoxal 5′‐phosphate (PLP), the catalytically active form of the vitamin. Regulation of this pathway, widespread in living organisms including humans and many bacteria, is very important to vitamin B6 homeostasis but poorly understood. Although some information is available on the enzymatic regulation of PNPOx and PLK, little is known on their regulation at the transcriptional level. In the present work, we identified a new MocR‐like regulator, PtsJ from Salmonella typhimurium, which controls the expression of the pdxK gene encoding one of the two PLKs expressed in this organism (PLK1). Analysis of pdxK expression in a ptsJ knockout strain demonstrated that PtsJ acts as a transcriptional repressor. This is the first case of a MocR‐like regulator acting as repressor of its target gene. Expression and purification of PtsJ allowed a detailed characterisation of its effector and DNA‐binding properties. PLP is the only B6 vitamer acting as effector molecule for PtsJ. A DNA‐binding region composed of four repeated nucleotide sequences is responsible for binding of PtsJ to its target promoter. Analysis of binding stoichiometry revealed that protein subunits/DNA molar ratio varies from 4 : 1 to 2 : 1, depending on the presence or absence of PLP. Structural characteristics of DNA transcriptional factor‐binding sites suggest that PtsJ binds DNA according to a different model with respect to other characterised members of the MocR subgroup.
Caracterização anestésica da nanoemulsão não lipídica de propofol

JUSTIFICATIVA Y OBJETIVOS: El uso clinico de la formulacion lipidica del propofol, causa dolor durante la inyeccion, reaccion alergica y crecimiento microbiano. El propofol ha sido reformulado en diferentes presentaciones no lipidicas para reducir los efectos adversos, pero esos cambios pueden modificar su farmacocinetica y farmacodinamica. En este trabajo, investigamos la farmacologia y la toxicologia del propofol lipidico (CLP) y de la nanoemulsion no lipidica (NLP). METODO: El CLP y el NLP fueron infundidos en la vena yugular de ratones midiendo la presion arterial (PA), frecuencia cardiaca (FC) y frecuencia respiratoria (FR). Las dos formulaciones (1%) fueron infundidas (40 µL.min-1) durante 1 hora. Dosis hipnoticas y anestesicas y recuperaciones, fueron determinadas. El dolor inducido por el vehiculo del CLP y NLP se comparo por medio del conteo del numero de contorciones abdominales ("writhing test") despues de la inyeccion intraperitoneal en ratones. El acido acetico (0,6%) fue usado como control positivo. RESULTADOS: Las dosis hipnoticas y anestesicas con 1% CLP (6,0 ± 1,3 y 17,8 ± 2,6 mg.kg-1, respectivamente) y 1% NLP (5,4 ± 1,0 y 16,0 ± 1,4 mg.kg-1, respectivamente), no fueron significativamente diferentes. La recuperacion de la hipnosis y de la anestesia fue mas rapida con NLP que con CLP. Las alteraciones de FC, PA y FR causadas por el NLP no fueron significativamente diferentes de las del CLP. El acido acetico y el vehiculo del CLP provocaron 46,0 ± 2,0 y 12,5 ± 0,6 contorciones en 20 minutos despues de la inyeccion i.p., respectivamente. No se observaron contorciones abdominales con vehiculo de NLP. Ninguna respuesta inflamatoria abdominal fue notada con la inyeccion i.p. de los dos vehiculos de propofol. CONCLUSIONES: El NLP puede representar una mejor alternativa que el CLP para la anestesia venosa, con menores efectos adversos
An engineered photoswitchable mammalian pyruvate kinase

Changes in allosteric regulation of glycolytic enzymes have been linked to metabolic reprogramming involved in cancer. Remarkably, allosteric mechanisms control enzyme function at significantly shorter time‐scales compared to the long‐term effects of metabolic reprogramming on cell proliferation. It remains unclear if and how the speed and reversibility afforded by rapid allosteric control of metabolic enzymes is important for cell proliferation. Tools that allow specific, dynamic modulation of enzymatic activities in mammalian cells would help address this question. Towards this goal, we have used molecular dynamics simulations to guide the design of mPKM2 internal light/oxygen/voltage‐sensitive domain 2 (LOV2) fusion at position D24 (PiL[D24]), an engineered pyruvate kinase M2 (PKM2) variant that harbours an insertion of the light‐sensing LOV2 domain from Avena Sativa within a region implicated in allosteric regulation by fructose 1,6‐bisphosphate (FBP). The LOV2 photoreaction is preserved in the PiL[D24] chimera and causes secondary structure changes that are associated with a 30% decrease in the Km of the enzyme for phosphoenolpyruvate resulting in increased pyruvate kinase activity after light exposure. Importantly, this change in activity is reversible upon light withdrawal. Expression of PiL[D24] in cells leads to light‐induced increase in labelling of pyruvate from glucose. PiL[D24] therefore could provide a means to modulate cellular glucose metabolism in a remote manner and paves the way for studying the importance of rapid allosteric phenomena in the regulation of metabolism and enzyme control.
Crystal structure of a lipase from Streptomyces sp. strain W007 – implications for thermostability and regiospecificity

