Miracle-dz/UniFAR-FTUs huggingface dataset:
Stimulation of p42 and p44 Mitogen‐Activated Protein Kinases by Reactive Oxygen Species and Nitric Oxide in Hippocampus

Abstract: Reactive oxygen species (ROS) have been suggested to act as cellular messengers that mediate signal transduction cascades in various cell types. However, little is known about their role in this capacity in the nervous system. We have begun to investigate the role of ROS, and that of nitric oxide (NO), in mediating mitogen‐activated protein kinase (MAPK) signaling in rat hippocampal slices. Our studies have revealed that direct exposure of hippocampal slices to hydrogen peroxide, xanthine/xanthine oxidase (a superoxide‐generating system), sodium nitroprusside (an NO donor compound), S‐nitroso‐N‐acetylpenicillamine (an NO donor compound), or 3‐morpholinosydnonimine (a compound that produces NO and superoxide) results in an enhancement in tyrosine phosphorylation of several proteins, including proteins with apparent molecular masses of 42 and 44 kDa. We investigated the possibility that these proteins correspond to the active forms of p42 MAPK and p44 MAPK. Hippocampal slices exposed to various ROS and NO donors resulted in increases in levels of the active forms of both p42 MAPK and p44 MAPK. The ROS‐ and NO‐enhanced tyrosine phosphorylation and activation of p42 MAPK and p44 MAPK were inhibited by pretreatment with the antioxidant N‐acetyl‐l‐cysteine. Our observations indicate that ROS and NO can mediate protein tyrosine phosphorylation and MAPK signaling in the hippocampus via a redox‐sensitive mechanism and suggest a potential cellular mechanism for their effects in the nervous system.
Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial

Abstract Glutamate antagonists such as topiramate have been proposed based on the glutamate hypothesis of schizophrenia because its properties encourage its exploration and possible development as a medication for the treatment of schizophrenia. A randomised, double-blind, placebo-controlled clinical trial was performed on 18- to 45-year-old patients with schizophrenia. Baseline information including vital signs, height, weight, smoking status, demographic characteristics, (past) psychiatric history, medication history and medication-related adverse effects were collected. Patients were randomly assigned to a topiramate or placebo group. Efficacy of medication was measured by administering Positive and Negative Syndrome Scale (PANSS), and tolerability of treatment was recorded on day 0 (baseline), day 28 and day 56. PANSS values (95% confidence interval) at baseline, day 28 and day 56 in the topiramate group were 96.87 (85.37–108.37), 85.68 (74.67–96.70) and 76.87 (66.06–87.69), respectively; compared with 101.87 (90.37–113.37), 100.31 (89.29–111.32) and 100.56 (89.74–111.37) in the placebo group. General linear model for repeated measures analysis showed that topiramate has lowered PANSS values significantly compared with the placebo group. Similar significant decline patterns were found in all three subscales (negative, positive and psychopathology sign). Clinical response (more than 20% reduction in PANSS) was significantly higher in topiramate-treated subjects than controls (50% vs 12.5%). Topiramate can be an effective medication in controlling schizophrenic symptoms, considering its effect on negative symptoms and controlling antipsychotic-associated weight gain.
Choice of airway devices for 12,020 cases of nontraumatic cardiac arrest in Japan.

OBJECTIVE This retrospective study was designed to determine the choice of airway devices used for nontraumatic, out-of-hospital cardiac arrest patients and to evaluate the success and failure of insertion and airway control/ventilation by three airway adjuncts, the Combitube, the esophageal gastric tube airway (EGTA), and the laryngeal mask (LM), which were used in conjunction with the bag-valve-mask (BVM) by emergency life-saving technicians (ELSTs) in Japan. METHODS A survey of 1,085 ELSTs was performed to identify the type of airway devices, the success rates of airway insertion, the effectiveness of airway control/ventilation in comparison with the BVM prior to each airway insertion, and associated complications. The type of education for airway skills was also surveyed. RESULTS 1,079 surveys were returned and 12,020 cases of cardiac arrest were studied. Choice of airway devices: BVM, 7,180 cases; EGTA, 545 cases; Combitube, 1,594 cases; and LM, 2,701 cases. Successful insertion rates on the first attempt: EGTA, 82.7%; Combitube, 82.4%; and LM, 72.5% (p < 0.0001). Failed insertions: EGTA, 8.2%; Combitube, 6.9%; and LM, 10.5% (p < 0.0001). Successful ventilation: EGTA, 71.0%; Combitube, 78.9%; and LM, 71.5% (p < 0.0004). Six cases of aspiration were reported in the LM group, whereas nine cases of soft-tissue injuries, including esophageal perforation, were reported in the Combitube group. 17.8% had vomited either prior or during airway placement. CONCLUSION The Combitube appears to be the most appropriate choice among the airway devices examined. However, serious injuries to the tissues, though they rarely occurred in the study, remain a major concern.
The Effect of Short Periods of Caloric Restriction on Weight Loss and Glycemic Control in Type 2 Diabetes

