Miracle-dz/UniFAR-FTUs huggingface dataset:
A Conformational Transition Observed in Single HIV-1 Gag Molecules during In Vitro Assembly of Virus-Like Particles

ABSTRACT The conformational changes within single HIV-1 Gag molecules that occur during assembly into immature viruses are poorly understood. Using an in vitro assembly assay, it has been proposed that HIV-1 Gag undergoes a conformational transition from a compact conformation in solution to an extended rod-like conformation in virus-like particles (VLPs). Here we used single-molecule Förster resonance energy transfer (smFRET) to test this model by directly probing the conformation of single HIV-1 Gag molecules. We demonstrate that monomeric HIV-1 Gag lacking the p6 domain and the N-terminal myristoyl moiety is found in solution predominantly in a compact conformation. Gag in this conformation, and in the presence of nucleic acid, assembles into 30-nm-diameter particles. However, with the addition of inositol hexakisphosphate, Gag adopts a linear conformation and assembles into full-sized ∼100-to-150-nm-diameter VLPs. Parallel fluorescence correlation spectroscopy measurements show that this conformational transition occurs early in the assembly process when Gag oligomers are small, perhaps as early as upon dimerization. Thus, smFRET measurements confirm that HIV-1 Gag transitions from a compact to a linear conformation during the formation of VLPs. Our results are consistent with a model whereby binding of HIV-1 Gag to phosphoinositides at the plasma membrane stabilizes an extended conformation and promotes oligomerization into the radially aligned immature capsid. IMPORTANCE The establishment of single-molecule fluorescence techniques reveals the conformational state of individual HIV-1 Gag molecules prior to and during in vitro assembly into virus-like particles. The data demonstrate that Gag in distinct conformations forms particles with different morphologies. In the compact conformation, in the presence of nucleic acid, Gag forms spherical particles of a diameter of approximately 30 nm. In the extended conformation, Gag forms spherical virus-like particles of approximately 100-nm diameter. The adoption of the extended conformation required the presence of inositol hexakisphosphate in addition to nucleic acid. Our results are consistent with a model whereby binding of HIV-1 Gag to phosphoinositides at the plasma membrane stabilizes an extended conformation and promotes oligomerization into the radially aligned immature capsid.
SPECT imaging of pre- and postsynaptic dopaminergic alterations in l-dopa–untreated PD

Background: In PD, presynaptic dopamine transporters are known to be decreased, whereas postsynaptic striatal D2 receptors are proposed to be upregulated. However, the relationship between these alterations is not clear. Objective: To evaluate the ability of SPECT to detect both the pre- and postsynaptic dopaminergic alterations of the striatum in patients with l-dopa–untreated PD. Methods: We studied 10 l-dopa–untreated patients with clinically mild PD and 21 age-matched normal controls. Individuals had both presynaptic [123I]β-CIT dopamine transporter and postsynaptic [123I]IBF D2 SPECT studies 1 week apart. Results: In PD patients, the dopamine transporter binding potential Rv ipsilateral/contralateral to the most affected limbs was 30%/41%, 41%/50%, and 59%/68% lower than controls for caudate, anterior putamen, and posterior putamen, respectively. These bilateral Rv decreases showed a lateralized difference more reduced in the contralateral striatum as well as intrastriatal differences most reduced in the posterior putamen. In contrast, in PD patients the D2 binding potential Rv ipsilateral/contralateral was 15%/16% higher for caudate, 18%/14% higher for anterior putamen, and 28%/31% higher for posterior putamen. These bilateral Rv increases showed no lateralized differences and less marked intrastriatal differences. The motor Unified Parkinson’s Disease Rating Scale scores negatively correlated with dopamine transporter Rv but not with D2 Rv. Conclusions: SPECT imaging can detect characteristic dopaminergic alterations in the striatum of dopa-untreated PD patients including the upregulation of postsynaptic D2 receptors (denervation supersensitivity). SPECT is widely available and is a promising clinical tool to evaluate PD patients.
Type 1 diabetes: can exercise impair the autoimmune event? The L‐arginine/glutamine coupling hypothesis