MAS1 from marine Streptomyces sp. strain W007 belongs to the bacterial lipase I.7 subfamily and is characterized as a thermostable and nonregiospecific lipase. To shed light on the catalytic mechanism of MAS1, we determined its crystal structure with closed conformation in two crystal forms at 2.3 Å resolution. MAS1 adopts the canonical α/β hydrolase core fold with its catalytic triad being formed by S109, D200 and H232. Structural analysis and biochemical assays revealed that disulfide bonds and salt bridges play a vital role in the thermostability of MAS1. In addition, we discovered that the replacement of H108 with a tryptophan converts MAS1 from a nonregiospecific to an sn‐1,3‐specific lipase, suggesting the functional importance of the second position from the conserved pentapeptide motif in defining the regiospecificity of MAS1. Our present study provides insights into the molecular basis for the thermostability and regiospecificity of MAS1, and it may aid in the rational design of thermostable or regiospecific lipases for potential industrial applications.
Structural characterization of FlgE2 protein from Helicobacter pylori hook

The Helicobacter pylori flagellum is a complex rotatory nanomachine fundamental for the bacterium's survival in the human stomach. Protein FlgE is a component of the hook, a flexible junction exposed on the cell surface. In the H. pylori genome two different genes are present in different positions coding for hypothetical FlgE. The first protein, FlgE1, is the actual component of the flagellum hook, whilst the second, FlgE2, shares only 26% of the sequence identity with the other and its physiological function is still undefined. We have cloned, purified and crystallized FlgE2, whose structure, determined by the single‐wavelength anomalous diffraction method, shows that in overall organization, the protein is composed of three distinct domains, two of them relatively similar to those of FlgE from other Gram‐negative bacteria, whilst the third is peculiar to H. pylori. The crystal structure, along with the detected interaction with the regulatory cap protein FlgD, suggests a complementary function of FlgE1 and FlgE2 in the H. pylori flagellum, possibly typical of polar flagella, confirming the role of both proteins in the flagellar hook organization. Although some general features are shared with other Gram‐negative bacteria, the presence of two different hook proteins indicates that the molecular organization of H. pylori flagellum has its own peculiarities.
Zarit Burden Interview: pragmatic study in a dedicated cognitive function clinic

Increased caregiver burden impacts adversely not only on caregivers, in terms of physical and psychological morbidity, but also on people with dementia, since it is associated with an increased likelihood of patient institutionalisation. Here, the authors examine effectiveness and ease of administration of the Zarit Burden Interview (ZBI) tool in day‐to‐day clinical practice for identifying caregiver burden.
Respiratory Syncytial Virus (RSV) Infects CD4+ T Cells: Frequency of Circulating CD4+ RSV+ T Cells as a Marker of Disease Severity in Young Children

Background Although human airway epithelial cells are the main target of respiratory syncytial virus (RSV), it also infects immune cells, such as macrophages and B cells. Whether T cells are permissive to RSV infection is unknown. We sought to analyze the permissiveness of CD4+ T cells to RSV infection. Methods CD4+ and CD8+ T cells from cord blood, healthy young children, and adults were challenged by RSV or cocultured with infected HEp-2 cells. Infection, phenotype, and cytokine production by T cells were analyzed by flow cytometry or enzyme-linked immunosorbent assay. Expression of RSV antigens by circulating CD4+ T cells from infected children was analyzed by flow cytometry, and disease severity was defined by standard criteria. Results CD4+ and CD8+ T cells were productively infected by RSV. Infection decreased interleukin 2 and interferon γ production as well as the expression of CD25 and Ki-67 by activated CD4+ T cells. Respiratory syncytial virus antigens were detected in circulating CD4+ and CD8+ T cells during severe RSV infection of young children. Interestingly, the frequency of CD4+ RSV+ T cells positively correlated with disease severity. Conclusions Respiratory syncytial virus infects CD4+ and CD8+ T cells and compromises T-cell function. The frequency of circulating CD4+ RSV+ T cells might represent a novel marker of severe infection.
Sensorimotor gating and spatial learning in α7‐nicotinic receptor knockout mice

