Miracle-dz/UniFAR-FTUs huggingface dataset:
First principles computational study of the active site of arginase

Ab initio density functional theory (DFT) methods were used to investigate the structural features of the active site of the binuclear enzyme rat liver arginase. Special emphasis was placed on the crucial role of the second shell ligand interactions. These interactions were systematically studied by performing calculations on models of varying size. It was determined that a water molecule, and not hydroxide, is the bridging exogenous ligand. The carboxylate ligands facilitate the close approach of the Mn (II) ions by attenuating the metal–metal electrostatic repulsion. Of the two metals, MnA was shown to carry a larger positive charge. Analysis of the electronic properties of the active site revealed that orbitals involving the terminal Asp234 residue, as well as the flexible μ‐1,1 bridging Asp232, lie at high energies, suggesting weaker coordination. This is reflected in certain structural variability present in our models and is also consistent with recent experimental findings. Finally, implications of our findings for the biological function of the enzyme are delineated. Proteins 2004. © 2003 Wiley‐Liss, Inc.
Toll-Like Receptor 9-Mediated Inflammation Triggers Alveolar Bone Loss in Experimental Murine Periodontitis

ABSTRACT Chronic periodontitis is a local inflammatory disease induced by a dysbiotic microbiota and leading to destruction of the tooth-supporting structures. Microbial nucleic acids are abundantly present in the periodontium, derived through release after phagocytic uptake of microbes and/or from biofilm-associated extracellular DNA. Binding of microbial DNA to its cognate receptors, such as Toll-like receptor 9 (TLR9), can trigger inflammation. In this study, we utilized TLR9 knockout (TLR9−/−) mice and wild-type (WT) controls in a murine model of Porphyromonas gingivalis-induced periodontitis and report the first in vivo evidence that TLR9 signaling mediates the induction of periodontal bone loss. P. gingivalis-infected WT mice exhibited significantly increased bone loss compared to that in sham-infected WT mice or P. gingivalis-infected TLR9−/− mice, which were resistant to bone loss. Consistent with this, the expression levels of interleukin 6 (IL-6), tumor necrosis factor (TNF), and receptor-activator of nuclear factor kappa B ligand (RANKL) were significantly elevated in the gingival tissues of the infected WT mice but not in infected TLR9−/− mice compared to their levels in controls. Ex vivo studies using splenocytes and bone marrow-derived macrophages revealed significantly diminished cytokine production in TLR9−/− cells relative to the cytokine production in WT cells in response to P. gingivalis, thereby implicating TLR9 in inflammatory responses to this organism. Intriguingly, compared to the cytokine production in WT cells, TLR9−/− cells exhibited significantly decreased proinflammatory cytokine production upon challenge with lipopolysaccharide (LPS) (TLR4 agonist) or Pam3Cys (TLR2 agonist), suggesting possible cross talk between TLR9, TLR4, and TLR2. Collectively, our results provide the first proof-of-concept evidence implicating TLR9-triggered inflammation in periodontal disease pathogenesis, thereby identifying a new potential therapeutic target to control periodontal inflammation.
Cholinergic modulation of the hippocampal region and memory function

Acetylcholine (ACh) plays an important role in memory function and has been implicated in aging‐related dementia, in which the impairment of hippocampus‐dependent learning strongly manifests. Cholinergic neurons densely innervate the hippocampus, mediating the formation of episodic as well as semantic memory. Here, we will review recent findings on acetylcholine's modulation of memory function, with a particular focus on hippocampus‐dependent learning, and the circuits involved. In addition, we will discuss the complexity of ACh actions in memory function to better understand the physiological role of ACh in memory.
"Wii-Hab" in critically ill children: a pilot trial.

