Miracle-dz/UniFAR-FTUs huggingface dataset:
Partial agonists and antagonists reveal a second permeability state of human lymphocyte P2Z/P2X7channel.

Extracellular ATP is known to trigger apoptosis of thymocytes and lymphocytes through a P2Z receptor at which ATP is a partial agonist, giving only 70% of the maximum response of 3'- O-(4-benzoyl)benzoyl-adenosine 5'-triphosphate (BzATP), a full agonist. This cytolytic receptor and its associated ion channel are Ca2+ (and Ba2+) selective but also pass molecules up to the size of ethidium cation (314 Da). RT-PCR showed identity between lymphocyte P2Z and the hP2X7 gene recently cloned from human monocytes. When human leukemic B lymphocytes were incubated with ATP and133Ba2+, an immediate influx of isotope occurred. It was augmented by 45% when ATP was added 10 min before isotope. Time-resolved flow cytometry was used to examine kinetics of ethidium uptake in cells incubated with BzATP or the partial agonists ATP, 2-methylthioadenosine 5'-triphosphate, or adenosine 5'- O-(3-thiotriphosphate). Maximally effective concentrations of BzATP (50 μM) induced immediate uptake of ethidium at a rate linear with time. In contrast, a delay was observed (30 s) before ethidium uptake commenced after addition of maximally effective ATP concentrations (500 μM) at 37°C, and the delay was longer at 24°C. ATP addition 2-10 min before ethidium abolished the delay. The delay was longer with other partial agonists and inversely related to maximal flux produced by agonist. A delay was also observed for submaximal BzATP concentrations (10-20 μM). P2Z/P2X7 inhibitors, KN-62 and 5-( N, N-hexamethylene)-amiloride, reduced the rate of agonist-induced ethidium uptake and lengthened the delay. The results support a model in which agonists for P2Z/P2X7 receptor mediate an immediate channel opening allowing passage of small inorganic cations, followed by a slow further permeability increase allowing passage of larger permeant cations like ethidium. The rate of the second step depends on time and temperature and the efficacy and concentration of agonist and is slowed by antagonists, suggesting it depends on the fraction of P2Z/P2X7 channels held in the initial open state.
Translating Divergent Environmental Stresses into a Common Proteome Response through the Histidine Kinase 33 (Hik33) in a Model Cyanobacterium*

The histidine kinase Hik33 plays important roles in mediating cyanobacterial response to divergent types of abiotic stresses including cold, salt, high light (HL), and osmotic stresses. However, how these functions are regulated by Hik33 remains to be addressed. Using a hik33-deficient strain (Δhik33) of Synechocystis sp. PCC 6803 (Synechocystis) and quantitative proteomics, we found that Hik33 depletion induces differential protein expression highly like that induced by divergent types of stresses. This typically includes downregulation of proteins in photosynthesis and carbon assimilation that are necessary for cell propagation, and upregulation of heat shock proteins, chaperons, and proteases that are important for cell survival. This observation indicates that depletion of Hik33 alone mimics divergent types of abiotic stresses, and that Hik33 could be important for preventing abnormal stress response in the normal condition. Moreover, we found most proteins of plasmid origin were significantly upregulated in Δhik33, though their biological significance remains to be addressed. Together, the systematically characterized Hik33-regulated cyanobacterial proteome, which is largely involved in stress responses, builds the molecular basis for Hik33 as a general regulator of stress responses.
Graph Theory at the Service of Electroencephalograms

The brain is one of the largest and most complex organs in the human body and EEG is a noninvasive electrophysiological monitoring method that is used to record the electrical activity of the brain. Lately, the functional connectivity in human brain has been regarded and studied as a complex network using EEG signals. This means that the brain is studied as a connected system where nodes, or units, represent different specialized brain regions and links, or connections, represent communication pathways between the nodes. Graph theory and theory of complex networks provide a variety of measures, methods, and tools that can be useful to efficiently model, analyze, and study EEG networks. This article is addressed to computer scientists who wish to be acquainted and deal with the study of EEG data and also to neuroscientists who would like to become familiar with graph theoretic approaches and tools to analyze EEG data.
Mothers’ Perceived Neighbourhood Environment and Outdoor Play of 2- to 3.5-Year-Old Children: Findings from the Healthy Beginnings Trial