The role of acetylcholine and specific nicotinic receptors in sensorimotor gating and higher cognitive function has been controversial. Here, we used a commercially available mouse with a null mutation in the Chrna7tm1Bay gene [α7‐nicotinic acetylcholine receptor (nAChR) knockout (KO) mouse] in order to assess the role of the α7‐nAChR in sensorimotor gating and spatial learning. We examined prepulse inhibition (PPI) of startle and nicotine‐induced enhancement of PPI. We also tested short‐ and long‐term habituation of the startle response as well as of locomotor behaviour in order to differentiate the role of this receptor in the habituation of evoked behaviour (startle) vs. motivated behaviour (locomotion). To address higher cognition, mice were also tested in a spatial learning task. Our results showed a mild but consistent PPI deficit in α7‐nAChR KO mice. Furthermore, they did not show nicotine‐induced enhancement of startle or PPI. Short‐ and long‐term habituation was normal in KO mice for both types of behaviours, evoked or motivated, and they also showed normal learning and memory in the Barnes maze. Thorough analysis of the behavioural data indicated a slightly higher degree of anxiety in α7‐nAChR KO mice; however, this could only be partially confirmed in an elevated plus maze test. In summary, our data suggest that α7‐nAChRs play a minor role in PPI, but seem to mediate nicotine‐induced PPI enhancement. We found no evidence to suggest that they are important for habituation or spatial learning.
Standardizing the analysis of conditioned fear in rodents: a multidimensional software approach

Data comparability between different laboratories strongly depends on the individually applied analysis method. This factor is often a critical source of variation in rodent phenotyping and has never been systematically investigated in Pavlovian fear conditioning paradigms. In rodents, fear is typically quantified in terms of freezing duration via manual observation or automated systems. While manual analysis includes biases such as tiredness or inter‐personal scoring variability, computer‐assisted systems are unable to distinguish between freezing and immobility. Consequently, the novel software called MOVE follows a semi‐automatized approach that prefilters video sequences of interest for the final human judgment. Furthermore, MOVE allows integrating additional data sources (e.g. force‐sensitive platform, EEG) to reach the most accurate and precise results. MOVE directly supports multi‐angle video recordings with webcams or standard laboratory equipment. The integrated manual key logger and internal video player complement this all‐in‐one software solution. Calculating the interlaboratory variability of manual freezing evaluation revealed significantly different freezing scores in two out of six laboratories. This difference was minimized when all experiments were analyzed with MOVE. Applied to a genetically modified mouse model, MOVE revealed higher fear responses of CB1 deficient mice compared to their wild‐type littermates after foreground context fear conditioning. Multi‐angle video analysis compared to the single‐camera approach reached up to 15% higher accuracy and two fold higher precision. Multidimensional analysis provided by integration of additional data sources further improved the overall result. We conclude that the widespread usage of MOVE could substantially improve the comparability of results from different laboratories.
CB1 receptor signaling regulates social anxiety and memory

The endocannabinoid (eCB) system regulates emotion, stress, memory and cognition through the cannabinoid type 1 (CB1) receptor. To test the role of CB1 signaling in social anxiety and memory, we utilized a genetic knockout (KO) and a pharmacological approach. Specifically, we assessed the effects of a constitutive KO of CB1 receptors (CB1KOs) and systemic administration of a CB1 antagonist (AM251; 5 mg/kg) on social anxiety in a social investigation paradigm and social memory in a social discrimination test. Results showed that when compared with wild‐type (WT) and vehicle‐treated animals, CB1KOs and WT animals that received an acute dose of AM251 displayed anxiety‐like behaviors toward a novel male conspecific. When compared with WT animals, KOs showed both active and passive defensive coping behaviors, i.e. elevated avoidance, freezing and risk‐assessment behaviors, all consistent with an anxiety‐like profile. Animals that received acute doses of AM251 also showed an anxiety‐like profile when compared with vehicle‐treated animals, yet did not show an active coping strategy, i.e. changes in risk‐assessment behaviors. In the social discrimination test, CB1KOs and animals that received the CB1 antagonist showed enhanced levels of social memory relative to their respective controls. These results clearly implicate CB1 receptors in the regulation of social anxiety, memory and arousal. The elevated arousal/anxiety resulting from either total CB1 deletion or an acute CB1 blockade may promote enhanced social discrimination/memory. These findings may emphasize the role of the eCB system in anxiety and memory to affect social behavior.
A quantum mechanical study of the reactivity of (SiO)2-defective silica surfaces.