OBJECTIVE To determine whether an intermittent very-low-calorie diet (VLCD) improves weight loss and glycemic control more than moderate caloric restriction alone. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes (n = 54) who were ≥ 20% over ideal body weight participated in a 20-week behavioral weight control program. Subjects were randomized to either a standard behavioral therapy (SBT) group or to one of two VLCD groups. SBT subjects received a 1,500−1,800 kcal/day diet throughout. Both VLCD groups followed a VLCD for 5 consecutive days during week 2, followed by either intermittent VLCD therapy for 1 day/week for 15 weeks (1-day) or for 5 consecutive days every 5 weeks (5-day), with a 1,500−1,800 kcal/day diet at other times. RESULTS Both VLCD groups lost more weight than the SBT group over the 20 weeks (P = 0.04). Although the groups did not differ in fasting plasma glucose (FPG) changes at 20 weeks, more subjects in the 5-day group attained a normal HbA1c when compared with the SBT group (P = 0.04). This benefit was independent of the effects of weight loss. The best predictor of overall change in FPG and HbA1c was the FPG response during the first 3 weeks of the program. CONCLUSIONS Periodic VLCDs improved weight loss in diabetic subjects. A regimen with intermittent 5-day VLCD therapy seemed particularly promising, because more subjects in this group attained a normal HbA1c. Moreover, the glucose response to a 3-week period of diet therapy predicted glycemic response at 20 weeks, and it was a better predictor of the 20-week response than initial or overall weight loss.
Escape from bacterial iron piracy through rapid evolution of transferrin

Iron sequestration provides an innate defense, termed nutritional immunity, leading pathogens to scavenge iron from hosts. Although the molecular basis of this battle for iron is established, its potential as a force for evolution at host-pathogen interfaces is unknown. We show that the iron transport protein transferrin is engaged in ancient and ongoing evolutionary conflicts with TbpA, a transferrin surface receptor from bacteria. Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes. Furthermore, the C2 transferrin polymorphism in humans evades TbpA variants from Haemophilus influenzae, revealing a functional basis for standing genetic variation. These findings identify a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens. The primate iron transport protein and a bacterial transferrin surface receptor are in an evolutionary battle for iron. [Also see Perspective by Armitage and Drakesmith] The frontline of host-pathogen coevolution Pathogens have to subvert a host's innate defenses to avoid being killed. Barber and Elde now show that this principle extends to nutrient-transporting proteins, such as transferrin, which binds iron (see the Perspective by Armitage and Drakesmith). Without iron, invading pathogens cannot replicate, but iron is sequestered in transferrin, which stops pathogens using it. So pathogens have evolved a succession of transporters that can hijack transferrin's iron. Over time, the primate transferrin binding surface has coevolved to wrestle iron back from the grip of pathogens. Science, this issue p. 1362; see also p. 1299
Chromosome transfer and R-prime plasmid formation mediated by plasmid pULB113 (RP4::mini-Mu) in Alcaligenes eutrophus CH34 and Pseudomonas fluorescens 6.2