PURPOSE To evaluate the safety and feasibility of virtual reality (VR) exercise as a novel acute rehabilitation intervention in a Pediatric Critical Care Unit (PCCU) setting. METHODS Children aged 3-18 years with an anticipated PCCU stay > 48 hours, and baseline normal to moderate cognitive and functional disability were eligible. Exclusion criteria included: anticipated death, physical inability, or a contraindication to mobilization. Nintendo Wii™ Boxing was prescribed for a minimum of 10 minutes twice a day for 2 days. Primary outcomes were feasibility and safety. RESULTS Of 21 eligible patients, 12 (57.1%) were enrolled and 8 completed the study. 41.7% (5/12) were males, and the median age was 11 (3,16) years. Four of the 8 participants who received the intervention were mechanically ventilated during Wii™ play. Participants used the Wii™ a median of 2 times (1,5) over the 2-day intervention period, for a median total duration of 54.5 (15, 224) minutes. There were no adverse events attributable to the intervention. Upper limb activity during Wii™ was significantly greater than the average daily activity (p=0.049). Grip strength did not change significantly from baseline (p=0.20). CONCLUSION While the results of this pilot trial suggest that VR exercise may be safely applied in a subset of critically ill children, we observed several threats to its feasibility in this population.
Cloning of monomeric human papillomavirus type 16 DNA integrated within cell DNA from a cervical carcinoma

We have molecularly cloned and characterized monomeric human papillomavirus type 16 DNA with flanking cell DNA sequences from a cervical carcinoma. Determination of nucleotide sequence around the junctions of human papillomavirus and cell DNAs revealed that at the site of integration within cell DNA the cloned viral DNA had a deletion between nucleotides 1,284 and 4,471 (numbering system from K. Seedorf, G. Krämmer, M. Dürst, S. Suhai, and W. G. Röwekamp, Virology 145:181-185, 1985), which includes the greater part of E1 gene and the entire E2 gene. In the remaining part of the E1 gene, three guanines were found at the location where two guanines at nucleotides 1,137 and 1,138 have been recorded. This additional guanine shifted the reading frame and erased an interruption in the E1 gene described by Seedorf et al. The data strongly suggest that, like other papillomaviruses, human papillomavirus type 16 has an uninterrupted E1 gene.
PEDIATRIC AND CONGENITAL HEART DISEASE Original Studies A Comparative Study of Cardi-O-Fix Septal Occluder Versus Amplatzer Septal Occluder in Percutaneous Closure of Secundum Atrial Septal Defects

Aim: We sought to investigate the safety and efficacy of Cardio-O-Fix septal occluder (CSO) in percutaneous closure of atrial septal defects (ASD) as compared to the Amplatzer septal occluder (ASO). Methods: A consecutive of 351 patients received transcatheter ASD closure with CSO or ASO from July 2004 to October 2010 were studied. The ASDs were divided into simple(isolated defects <26 mm) or complex-types (isolated defect 26 mm, double or multifenestrated defects). The procedures were guided by fluoroscopy and transthoracic or transesophageal echocardiography. Clinical and echocardiographic follow-ups were arranged before discharge, at 1 month and then every 6-month after implantation. Results: During the study period, 185 (125 males, aged 18.5 6 15.6 years) and 166 (103 males, aged 21.0 6 15.7 years) patients attempted CSO and ASO implants, respectively. The CSO group had similar ASD and device sizes, prevalence of complex lesions (17 vs. 16%, P 5 0.796), procedural times and success rates (97% vs. 96%, P 5 0.635) as compared to the ASO group. Acute residual shunts were less prevalent in CSO than ASO group and most shunts closed spontaneously at 6-month follow-ups. The average equipment cost per patient was lower in CSO group (US$ 4,100 vs. US$ 5,900, P < 0.001). The prevalence of device embolization and atrial arrhythmia (all <2%) were similar in both patient groups. Conclusion: Transcatheter ASD occlusion with CSO is safe and effective and it appeared to be an attractive alternative to ASO in closing simple-type ASD because of its relatively low cost. VC 2013 Wiley Periodicals, Inc.
Self-reported visual impairment in elderly Canadians and its impact on healthy living.