Background: This study aims to investigate whether mothers’ perceived neighbourhood environment is associated with outdoor playtime of 2- to 3.5-year-old children. Methods: Cross-sectional analyses were conducted using data from the Healthy Beginnings Trial (HBT). Data on children’s outdoor playtime and mothers’ perceived neighbourhood environment were collected through face-to-face interviews with mothers when their children were 2 and 3.5 years old. Walk score was obtained from a publicly available website and population density data were obtained from Australian Census data. Multiple logistic regression models were built to investigate these associations. Results: A total of 497 and 415 mother-child dyads were retained at 2 years and 3.5 years. After adjusting for intervention group allocation and other confounding factors, at 2 years, mothers’ perceptions that ‘the neighbourhood is a good place to bring up children’, ‘it is safe to play outside during the day’, and ‘there are good parks or playgrounds in neighbourhood’ were positively associated with children’s outdoor playtime. At 3.5 years, living in a free-standing house was associated with more children’s outdoor playtime. Conclusions: Children may benefit from living in a neighbourhood that supports active lifestyle. Improving social and physical environments in neighbourhoods could be an important strategy for improving young children’s physical activity.
Glutamate in the nucleus of the solitary tract activates both ionotropic and metabotropic glutamate receptors.

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus of the solitary tract (NTS). Blockade of ionotropic glutamate receptors with kynurenic acid blocks the arterial baroreflex but, paradoxically, does not abolish the response to exogenous glutamate. This study tested the hypothesis that exogenous glutamate in the NTS activates both ionotropic and metabotropic glutamate receptors (mGluRs). In urethan-anesthetized rats, unilateral microinjections of glutamate into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The cardiovascular response to injection of glutamate was not altered by NTS blockade of mGluRs with α-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid attenuated the response to glutamate injection. After combined NTS injection of MCPG and kynurenic acid, the response to glutamate was blocked. These data suggest that exogenous glutamate microinjected into the NTS acts at both ionotropic glutamate receptors and mGluRs. In addition, blockade of both classes of glutamate receptors is required to block the cardiovascular response to microinjection of glutamate in the NTS.
A High-Level Tool for Enhancing the Performance and Scalability of Open-Source Relational Databases

In this paper, we present a high-level tool for partitioning open-source relational databases, thereby, enhancing their performance and scalability. The tool is implemented using Java and SQL, and has been tested on both MySQL and PostgreSQL databases. Our tool can be used through an interactive interface (both command-line interface and web-interface are supported ) and can help in automatically partitioning a given database using hash, key or range partitioning schemes. We evaluated the performance of the Select and Join queries before and after partitioning two real-world datasets - the U.S Department of Agriculture (USDA) food products database, and the Sloan Digital Sky Survey (SDSS) database. The results of this evaluation are presented in this paper. We also discuss the difference in performance of the queries before and after partitioning, and show the impact of the selection of different partitioning schemes - hash, key, range - on the performance of the queries. In some cases, a significant increase in query performance - up to 57% - is observed by partitioning the database tables appropriately.
Linear Growth and Fat and Lean Tissue Gain during Childhood: Associations with Cardiometabolic and Cognitive Outcomes in Adolescent Indian Children