Plasmid pULB113 (RP4::mini-Mu), which contains the mini-Mu transposon, promoted both homologous and heterologous gene transfer from Pseudomonas fluorescens 6.2 and Alcaligenes eutrophus CH34. Homologous gene transfer in P. fluorescens 6.2 and A. eutrophus CH34 occurred at a frequency of 10(-4) to 10(-5), and recombinants inherited unselected recessive markers, suggesting a process of chromosome mobilization. Loci involved in autotrophic growth were among those transferred in A. eutrophus. In heterospecific matings, markers were transferred from P. fluorescens to A. eutrophus, Salmonella typhimurium LT2, and Escherichia coli, from A. eutrophus to P. fluorescens, and from Erwinia carotovora subsp. chrysanthemi to A. eutrophus. Heterospecific matings resulted in the formation of R-prime plasmids at frequencies of 10(-7) to 10(-4) per transferred plasmid. When S. typhimurium was the recipient, we observed R-prime plasmids with both restriction-proficient and restriction-deficient strains, although restriction markedly affected the frequency of transfer of pULB113. R-prime plasmids were quite stable, but lost the transposed marker more easily in a rec+ background than in a recA background, suggesting excision of transposed material by reciprocal recombination between flanking copies of mini-Mu. R-prime plasmids could be transferred easily into different recipients and were used in complementation studies. PstI restriction digests of four R-prime plasmids carrying P. fluorescens 6.2 DNA showed a number of additional bands, suggesting that several genes were transposed together with the selected marker on the plasmid.
The Expression of Myogenin, but Not of MyoD, is Temperature-Sensitive in Mouse Skeletal Muscle Cells

Abstract Homothermal animals need to keep their body temperature within a narrow range. Only a few degrees Celsius change in temperature has a dynamic influence on many physiological processes. To investigate the effect of the body temperature on muscle cell differentiation, we cultured the mouse myoblast cell lines C2C12 and Sol8 at lower temperatures than mouse body temperature. At 38°C, the cells fused into multinucleated myotubes within 4 days after the induction of differentiation. However, myotube formation was blocked at 30°C, whereas it was delayed but relatively normal at 35°C. The myoblasts expressed MyoD, but not myogenin, at 30°C. Id3, which acts as a negative regulator of myogenic regulatory factors (MRFs), was expressed at a higher level at 30°C than at 38°C, whereas the expression level of E2A, which acts as a positive regulator of MRF expression, exhibited no difference between these temperatures. We also found that the expression of muscle-enriched microRNAs decreased at 30°C. In addition, we investigated the expressions of MyoD and myogenin during mouse satellite-cell activation in single-fiber culture as an in-vivo model, and found that the expression of myogenin, but not of MyoD, was inhibited. These results suggest that skeletal muscle formation can be regulated by temperature, and that the physiological body temperature plays a crucial role in the myogenesis of homothermal animals.
Polymorphic mimicry in Papilio dardanus: mosaic dominance, big effects, and origins

Summary The mocker swallowtail, Papilio dardanus, has a female‐limited polymorphic mimicry. This polymorphism is controlled by allelic variation at a single locus with at least 11 alleles. Many of the alternative morphs are accurate mimics of different species of distasteful butterflies. Geneticists have long been interested in the mechanism by which a single gene can have such diverse and profound effects on the phenotype and in the process by which these complex phenotypic effects could have evolved. Here we present the results of a morpho‐metric analysis of the pleiotropic effects of the mimicry gene on the array of elements that makes up the overall pattern. We show that the patterns controlled by mimicking alleles are more variable and less internally correlated than those controlled by nonmimicking alleles, suggesting the two are subject to different degrees of selection and mutational variance. Analysis of the pleiotropic dominance of the alleles reveals a consistent pattern of dominance within a coevolved genetic background and a mosaic pattern of dominant and recessive effects (including overdominance) in a heterologous genetic background. The alleles of the mimicry gene have big effects on some pattern elements and small effects on others. When the array of big phenotypic effects of the mimicry gene is applied to the presumptive ancestral color pattern, it produces a reasonable resemblance to distasteful models and suggests the initial steps that may have produced the mimicry as well as the polymorphism.
Dendritic Cell Programming by Cytomegalovirus Stunts Naive T Cell Responses via the PD-L1/PD-1 Pathway1