Prevention of type 1 diabetes mellitus (T1DM) requires early intervention in the autoimmune process directed against β‐cells of the pancreatic islets of Langerhans, which is believed to result from a disorder of immunoregulation. According to this concept, a T‐helper lymphocyte of type 1 (Th1) subset of T‐lymphocytes and their cytokine products, the type 1 cytokines [e.g. interleukin 2 (IL‐2), interferon gamma (IFN‐γ) and tumour necrosis factor beta (TNF‐β)] prevail over immunoregulatory (anti‐inflammatory) Th2 subset and its cytokine products, i.e. type 2 cytokines (e.g. IL‐4, IL‐6 and IL‐10). This allows type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in β‐cell destruction. Activation of sympathetic‐corticotropin‐releasing hormone (CRH) axis by psychological stress induces specifically Th1 cell overactivity that determines enhanced glutamine utilization and consequent poor L‐arginine supply for nitric oxide (NO)‐assisted insulin secretion. This determines the shift of intraislet glutamate metabolism from the synthesis of glutathione (GSH) to that of L‐arginine, leading to a redox imbalance that activates nuclear factor κB exacerbating inflammation and NO‐mediated cytotoxicity. Physical exercise is capable of inducing changes in the pattern of cytokine production and release towards type 2 class and to normalize the glutamine supply to the circulation, which reduces the need for glutamate, whose metabolic fate may be restored in the direction of GSH synthesis and antioxidant defence. Also, the 70‐kDa heat shock protein (hsp70), which is immunoregulatory, may modulate exercise‐induced anti‐inflammation. In this work, we envisage how exercise can intervene in the mechanisms involved in the autoimmune process against β‐cells and how novel therapeutic approaches may be inferred from these observations. Copyright © 2008 John Wiley & Sons, Ltd.
Concomitant Caffeine Increases Binge Consumption of Ethanol in Adolescent and Adult Mice, But Produces Additive Motor Stimulation Only in Adolescent Animals.

BACKGROUND Binge co-consumption of highly caffeinated energy drinks with alcohol (ethanol [EtOH]) has become a common practice among adolescents/young adults and has been associated with an increased incidence of hazardous behaviors. Animal models are critical in advancing our understanding the neurobehavioral consequences of this form of binge drinking. Surprisingly, virtually no work has explored caffeine and EtOH co-consumption or its long-term consequences in adolescent animals. The primary objective of the current study was to extend a previously established mouse model of voluntary binge caffeine and EtOH co-consumption to explore adolescent consumption and responses compared to adults. METHODS Adolescent and adult male C57BL/6J mice had daily limited access to caffeine (0.03% w/v), EtOH (20% v/v), a combined EtOH/caffeine solution, or water for 14 days via the binge-like drinking paradigm, drinking-in-the-dark (DID). Home cage locomotor activity was measured during DID in a subset of mice. Following DID, all mice rested for 18 days so that adolescents reached adulthood, whereupon all mice underwent 7 days of continuous access 2-bottle choice drinking for 10% (v/v) EtOH or water. RESULTS Co-consumption with caffeine significantly increased EtOH intake and resultant blood ethanol concentrations in both adolescent and adult mice. In addition, adolescent mice exhibited a uniquely robust locomotor stimulant response to caffeine and EtOH co-consumption. Later EtOH intake and preference was not influenced, however, by prior fluid consumption history via DID. CONCLUSIONS Together with findings from the human literature, our results suggest that caffeine co-consumption may positively influence binge alcohol consumption in adolescents/young adults. Importantly, this age group may be particularly sensitive to the additive stimulant effects of caffeinated alcohol consumption, an effect which may be related to the high incidence of associated negative outcomes in this population. These observations are particularly concerning considering the heightened plasticity of the adolescent brain.
A Note on Corrodies in the Fourteenth Century