Background We aimed to determine how linear growth and fat and lean tissue gain during discrete age periods from birth to adolescence are related to adolescent cardiometabolic risk factors and cognitive ability. Methods Adolescents born to mothers with normal glucose tolerance during pregnancy from an Indian birth cohort (N = 486, age 13.5 years) had detailed anthropometry and measurements of body fat (fat%), fasting plasma glucose, insulin and lipid concentrations, blood pressure and cognitive function. Insulin resistance (HOMA-IR) was calculated. These outcomes were examined in relation to birth measurements and statistically independent measures (conditional SD scores) representing linear growth, and fat and lean tissue gain during birth-1, 1–2, 2–5, 5–9.5 and 9.5–13.5 years in 414 of the children with measurements at all these ages. Results Birth length and linear growth at all ages were positively associated with current height. Fat gain, particularly during 5–9.5 years was positively associated with fat% at 13.5 years (0.44 SD per SD [99.9% confidence interval: 0.29,0.58]). Greater fat gain during mid-late childhood was associated with higher systolic blood pressure (5–9.5 years: 0.23 SD per SD [0.07,0.40]) and HOMA-IR (5–9.5 years: 0.24 [0.08,0.40], 9.5–13.5 years: 0.22 [0.06,0.38]). Greater infant growth (up to age 2 years) in linear, fat or lean components was unrelated to cardiometabolic risk factors or cognitive function. Conclusion This study suggests that factors that increase linear, fat and lean growth in infancy have no adverse cardiometabolic effects in this population. Factors that increase fat gain in mid-late childhood may increase cardiometabolic risk, without any benefit to cognitive abilities.
Computer-aided design of temozolomide derivatives based on alkylglycerone phosphate synthase structure with isothiocyanate and their pharmacokinetic/toxicity prediction and anti-tumor activity in vitro

Despite the development of temozolomide (TMZ), a novel type of glioma therapeutic drug, malignant glioma remains to cause severe damage to human health. The present study aimed to utilize the molecular biological differences between tumor and normal cells to design TMZ derivatives with improved selectivity and targeting using computer-aided drug design (CADD). Taking alkylglycerone phosphate synthase (AGPS) as a target, a 3D structure-activity relationship model was built using CADD technology; molecular docking of isothiocyanate (ITC) and TMZ compounds was conducted; ITC-TMZ derivatives were designed; and predictions on the absorption, distribution, metabolism and excretion (ADME) processes and toxicity of the ITC-TMZ derivatives were established in order to obtain improved understanding of the structure-activity relationship of the candidate compounds. Using these techniques, it was identified that the docking scores of the structural derivatives S1-9 were higher than that of TMZ. Additionally, S3, −6, −7, −8, −9 and −10 exhibited enhanced ADME and similar toxicity to that of TMZ. The half maximal inhibitory concentrations of the CADD derivatives were also assessed in the glioma U87MG and U251 cell lines, and the activities of S1, −3, −8 and −10 were determined to be greater than that of TMZ, suggesting their potential as anti-cancer drugs with adequate AGPS targeting, ADME/toxicity and anti-tumor activity.
Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer

The epidermis is the outermost layer of the skin and provides a protective barrier against environmental insults. It is a rapidly-renewing tissue undergoing constant regeneration, maintained by several types of stem cells. The Hedgehog (HH) signaling pathway is one of the fundamental signaling pathways that contributes to epidermal development, homeostasis, and repair, as well as to hair follicle development and follicle bulge stem cell maintenance. The HH pathway interacts with other signal transduction pathways, including those activated by Wnt, bone morphogenetic protein, platelet-derived growth factor, Notch, and ectodysplasin. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important for elucidating fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in the development and homeostasis epidermis and hair follicles, and in basal cell carcinoma formation, providing an update of current knowledge in this field.
Chloride ion currents contribute functionally to norepinephrine-induced vascular contraction.

Norepinephrine (NE) increases Cl- efflux from vascular smooth muscle (VSM) cells. An increase in Cl- conductance produces membrane depolarization. We hypothesized that if Cl- currents are important for agonist-induced depolarization, then interfering with cellular Cl- handling should alter contractility. Isometric contraction of rat aortic rings was studied in a bicarbonate buffer. Substitution of extracellular Cl- with 130 mM methanesulfonate (MS; 8 mM Cl-) did not cause contraction. NE- and serotonin-induced contractions were potentiated in this low-Cl- buffer, whereas responses to K+, BAY K 8644, or NE in the absence of Ca2+ were unaltered. Substitution of Cl- with I- or Br- suppressed responses to NE. Inhibition of Cl-transport with bumetanide (10-5 M) or bicarbonate-free conditions (10 mM HEPES) inhibited NE- but not KCl-induced contraction. The Cl--channel blockers DIDS (10-3 M), anthracene-9-carboxylic acid (10-3 M), and niflumic acid (10-5 M) all inhibited NE-induced contraction, whereas tamoxifen (10-5 M) did not. Finally, disruption of sarcoplasmic reticular function with cyclopiazonic acid (10-7 M) or ryanodine (10-5 M) prevented the increase in the peak response to NE produced by low-Cl- buffer. We conclude that a Cl- current with a permeability sequence of I-> Br- > Cl- > MS is critical to agonist-induced contraction of VSM.
miR-124 antagonizes the antidepressant-like effects of standardized gypenosides in mice