BACKGROUND Using a nationwide sample from community- and institution-dwelling residents, we describe the prevalence of self-reported visual impairment in elderly Canadians and examine its association with selected social demographics and health factors. METHODS Subjects were participants in the phase I clinical examination of the Canadian Study of Health and Aging. Vision state was ascertained from a self-reported question: "How is your eyesight (with glasses or contacts if you wear them)? " A response of "poor" (referred to as poor vision) or "unable to see" (referred to as blindness) was considered visual impairment. Other information was from in-person interviews or clinical examinations. Standardized weights were used in all analyses. RESULTS Analyses included 2671 participants with a median age of 72 years. The overall prevalence was 6.2% for poor vision, 0.7% for blindness, and 6.8% for either. A higher prevalence was seen in women and in people aged 85 years or older. Participants with < or = 6 years of education were approximately 2 times more likely to report visual impairment. Institutional residents and people with falls or a depressed mood were approximately 3 times more likely to state visual impairment. Smoking was associated with approximately 4 times higher odds of visual impairment, while persons presenting difficulty with everyday activities or with self-rated poor health were approximately 7 and 15 times more likely to report visual impairment. INTERPRETATION Visual impairment in elderly Canadians is common and is associated with increased odds of institutionalization, frequent falls, difficulty with everyday activities, and poor health. Good eyesight may imply good health and good independence in the elderly.
Week 48 results of a Phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected treatment-experienced adults

In DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r.
Antiretroviral Concentrations in Breast-Feeding Infants of Mothers Receiving Highly Active Antiretroviral Therapy

ABSTRACT There are limited data describing the concentrations of zidovudine, lamivudine, and nevirapine in nursing infants as a result of transfer via breast milk. The Kisumu Breastfeeding Study is a phase IIb open-label trial of prenatal, intrapartum, and postpartum maternal treatment with zidovudine, lamivudine, and nevirapine from 34 weeks of gestation to 6 months postpartum. In a pharmacokinetic substudy, maternal plasma, breast milk, and infant dried blood spots were collected for drug assay on the day of delivery and at 2, 6, 14, and 24 weeks after delivery. Sixty-seven mother-infant pairs were enrolled. The median concentrations in breast milk of zidovudine, lamivudine, and nevirapine during the study period were 14 ng/ml, 1,214 ng/ml, and 4,546 ng/ml, respectively. Zidovudine was not detectable in any infant plasma samples obtained after the day of delivery, while the median concentrations in infant plasma samples from postpartum weeks 2, 6, and 14 were 67 ng/ml, 32 ng/ml, and 24 ng/ml for lamivudine and 987 ng/ml, 1,032 ng/ml, and 734 ng/ml for nevirapine, respectively. Therefore, lamivudine and nevirapine, but not zidovudine, are transferred to infants via breast milk in biologically significant concentrations. The extent and effect of infant drug exposure via breast milk must be well understood in order to evaluate the benefits and risks of maternal antiretroviral use during lactation.
The influence of smoking and other cofactors on the time to onset to cervical cancer in a southern European population

Cervical cancer is a complex and multifactorial disease. Although there are substantial data supporting the causative role of persistent human papillomavirus (HPV) infection in the development of cervical cancer, the complete course of the disease has never been completely understood. Several risk cofactors have been suggested with controversial results. Portugal has the highest incidence of squamous cell carcinoma (SCC) within western Europe and there are no known studies regarding the role of cofactors in SCC. The aim of our study was to evaluate the role of smoking, sexual behaviour, reproductive and contraceptive history, in the time-to-onset (TTO) of severe cervical lesions (HGSIL/SCC) in the Portuguese population. We verified that age of first sexual intercourse under 18 years (odds ratio (OR) 2.8), pregnancy (OR 2.9), first pregnancy under 21 years (2.6), number of pregnancies (OR 2.3–5.4) and parity (OR 1.9–5.7) are risk factors in the development of cervical neoplasia. Smoke exposure index (SEI) was significantly different (P=0.002) between cases and controls. Our results regarding time-to-onset demonstrate that smoking (P<0.001, log rank test), number of sexual partners (P<0.001, log rank test) and use of oral contraceptives (P<0.001, log rank test) are important determinants in the earlier onset of severe cervical lesions. Using this approach, our findings may help to clarify the role of smoking and other cofactors in the persistence and progression of cervical lesions.
Tis 7 deletion reduces survival and induces intestinal anastomotic inflammation and obstruction in high-fat diet-fed mice with short bowel syndrome

Amy M. Garcia, Derek Wakeman, Jianyun Lu, Christopher Rowley, Taylor Geisman, Catherine Butler, Shashi Bala, Elzbieta A. Swietlicki, Brad W. Warner, Marc S. Levin, and Deborah C. Rubin Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; Division of Pediatric Gastroenterology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; Department of Pediatric Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Medicine, Veterans Affairs St. Louis Health Care System; St. Louis, Missouri; and Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri
Effectiveness and cost effectiveness of counselling in primary care.