Early during infection, CMV targets dendritic cells (DC) and alters their functions. Herein we show that CMV-infected DC maintain the ability to present both virus-derived and exogenous Ags, but that they actively induce tolerance or anergy in Ag-specific T cells. CMV accomplishes this by selectively maintaining high-level expression of the negative costimulatory molecule programmed death ligand-1 (PD-L1), while commensurately down-regulating positive costimulatory molecules and MHC on the DC surface. Consequently, CD4 and CD8 T cells activated by these infected DC have a stunted phenotype, characterized by poor proliferation, effector function. and recall responses. Blocking PD-L1, but not PD-L2, during direct priming of naive T cells by infected DC significantly restores Ag-specific T cell functions. Using systems where direct and cross-priming of T cells can be distinguished revealed that PD-L1/PD-1 signaling contributes only when naive T cells are primed directly by infected DC, and not upon cross-presentation of viral Ags by uninfected DC. These data suggest that murine CMV programs infected DC during acute infection to inhibit early host adaptive antiviral responses by tipping the balance between negative and positive cosignals.
Functional Expression of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Human Colonic Adenocarcinoma Cells

TNF-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in various transformed cell lines. Therefore, we investigated TRAIL sensitivity, TRAIL-induced nuclear factor-κB (NF-κB) activation, and expression of TRAIL in human colonic adenocarcinoma cell lines (HT-29, LS180, SK-CO-1). All four TRAIL receptors (TRAIL-R1 through TRAIL-R4) are expressed in these cell lines. TRAIL sensitivity was assessed by assay of cell viability. Cancer cell viabilities were 83 ± 3.1% (HT-29), 90 ± 4.3% (LS180), and 88 ± 6.3% (SK-CO-1) at 24 hours after the addition of 100 ng/ml TRAIL, indicating that these cell lines were relatively resistant to TRAIL. Activation of NF-κB was variably influenced by TRAIL administration, with no consistent tendency among the cell lines, indicating that TRAIL-induced NF-κB activation might be cell-type dependent. In contrast, TRAIL was expressed in the human colonic adenocarcinoma cell lines by Western blotting and RT-PCR. Increased expression of TRAIL on tumor cells was observed by flow cytometry after cytokine stimulation (IFN-γ, TNF-α) or the addition of chemotherapeutic agents (camptothecin, doxolubicin hydrochloride). TRAIL on HT-29 cells was functional and able to induce apoptosis in Jurkat cells. Jurkat cell viability was increased by the addition of TRAILR1-R4-Fc. In the presence of various cytokines or chemotherapeutic agents, functional TRAIL is expressed on the surface of tumor cells, and this expressed TRAIL might contribute to tumor immune privilege by inducing apoptosis of activated human lymphocytes.
Molecular Dynamics of Channelrhodopsin at the Early Stages of Channel Opening

Channelrhodopsin (ChR) is a light-gated cation channel that responds to blue light. Since ChR can be readily expressed in specific neurons to precisely control their activities by light, it has become a powerful tool in neuroscience. Although the recently solved crystal structure of a chimeric ChR, C1C2, provided the structural basis for ChR, our understanding of the molecular mechanism of ChR still remains limited. Here we performed electrophysiological analyses and all-atom molecular dynamics (MD) simulations, to investigate the importance of the intracellular and central constrictions of the ion conducting pore observed in the crystal structure of C1C2. Our electrophysiological analysis revealed that two glutamate residues, Glu122 and Glu129, in the intracellular and central constrictions, respectively, should be deprotonated in the photocycle. The simulation results suggested that the deprotonation of Glu129 in the central constriction leads to ion leakage in the ground state, and implied that the protonation of Glu129 is important for preventing ion leakage in the ground state. Moreover, we modeled the 13-cis retinal bound; i.e., activated C1C2, and performed MD simulations to investigate the conformational changes in the early stage of the photocycle. Our simulations suggested that retinal photoisomerization induces the conformational change toward channel opening, including the movements of TM6, TM7 and TM2. These insights into the dynamics of the ground states and the early photocycle stages enhance our understanding of the channel function of ChR.
Pentavalent Rotavirus Vaccine and Prevention of Gastroenteritis Hospitalizations in Australia