Our previous study demonstrated that gypenosides produced antidepressant-like effects in mice exposed to chronic mild stress in a brain-derived neurotrophic factor-dependent manner. However, whether other mechanisms are involved in the antidepressant-like effects of gypenosides is not clear. miR-124 is one of the most abundant microRNAs in the hippocampus, and its dysregulation is related to the pathophysiology of depression. The glucocorticoid receptor is dysfunctional in depression, and it is a direct target of miR-124. Therefore, the present study used corticosterone-induced mice as a model to evaluate the role of miR-124 on the antidepressant-like effects of gypenosides. miR-124 agomir was intracerebrally injected prior to administration of gypenosides and corticosterone injection. Sucrose preference and forced swimming tests were performed 21 days later. Proteins related to glucocorticoid receptors and brain-derived neurotrophic factor-tyrosine receptor kinase B signaling in the hippocampus were evaluated. Our results demonstrated that gypenosides reversed the chronic corticosterone injection-induced decreased sucrose preference and increased immobility time. In contrast, this effect was antagonized by miR-124 injection. In addition, gypenosides increased glucocorticoid receptor and tyrosine receptor kinase B expression in the hippocampus, which activated brain-derived neurotrophic factor signaling. miR-124 also blocked these effects. In conclusion, this study demonstrated that a reduction in miR-124 was required for the antidepressant-like effects of gypenosides induced by chronic corticosterone injection in mice.
Sublethal health effects in laboratory rodents from environmentally relevant exposures to oil sands contaminants

Increasing activity of oil sands extraction and processing in northern Alberta is marked by ongoing controversy about the nature and extent of associated environmental impacts. Bitumen contains a mixture of toxic chemicals, including metals and residual polycyclic aromatic hydrocarbons (PAHs), whose release into the environment poses a distinct risk to the surrounding environment, plus wildlife and human health. In the present study, the authors evaluated several subclinical biomarkers of exposure and effect to mixtures of metals (Pb, Cd, and Hg) and/or PAHs (3 alkylated forms) at environmentally relevant concentrations (100‐fold and 10‐fold higher than the maximum dissolved concentrations found in snow, to simulate a worst‐case scenario), using laboratory mice as a model for future studies of small mammals in the wild. Both metals and alkyl‐PAHs exposure were associated with 1) increased relative liver, kidney, and spleen size; 2) alterations in the homeostasis of the antioxidant vitamins A and E in liver; and 3) compromised glutathione redox status in testes, with results also indicating synergistic interactions from co‐exposure. The combination of morphometric and oxidative stress biomarkers provide reliable and sensitive measures of the response to contaminant exposure in a mammalian model, suggesting associated physiological costs. Based on the present experimental study, the authors propose that wild small mammals will prove to be valuable sentinel species reflecting sublethal health effects from oil sands–related contaminants. The present study's results also present a basis for the interpretation of future field data. Environ Toxicol Chem 2015;34:2884–2897. © 2015 SETAC
Pharmacogenomics in IVF: A New Era in the Concept of Personalized Medicine

Pharmacogenomics is a promising approach in the field of individualized medicine in in vitro fertilization (IVF) treatment that aims to develop optimized pharmacotherapy depending on the genetic background of each infertile woman, thus to ensure maximum effectiveness of the medication used, with minimal side effects. The unique genetic information of each infertile woman, in combination with already known, as well as new predictors of ovarian response and the progress of pharmacoepigenomics, is anticipated to greatly benefit the process of controlled ovarian stimulation. This review analyses current data on IVF pharmacogenomics, a new approach that is gradually moving to the frontline of modern IVF treatment.
Volume repletion after exercise-induced volume depletion in humans: replacement of water and sodium losses.