The reactivity of the strained (SiO)(2)-four atom ring defect at the silica surfaces has been studied in a cluster approach adopting the ONIOM2[B3LYP6-31+G(d,p):MNDO] method to compute the ring opening reaction by interaction with H(2)O and NH(3). The vibrational "fingerprints" of the isolated defect are computed at 921, 930, and 934 cm(-1) in reasonable agreement with experimental evidence on amorphous silica outgassed at T>900 K. The opening of the (SiO)(2)-four-member ring by the considered molecules is exergonic and the actual value depends on the possible constraints enforced on the reaction products by the silica surrounding. The free kinetic energy barriers result from the interplay between the nucleophilic/electrophilic character of the adsorbed molecule and are 22 and 25 kcal mol(-1) for NH(3) and H(2)O, respectively. All free energy profiles envisage an activated complex in which the nucleophilic part of the molecule interacts on the coordinatively strained silicon atom of the (SiO)(2) defect followed by the proton transfer from the coordinated molecule towards the oxygen of the defective ring. Calculations show that this step can be speed up by the presence of more than one adsorbed molecule or even more (about seven orders of magnitude), by the copresence of water molecules acting as "proton transfer helpers. " In these cases, the free energy barriers decrease to approximately 13 and 15 kcal mol(-1) for NH(3) and H(2)O, respectively. For the case of H(2)O adsorption, benchmark test calculations reveal that MP2, BLYP, and B3LYP energy profiles are in very good agreement with each other, whereas for PBE, both the reaction energy and the activation barrier are underestimated. Present data also show that the molecular model mimicking the (SiO)(2) defect is far less reactive than what appears to occur on the real defect at the surface of amorphous silica. So, only a combination of some further geometrical strains imparted by the solid on the (SiO)(2) defect, not accounted for by the cluster models, and higher adsorbate loadings are needed to reharmonize experiment and simulation. Notwithstanding, the vibrational features of the reaction products have been characterized and support the available experimental measurements.
Cortical–striatal gene expression in neonatal hippocampal lesion (NVHL)‐amplified cocaine sensitization

Cortical–striatal circuit dysfunction in mental illness may enhance addiction vulnerability. Neonatal ventral hippocampal lesions (NVHL) model this dual diagnosis causality by producing a schizophrenia syndrome with enhanced responsiveness to addictive drugs. Rat genome‐wide microarrays containing >24 000 probesets were used to examine separate and co‐occurring effects of NVHLs and cocaine sensitization (15 mg/kg/day × 5 days) on gene expression within medial prefrontal cortex (MPFC), nucleus accumbens (NAC), and caudate‐putamen (CAPU). Two weeks after NVHLs robustly amplified cocaine behavioral sensitization, brains were harvested for genes of interest defined as those altered at P < 0.001 by NVHL or cocaine effects or interactions. Among 135 genes so impacted, NVHLs altered twofold more than cocaine, with half of all changes in the NAC. Although no genes were changed in the same direction by both NVHL and cocaine history, the anatomy and directionality of significant changes suggested synergy on the neural circuit level generative of compounded behavioral phenotypes: NVHL predominantly downregulated expression in MPFC and NAC while NVHL and cocaine history mostly upregulated CAPU expression. From 75 named genes altered by NVHL or cocaine, 27 had expression levels that correlated significantly with degree of behavioral sensitization, including 11 downregulated by NVHL in MPFC/NAC, and 10 upregulated by NVHL or cocaine in CAPU. These findings suggest that structural and functional impoverishment of prefrontal‐cortical‐accumbens circuits in mental illness is associated with abnormal striatal plasticity compounding with that in addictive disease. Polygenetic interactions impacting neuronal signaling and morphology within these networks likely contribute to addiction vulnerability in mental illness.
Brain morphology in children with 47,XYY syndrome: a voxel‐ and surface‐based morphometric study

The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y‐chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y‐chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age‐matched healthy controls by combining voxel‐based morphometry (VBM) and surface‐based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y‐chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.