BACKGROUND The prevalence of mental health and psychosocial problems in primary care is high. This review examines the clinical and cost-effectiveness of psychological therapies provided in primary care by counsellors. OBJECTIVES To assess the effectiveness and cost effectiveness of counselling in primary care by reviewing cost and outcome data in randomised controlled trials for patients with psychological and psychosocial problems considered suitable for counselling. SEARCH STRATEGY To update the review, the following electronic databases were searched on 25-10-2005: MEDLINE, EMBASE, PsycLIT, CINAHL, the Cochrane Controlled Trials register and the Cochrane Collaboration Depression, Anxiety and Neurosis (CCDAN) trials registers. SELECTION CRITERIA All controlled trials comparing counselling in primary care with other treatments for patients with psychological and psychosocial problems considered suitable for counselling. Trials completed before the end of June 2005 were included in the review. DATA COLLECTION AND ANALYSIS Data were extracted using a standardised data extraction sheet. Trials were rated for quality using CCDAN criteria, to assess the extent to which their design and conduct were likely to have prevented systematic error. Continuous measures of outcome were combined using standardised mean differences. An overall effect size was calculated for each outcome with 95% confidence intervals (CI). Continuous data from different measuring instruments were transformed into a standard effect size by dividing mean values by standard deviations. Sensitivity analyses were undertaken to test the robustness of the results. Economic analyses were summarised in narrative form. MAIN RESULTS Eight trials were included in the review. The analysis found significantly greater clinical effectiveness in the counselling group compared with usual care in the short-term (standardised mean difference -0.28, 95% CI -0.43 to -0.13, n = 772, 6 trials) but not the long-term (standardised mean difference -0.09, 95% CI -0.27 to 0.10, n = 475, 4 trials). Levels of satisfaction with counselling were high. There was some evidence that the overall costs of counselling and usual care were similar. AUTHORS' CONCLUSIONS Counselling is associated with modest improvement in short-term outcome compared to usual care, but provides no additional advantages in the long-term. Patients are satisfied with counselling. Although some types of health care utilisation may be reduced, counselling does not seem to reduce overall healthcare costs.
Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction

Anxiety disorders are thought to reflect deficits in the regulation of fear expression. Evidence from rodent studies implicates the ventromedial prefrontal cortex (vmPFC) in the regulation of conditioned fear. Lesions of the vmPFC have had differing effects on the acquisition and expression of conditioned fear, as well as on recall of extinction. The use of permanent lesions, however, makes it difficult to assess the phase of training in which the vmPFC is acting and can trigger recruitment of other structures, thereby masking lesion deficits. To overcome these problems, we temporarily inactivated the vmPFC of rats with tetrodotoxin (10 ng in a 0.5‐µl midline infusion) at one of four time points: prior to conditioning, prior to extinction, immediately after extinction or prior to recall of extinction. Consistent with lesion findings, inactivation of the vmPFC prior to acquisition had no effect but inactivation prior to extinction led to impaired recall of extinction the following day. In contrast to lesion findings, inactivation of the vmPFC decreased freezing at all time points, suggesting that some component of the vmPFC facilitates the expression of conditioned fear. These findings suggest that inactivation of the vmPFC can have opposite effects depending on the phase of training. The vmPFC appears to be involved both in stimulating the expression of conditioned fear and in serving as a site of extinction‐related plasticity that inhibits fear during recall of extinction.
Analysis of the Spatial Distribution of Free Radicals in Ammonium Tartrate by Pulse EPR Techniques