The corrody is harshly judged by many medieval historians; it is condemned because it introduced into the cloister a distracting and often boistrous presence from the secular world. With sharp hindsight, they argue that the corrodies were poor financial policy and often saddled a convent with an unwelcome boarder who lived off its resources long after his original investment had been consumed. I But the corrody was most often used, at least in the fourteenth century by bishops and archbishops, to reward a faithful servant or to provide care and maintenance for those who were unable to sustain themselves. In this article, the corrody and its recipients are examined in an effort to redress the balance and demonstrate its praiseworthy character as an institution of medieval charity. But first things first. What is a corrody? Following the etymological derivation of the word made by A. Hamilton Thompson, corredium, corradium, corrodium and other variations are derived from conredum and conredium, which have "the primary connotation of equipage, and among others, it was especially applied to the provision made by a feudal vassal for the entertainment of his lord when he made his round. The corrody was the provender or prebend which was the lord's due . [The] corrody became first and foremost a grant of money or victuals, or of other means of livelihood, made by a monastery or other religious or charitable corporation to dependents upon its bounty. "2 According to one authority, the first usage of the word in this sense in England was in a deed of 1197.3 Why were corrodies granted? Again quoting A. Hamilton Thompson, "The credit balance of the state of the house was at best small, and usually the balance was on the debit side. Houses were burthened with yearly pensions and annuities; there was the weight of taxation to meet; and all this at
Square-lattice site percolation at increasing ranges of neighbor bonds.

We report site percolation thresholds for square lattice with neighbor bonds at various increasing ranges. Using Monte Carlo techniques we found that nearest neighbors (NN), next-nearest neighbors (NNN), next-next-nearest neighbors (4N), and fifth-nearest neighbors (6N) yield the same pc = 0.592. The fourth-nearest neighbors (5N) give pc = 0.298. This equality is proved to be mathematically exact using symmetry argument. We then consider combinations of various kinds of neighborhoods with (NN+NNN), (NN+4N), (NN+NNN+4N), and (NN+5N). The calculated associated thresholds are respectively pc = 0.407. , 0.337. , 0.288. , and 0.234. The existing Galam-Mauger universal formula for percolation thresholds does not reproduce the data showing dimension and coordination number are not sufficient to build a universal law which extends to complex lattices.
Development and psychometric validation of social cognitive theory scales in an oral health context

Objective: This study aimed to develop and evaluate scales reflecting potentially modifiable social cognitive theory‐based risk indicators associated with homeless populations' oral health. The scales are referred to as the social cognitive theory risk scales in an oral health context (SCTOH) and are referred to as SCTOH(SE), SCTOH(K) and SCTOH(F), respectively.
Can education make a difference to undergraduate nursing students’ attitudes to psychiatric nursing?

Abstract The introduction of undergraduate nursing education throughout Australia has had serious implications for the position of psychiatric nursing in attracting graduates into this field. There is some evidence from the results of limited research that a more positive view of psychiatric nursing can emerge as the result of education. However, such a relationship has not been found to be strong. This paper reports the findings of a quasi-experimental research study, which compared student nurses’ attitudes towards psychiatric nursing as a career option both before and after completing the psychiatric nursing component of the course. The post-test results demonstrate a strong and statistically significant increase in the popularity of psychiatric nursing. Analysis of the open-ended responses suggests that exposure to the theory and practice of psychiatric nursing has dispelled many myths regarding this area of practice. The possible impact of problem-based learning on these results is discussed.
Role of Salmonella enterica Lipopolysaccharide in Activation of Dendritic Cell Functions and Bacterial Containment1

In contrast to nonpathogenic bacteria, the Gram-negative pathogen Salmonella enterica is not eradicated, but persists in murine dendritic cells (DC). The molecular basis of this phenotype is unknown. We set out to characterize bacterial and DC functions that are involved in Salmonella persistence. Our data prove that neither bacterial nor host cell de novo protein biosynthesis is required for Salmonella persistence in DC. We identified the Salmonella O-Ag of the LPS of Salmonella as an important factor for controlling the intracellular fate of Salmonella in DC. A Salmonella strain with entirely absent O-Ag showed an increased rate of uptake by DC, altered intracellular processing, and increased degradation, and also boosted the activation of immune functions of DC. These novel findings demonstrate that in addition to the multiple functions of the bacterial LPS in adaptation to the intestinal environment and protection against innate immune function, this molecule also has an important role in interaction of Salmonella with DC.
The required dose of erythropoietin during renal anaemia treatment is related to the degree of impairment in erythrocyte deformability.