OBJECTIVE: A publicly funded, universal infant pentavalent rotavirus vaccine (RV5) program was implemented in Queensland, Australia, in mid-2007. We sought to assess vaccine effectiveness (VE) of 3 doses of RV5 at preventing rotavirus and nonrotavirus acute gastroenteritis (AGE) hospitalizations in the first birth cohort and impact on hospitalizations in all age groups. METHODS: Hospitalization rates for rotavirus and nonrotavirus AGE in all age groups before and after RV5 introduction were compared. Population vaccine coverage, hospitalization data, and individual vaccination status were obtained from routinely collected, publicly funded state- and nationally based data sets. Data linkage was performed to calculate 3-dose VE for preventing hospitalization in the eligible age group. RESULTS: RV5 coverage in the first eligible birth cohort was 89.6% for at least 1 dose and 73.1% for 3 doses. Three-dose VE for preventing nonrotavirus AGE hospitalization was 62.3% to 63.9% (any/primary diagnosis) and 89.3% to 93.9% (any/primary diagnosis) for rotavirus hospitalizations. After program implementation, there were immediate and sustained reductions in rotavirus hospitalizations for those who were younger than 20 years and nonrotavirus AGE-coded hospitalizations for those who were younger than 5 years. CONCLUSIONS: RV5 is highly effective at preventing rotavirus hospitalizations in a developed country setting, confirming efficacy figures from the pivotal clinical trial. Additional direct and indirect effects are substantial and include reductions in nonrotavirus AGE hospitalizations in vaccinated age groups and rotavirus and nonrotavirus AGE hospitalization rates in older age groups.
Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

In 1996, the US Food and Drug Administration mandated the fortification of grain products with folic acid, a nutrient that has been associated with lower risk of colorectal neoplasia. We assessed the relation of plasma folate and homocysteine and colorectal adenoma recurrence separately in 2 studies: the first involved an intervention of a cereal supplement that contained folic acid, wheat bran fiber (WBF), and the second was conducted primarily during postfortification of the food supply using ursodeoxycholic acid (UDCA). Analyses were stratified for multivitamin use. Results show that plasma folate and homocysteine concentrations were associated with adenoma recurrence among nonusers of multivitamins only. Among nonmultivitamin users, the odds ratio [OR] (95% confidence interval [CI]) for those in the highest versus the lowest folate quartile was 0.65 (0.40–1.06) for the WBF study and 0.56 (0.31–1.02) for the UDCA; likewise, individuals in the highest versus the lowest quartile of homocysteine had higher odds of adenoma recurrence, in both the WBF (OR = 2.25; 95% CI = 1.38–3.66) and UDCA (OR = 1.93; 95% CI = 1.07–3.49) populations. Analyses comparing multivitamin users to different plasma folate concentrations among nonusers show that odds of recurrence for supplement users was lower only when compared to nonusers who had lower concentrations. Our results show that higher plasma folate or lower homocysteine levels are associated with lower odds of recurrence among nonusers of multivitamins in both studies. Our finding, suggesting that multivitamins or supplemental folate only benefit individuals with lower plasma folate concentrations, should be taken into consideration when designing and interpreting results of intervention studies. © 2006 Wiley‐Liss, Inc.
The American Academy of Orthopaedic Surgeons Outcomes Instruments: Normative Values from the General Population

Background: The collection of population-based normative data is a necessary step in the process of standardization of eleven American Academy of Orthopaedic Surgeons (AAOS) musculoskeletal outcomes measures. These data serve as comparative normative scores with which to assess the effectiveness of treatment regimens in clinical practice settings and to study the clinical outcomes of treatment in musculoskeletal research.Methods: With use of a panel mail methodology, self-reported data on the eleven AAOS musculoskeletal outcomes measures were collected from the general population of the United States.Results: The overall response rate of 67.4% for the various surveys met study expectations. For the eleven measures, the range of the confidence intervals for the surveys was ±1.6% to ±2.3%, exceeding the ±3% set a priori. With use of the Multitrait/Multi-Item Analysis Program, all of the scales within each of eleven measures exhibited high internal reliability as well as discriminant and convergent validity. Items within each of the scales contributed roughly equal proportions of information to the total scale scores.Conclusions: All eleven instruments met study expectations for providing reliable and valid normative data for use in clinical and research settings.