Abstract Marrale, M. , Brai, M. , Barbon, A. and Brustolon, M. Analysis of the Spatial Distribution of Free Radicals in Ammonium Tartrate by Pulse EPR Techniques. Radiat. Res. 171, 349–359 (2009). Using pulse electron paramagnetic resonance (EPR) on a series of l(+)-ammonium tartrate (AT) dosimeters exposed to radiations with different linear energy transfer (LET), we assessed the ability of pulse EPR spectroscopy to discriminate the quality of various radiation beams such as 60Co γ-ray photons, protons and thermal neutrons at various doses by analyzing the local radical distributions produced by the different beams. We performed two types of pulse EPR investigations: two-pulse electron spin echo decay obtained by varying the microwave power, and a double electron-electron resonance (DEER) study. Both methods provide information about the dipolar interactions among the free radicals and about their spatial distributions. The first method provided information on the instantaneous diffusion and hence the microscopic concentration of the radicals that is compared with the macroscopic one obtained by CW-EPR. The DEER spectra yielded the distributions of distances between pairs of radicals two to five crystal cells apart produced by the same radiation event, a result reported here for the first time. The inter-radical distributions given by the DEER results have been simulated by modeling the radical distributions according to the details of the matter-radiation interactions for the various beams. The results of both types of pulse experiments are strongly dependent on the radiation quality. This was also observed for samples giving indistinguishable CW-EPR spectral profiles. We conclude that the pulse EPR measurements can be valuable tools for distinguishing the LET of the radiation beams, an important parameter for radiobiological considerations.
Intra and intertribal genetic variation within a linguistic group: the Ge-speaking indians of Brazil.

A total of 562 individuals living in four villages of two Brazilian Indian tribes (Cayapo and Krahó) was studied in relation to blood groups ABO, MNSs, , Rh, Lewis, Duffy, Kidd and Diego; haptoglobin, Gc, acid phosphatase and phosphoglucomutase types. These results were compared with those obtained previously among the Xavante, and the inhabitants of three other Cayapo villages, all of whom speak Ge languages; the ranges in gene frequencies observed in a representative series of South American Indians from all over the continent were also compiled. The Ge Indians are characterized by low frequencies of RZ, medium frequencies of R1, R2, R0, or r, Jka and PGM1/1, and high frequencies of Gc2 and ACPA when compared with other South American tribes. Genetic distance analyses based on six loci indicate that the intratribal variability observed among Cayapo is of the same order of magnitude as those obtained among the Xavante and Krahó, being much less pronounced than those observed among the Yanomama and Makiritare. The intertribal differences within this linguistic group are much less pronounced than those encountered among tribes that speak more differentiated languages.
Association of interleukin‐8 and neutrophils with nasal symptom severity during acute respiratory infection

Using a large data set (n = 811), the relationship between acute respiratory infection illness severity and inflammatory biomarkers was investigated to determine whether certain symptoms are correlated more closely than others with the inflammatory biomarkers, interleukin‐8 (IL‐8) and nasal neutrophils. Participants with community acquired acute respiratory infection underwent nasal lavage for IL‐8 and neutrophil testing, in addition to multiplex polymerase chain reaction (PCR) methods for the detection and identification of respiratory viruses. Information about symptoms was obtained throughout the duration of the illness episode using the well‐validated Wisconsin Upper Respiratory Symptom Survey (WURSS‐21). Global symptom severity was calculated by the area under the curve (AUC) plotting duration versus WURSS total. Of the specimens tested, 56% were positively identified for one or more of nine different respiratory viruses. During acute respiratory infection illness, both IL‐8 and neutrophils positively correlate with AUC (rs = 0.082, P = 0.022; rs = 0.080, P = 0.030). IL‐8 and neutrophils correlate with nasal symptom severity: runny nose (r = 0.13, P = < 0.00001; r = 0.18, P = < 0.003), plugged nose (r = 0.045, P = 0.003; r = 0.14, P = 0.058), and sneezing (r = −0.02, P = < 0.0001; r = −0.0055, P = 0.31). Neutrophils correlate with some quality of life measures such as sleeping well (r = 0.15, P = 0.026). Thus, the study demonstrates that IL‐8 and neutrophils are correlated with severity of nasal symptoms during acute respiratory infection. Further research is necessary to determine if the concentration of these or other biomarkers can predict the overall duration and severity of acute respiratory infection illness. J. Med. Virol. 87:330–337, 2015. © 2014 Wiley Periodicals, Inc.