BACKGROUND Renal anaemia is rapidly corrected by recombinant human erythropoietin (rHuEpo) therapy, but the dose required varies greatly. Since impaired erythrocyte deformability may be one factor contributing to the development of renal anaemia, the interrelationship between that variable and the rHuEpo requirement was examined. METHODS Twenty-five patients treated with hemodialysis and rHuEpo for at least 6 months were included in the study. The Hb value had been stable and the rHuEpo dose unchanged the last two months. Using a rotational viscometer, the fluidity of erythrocytes, separated from plasma and re-suspended in isotonic buffered saline to a standardized haematocrit, was taken as a measure of erythrocyte deformability. RESULTS The average weekly dose of s.c. epoetin alpha was 186 +/- 93 U/kg body weight (range 56-370). The dose was correlated to the reticulocyte fraction (R = 0.69, P = 0.0001). When the rHuEpo dose was used as dependent variable and blood haemoglobin concentration, serum (S) albumin, S ferritin, S aluminium, S PTH, S urea, Kt/V/week, erythrocyte fluidity, and plasma viscosity were used as independent variables in a stepwise multiple regression analysis, only erythrocyte fluidity remained significantly negatively correlated to the rHuEpo dose (R = 0.5, P = 0.01). Despite a tendency towards higher doses of rHuEpo in patients with a C-reactive protein concentration exceeding 20 mg/l, the Hb was lower in these patients. CONCLUSIONS We conclude that the interindividual differences in bone marrow response to rHuEpo were small in these patients. Impaired erythrocyte deformability and inflammation seem to be factors associated with increased rHuEpo requirement.
High prevalence of Mycobacterium avium subspecies paratuberculosis IS900 DNA in gut tissues from individuals with Crohn’s disease

Background and aims: Conflicting results exist about the presence of Mycobacterium avium subspecies paratuberculosis (MAP) specific IS900 DNA in Crohn’s disease (CD) tissues. Therefore, we examined IS900 in a large number of gut samples from patients with CD (n = 100) and ulcerative colitis (UC, n = 100), and in non-inflamed control tissues (nIBD, n = 100). We hypothesised that IS900 DNA detection might be associated with distinct clinical phenotypic characteristics in CD. Methods: The prevalence of MAP DNA in surgically resected tissues was examined using a mechanical-enzymatic disruption technique and nested IS900 specific polymerase chain reaction (PCR). CD patients were stratified according to the criteria of the Vienna classification and other clinical characteristics. Results: IS900 PCR detection rate was significantly higher in CD tissue samples (52%) than in UC (2%) or nIBD (5%) specimens (p<0.0001). In CD patients, IS900 DNA was detected in samples from both diseased small bowel (47%) as well as from the colon (61%). No firm association between MAP specific IS900 detection rates and clinical phenotypic characteristics in CD could be established. However, corticosteroid medication constituted a factor which tended to have a negative influence on IS900 DNA detection rates in CD (p<0.01). Conclusions: The presence of MAP specific IS900 DNA is a predominant feature of CD. Therapeutic intervention against MAP might represent a potential target for disease mitigation in Crohn’s disease.
Na-H Exchange-dependent Increase in Intracellular pH Times G2/M Entry and Transition*

It is well established that activation of the Na-H exchanger NHE1 and increases in intracellular pH (pHi) are early and universal responses to mitogens and have permissive effects in promoting cell proliferation. Despite this evidence, a specific role for NHE1 or pHi in cell cycle progression remains undetermined. We now show that NHE1 activity and pHi regulate the timing of G2/M entry and transition. Prior to G2/M entry there is a rapid and transient increase in NHE1 activity and pHi, but in fibroblasts expressing a mutant NHE1 that lacks ion translocation activity, this increase in pHi is attenuated, S phase is delayed, and G2/M transition is impaired. In the absence of ion translocation by NHE1, expression of cyclin B1 and the kinase activity of Cdc2 are decreased and Wee1 kinase expression increases. Increasing pHi in the absence of NHE1 activity, however, is sufficient to restore Cdc2 activity and cyclin B1 expression and to promote G2/M entry and transition. These data indicate that a transient increase in pHi induced by NHE1 promotes the timing of G2/M, and they suggest that increases in pHi at the completion of S phase may constitute a previously unrecognized checkpoint for progression to G2 and mitosis.
Vascular Endothelial Growth Factor–Expressing Mesenchymal Stem Cell Transplantation for the Treatment of Acute Myocardial Infarction