Sodium and water loss during, and replacement after, exercise-induced volume depletion was investigated in six volunteers volume depleted by 1.89 ± 0.17% (SD) of body mass by intermittent exercise in a warm, humid environment. Subjects exercised in a large, open plastic bag, allowing collection of all sweat secreted during exercise. For over 60 min beginning 40 min after the end of exercise, subjects ingested drinks containing 0, 25, 50, or 100 mmol/l sodium ( trials 0, 25, 50, and 100) in a volume (ml) equivalent to 150% of the mass lost (g) by volume depletion. Body mass loss and sweat electrolyte (Na+, K+, and Cl-) loss were the same on each trial. The measured sweat sodium concentration was 49.2 ± 18.5 mmol/l, and the total loss (63.9 ± 38.7 mmol) was greater than that ingested on trials 0 and 25. Urine production over the 6-h recovery period was inversely related to the amount of sodium ingested. Subjects were in whole body negative sodium balance on trials 0 (-104 ± 48 mmol) and 25 (-65 ± 30 mmol) and essentially in balance on trial 50(-13 ± 29 mmol) but were in positive sodium balance on trial 100 (75 ± 40 mmol). Only on trial 100 were subjects in positive fluid balance at the end of the study. There was a large urinary loss of potassium over the recovery period on trial 100, despite a negligible intake during volume repletion. These results confirm the importance of replacement of sodium as well as water for volume repletion after sweat loss. The sodium intake on trial 100 was appropriate for acute fluid balance restoration, but its consequences for potassium levels must be considered to be undesirable in terms of whole body electrolyte homeostasis for anything other than the short term.
DNA Priming Increases Frequency of T-Cell Responses to a Vesicular Stomatitis Virus HIV Vaccine with Specific Enhancement of CD8+ T-Cell Responses by Interleukin-12 Plasmid DNA

ABSTRACT The HIV Vaccine Trials Network (HVTN) 087 vaccine trial assessed the effect of increasing doses of pIL-12 (interleukin-12 delivered as plasmid DNA) adjuvant on the immunogenicity of an HIV-1 multiantigen (MAG) DNA vaccine delivered by electroporation and boosted with a vaccine comprising an attenuated vesicular stomatitis virus expressing HIV-1 Gag (VSV-Gag). We randomized 100 healthy adults to receive placebo or 3 mg HIV-MAG DNA vaccine (ProfectusVax HIV-1 gag/pol or ProfectusVax nef/tat/vif, env) coadministered with pIL-12 at 0, 250, 1,000, or 1,500 μg intramuscularly by electroporation at 0, 1, and 3 months followed by intramuscular inoculation with 3.4 × 107 PFU VSV-Gag vaccine at 6 months. Immune responses were assessed after the prime and boost and 6 months after the last vaccination. High-dose pIL-12 increased the magnitude of CD8+ T-cell responses postboost compared to no pIL-12 (P = 0.02), while CD4+ T-cell responses after the prime were higher in the absence of pIL-12 than with low- and medium-dose pIL-12 (P ≤ 0.05). The VSV boost increased Gag-specific CD4+ and CD8+ T-cell responses in all groups (P < 0.001 for CD4+ T cells), inducing a median of four Gag epitopes in responders. Six to 9 months after the boost, responses decreased in magnitude, but CD8+ T-cell response rates were maintained. The addition of a DNA prime dramatically improved responses to the VSV vaccine tested previously in the HVTN 090 trial, leading to broad epitope targeting and maintained CD8+ T-cell response rates at early memory. The addition of high-dose pIL-12 given with a DNA prime by electroporation and boosted with VSV-Gag increased the CD8+ T-cell responses but decreased the CD4+ responses. This approach may be advantageous in reshaping the T-cell responses to a variety of chronic infections or tumors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01578889.)