Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction.
The accumulation of oxidatively modified proteins has been shown to be a characteristic feature of many neurodegenerative disorders and its regulation requires efficient proteolytic processing. One component of the mitochondrial proteolytic system is Lon, an ATP-dependent protease that has been shown to degrade oxidatively modified aconitase in vitro and may thus play a role in defending against the accumulation of oxidized matrix proteins in mitochondria. Using an assay system that allowed us to distinguish between basal and ATP-stimulated Lon protease activity, we have shown in isolated non-synaptic rat brain mitochondria that Lon protease is highly susceptible to oxidative inactivation by peroxynitrite (ONOO(-)). This susceptibility was more pronounced with regard to ATP-stimulated activity, which was inhibited by 75% in the presence of a bolus addition of 1mM ONOO(-), whereas basal unstimulated activity was inhibited by 45%. Treatment of mitochondria with a range of peroxynitrite concentrations (10-1000 microM) revealed that a decline in Lon protease activity preceded electron transport chain (ETC) dysfunction (complex I, II-III and IV) and that ATP-stimulated activity was approximately fivefold more sensitive than basal Lon protease activity. Furthermore, supplementation of mitochondrial matrix extracts with reduced glutathione, following ONOO(-) exposure, resulted in partial restoration of basal and ATP-stimulated activity, thus suggesting possible redox regulation of this enzyme complex. Taken together these findings suggest that Lon protease may be particularly vulnerable to inactivation in conditions associated with GSH depletion and elevated oxidative stress.


Minimal hepatic encephalopathy.
Minimal hepatic encephalopathy (MHE) is the mildest form of spectrum of hepatic encephalopathy (HE). Patients with MHE have no recognizable clinical symptoms of HE but have mild cognitive and psychomotor deficits. The prevalence of MHE is high in patients with cirrhosis of liver and varies between 30% and 84%; it is higher in patients with poor liver function. The diagnostic criteria for MHE have not been standardized but rest on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognition and/or neurophysiological function, and exclusion of concomitant neurological disorders. MHE is associated with impaired health-related quality of life, predicts the development of overt HE and is associated with poor survival. Hence, screening all patients with cirrhosis for MHE using psychometric tests, and treatment of those patients diagnosed to have MHE has been recommended. Ammonia plays a key role in the pathogenesis of MHE, which is thought to be similar to that of overt HE. Thus, ammonia-lowering agents such as lactulose and probiotics have been tried. These agents have been shown to improve cognitive and psychometric deficits, and have good safety profile. Future studies will better define the role of other drugs, such as rifaximin, acetyl L-carnitine and L-ornithine L-aspartate.


GenoType NTM-DR Performance Evaluation for Identification of Mycobacterium avium Complex and Mycobacterium abscessus and Determination of Clarithromycin and Amikacin Resistance.
We evaluated the GenoType NTM-DR (NTM-DR) line probe assay for identifying Mycobacterium avium complex (MAC) species and Mycobacterium abscessus subspecies and for determining clarithromycin and amikacin resistance. Thirty-eight reference strains and 145 clinical isolates (58 MAC and 87 M. abscessus isolates), including 54 clarithromycin- and/or amikacin-resistant strains, were involved. The performance of the NTM-DR assay in rapid identification was evaluated by comparison with results of multigene sequence-based typing, whereas performance in rapid detection of clarithromycin and amikacin resistance was evaluated by comparison with sequencing of the erm(41), rrl, and rrs genes and drug susceptibility testing (DST). The accuracies of MAC and M. abscessus (sub)species identification were 92.1% (35/38) and 100% (145/145) for the 38 reference strains and 145 clinical isolates, respectively. Three MAC strains other than M. intracellulare were found to cross-react with the M. intracellulare probe in the assay. Regarding clarithromycin resistance, NTM-DR detected rrl mutations in 52 isolates and yielded 99.3% (144/145) and 98.6% (143/145) concordant results with sequencing and DST, respectively. NTM-DR sensitivity and specificity in the detection of clarithromycin resistance were 96.3% (52/54) and 100% (91/91), respectively. The NTM-DR yielded accurate erm(41) genotype results for all 87 M. abscessus isolates. Regarding amikacin resistance, NTM-DR detected rrs mutations in five isolates and yielded 99.3% (144/145) and 97.9% (142/145) concordant results with sequencing and DST, respectively. Our results indicate that the NTM-DR assay is a straightforward and accurate approach for discriminating MAC and M. abscessus (sub)species and for detecting clarithromycin and amikacin resistance mutations and that it is a useful tool in the clinical setting.