Objective—Vascular endothelial growth factor (VEGF) plays an important role in inducing angiogenesis. Mesenchymal stem cells (MSCs) may have potential for differentiation to several types of cells, including myocytes. We hypothesized that transplantation of VEGF-expressing MSCs could effectively treat acute myocardial infarction (MI) by providing enhanced cardioprotection, followed by angiogenic effects in salvaging ischemic myocardium. Methods and Results—The human VEGF165 gene was transfected to cultured MSCs of Lewis rats using an adenoviral vector. Six million VEGF-transfected and LacZ-transfected MSCs (VEGF group), LacZ-transfected MSCs (control group), or serum-free medium only (medium group) were injected into syngeneic rat hearts 1 hour after left coronary artery occlusion. At 1 week after MI, MSCs were detected by X-gal staining in infarcted region. High expression of VEGF was immunostained in the VEGF group. At 28 days after MI, infarct size, left ventricular dimensions, ejection fraction, E wave/A wave ratio and capillary density of the infarcted region were most improved in the VEGF group, compared with the medium group. Immunohistochemically, &agr;-smooth muscle actin–positive cells were most increased in the VEGF group. Conclusions—This combined strategy of cell transplantation with gene therapy could be a useful therapy for the treatment of acute MI.
Monovalent cation activation in Escherichia coli inosine 5'-monophosphate dehydrogenase.

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate with the concomitant reduction of NAD to NADH. Escherichia coli IMPDH is activated by K(+), Rb(+), NH(+)(4), and Cs(+). K(+) activation is inhibited by Li(+), Na(+), Ca(2+), and Mg(2+). This inhibition is competitive versus K(+) at high K(+) concentrations, noncompetitive versus IMP, and competitive versus NAD. Thus monovalent cation activation is linked to the NAD site. K(+) increases the rate constant for the pre-steady-state burst of NADH production, possibly by increasing the affinity of NAD. Three mutant IMPDHs have been identified which increase the value of K(m) for K(+): Asp13Ala, Asp50Ala, and Glu469Ala. In contrast to wild type, both Asp13Ala and Glu469Ala are activated by all cations tested. Thus these mutations eliminate cation selectivity. Both Asp13 and Glu469 appear to interact with the K(+) binding site identified in Chinese hamster IMPDH. Like wild-type IMPDH, K(+) activation of Asp50Ala is inhibited by Li(+), Na(+), Ca(2+), and Mg(2+). However, this inhibition is noncompetitive with respect to K(+) and competitive with respect to both IMP and NAD. Asp50 interacts with residues that form a rigid wall in the IMP site; disruption of this wall would be expected to decrease IMP binding, and the defect could propagate to the proposed K(+) site. Alternatively, this mutation could uncover a second monovalent cation binding site.
Effect of a social skills training group on everyday activities of children with attention‐deficit‐hyperactivity disorder

This preliminary study compared the daily living skills of children with and without attention‐deficit‐hyperactivity disorder (ADHD), and the influence of a social skills training group on these skills. Twenty‐seven children with ADHD (2 females, 25 males; age range 5 to 8y, mean 6y 6mo, SD 10mo), and 24 children without ADHD (8 females, 16 males; age range 5 to 8y, mean 6y 11mo, SD 10mo) performed the Assessment of Motor and Process Skills (AMPS). Fourteen of the children with ADHD used medication daily. Nine of the total group with ADHD were randomly selected to attend group treatment which focused on social skills training, through meaningful occupations (e.g. art, games, cooking). Children were evaluated at the beginning of group treatment and after 10 sessions. Ten children without ADHD were evaluated at similar intervals. Children with ADHD initially achieved significantly lower scores on the AMPS in all process skills (p<0.001) and in the coordination motor subtest (p<0.005) than children without ADHD. Children with ADHD significantly improved from the first to the second evaluation and no longer differed from the children without ADHD after treatment (p<0.008). The results emphasize the need for a focus upon occupation in assessment and treatment of children with ADHD.