Flavour chemistry of chicken meat: a review.
Flavour comprises mainly of taste and aroma and is involved in consumers' meat-buying behavior and preferences. Chicken meat flavour is supposed to be affected by a number of ante- and post-mortem factors, including breed, diet, post-mortem ageing, method of cooking, etc. Additionally, chicken meat is more susceptible to quality deterioration mainly due to lipid oxidation with resulting off-flavours. Therefore, the intent of this paper is to highlight the mechanisms and chemical compounds responsible for chicken meat flavour and off-flavour development to help producers in producing the most flavourful and consistent product possible. Chicken meat flavour is thermally derived and the Maillard reaction, thermal degradation of lipids, and interaction between these 2 reactions are mainly responsible for the generation of flavour and aroma compounds. The reaction of cysteine and sugar can lead to characteristic meat flavour specially for chicken and pork. Volatile compounds including 2-methyl-3-furanthiol, 2-furfurylthiol, methionol, 2,4,5-trimethyl-thiazole, nonanol, 2-trans-nonenal, and other compounds have been identified as important for the flavour of chicken. However 2-methyl-3-furanthiol is considered as the most vital chemical compound for chicken flavour development. In addition, a large number of heterocyclic compounds are formed when higher temperature and low moisture conditions are used during certain cooking methods of chicken meat such as roasting, grilling, frying or pressure cooking compared to boiled chicken meat. Major volatile compounds responsible for fried chicken are 3,5-dimethyl-1,2,4-trithiolanes, 2,4,6-trimethylperhydro-1,3,5-dithiazines, 3,5-diisobutyl-1,2,4-trithiolane, 3-methyl-5-butyl-1,2,4-trithiolane, 3-methyl-5-pentyl-1,2,4-trithiolane, 2,4-decadienal and trans-4,5-epoxy-trans-2-decenal. Alkylpyrazines were reported in the flavours of fried chicken and roasted chicken but not in chicken broth. The main reason for flavour deterioration and formation of undesirable "warmed over flavour" in chicken meat products are supposed to be the lack of α-tocopherol in chicken meat.


Evaluation of the effects of galbanic acid from Ferula szowitsiana and conferol from F. badrakema, as modulators of multi-drug resistance in clinical isolates of Escherichia coli and Staphylococcus aureus.
Galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana, and conferol, another sesquiterpene coumarin from F. badrakema, were evaluated for their effects on the reversal of multi-drug resistance in clinical isolates of Staphylococcus aureus and Escherichia coli, respectively. Neither galbanic acid (up to 1000 μg/ml) nor conferol (up to 400 μg/ml) by itself shows any antibacterial activities against tested strains. The minimum inhibitory concentrations (MICs) of ciprofloxacin and tetracycline were determined using macrodilution technique in the presence and absence of sub-inhibitory concentrations of galbanic acid (31.25-1000 μg/ml) or conferol (50-400 μg/ml), however they caused no change in MICs of the antibiotics. Galbanic acid did not show any inhibitory effect on efflux phenomenon of E. coli. This can be related to the outer membrane of gram-negative bacteria which is impermeable to lipophilic compounds or another mechanism rather than efflux responsible for resistance in tested E. coli strains. An inhibitory effect of conferol on the efflux was compared with verapamil as a positive control. Because efflux is the only known mechanism of resistance to ethidium bromide (model efflux substrate) and verapamil reduced MIC of ethidium bromide, efflux mechanism can be considered as one of the resistance mechanisms in tested S. aureus strains. Conferol, however, did not enhance the antibiotic efficacy mediated by inhibiting efflux pumps in bacteria.


Antidiabetic Activities of Abutilon indicum (L.) Sweet Are Mediated by Enhancement of Adipocyte Differentiation and Activation of the GLUT1 Promoter.
Abutilon indicum (L.) Sweet is an Asian phytomedicine traditionally used to treat several disorders, including diabetes mellitus. However, molecular mechanisms supporting the antidiabetic effect of A. indicum L. remain unknown. The aim of this study was to evaluate whether extract of A. indicum L. improves insulin sensitivity. First, we observed the antidiabetic activity of aqueous extract of the entire plant (leaves, twigs and roots) of A. indicum L. on postprandial plasma glucose in diabetic rats. The subsequent experiments revealed that butanol fractions of the extract bind to PPARγ and activate 3T3-L1 differentiation. To measure glucose uptake enhanced by insulin-like activity, we used rat diaphragm incubated with various concentrations of the crude extract and found that the extract enhances glucose consumption in the incubated solution. Our data also indicate that the crude extract and the fractions (water and butanol) did not affect the activity of kinases involved in Akt and GSK-3β pathways; however, the reporter assay showed that the crude extract could activate glucose transporter 1 (GLUT1) promoter activity. These results suggest that the extract from A. indicum L. may be beneficial for reducing insulin resistance through its potency in regulating adipocyte differentiation through PPARγ agonist activity, and increasing glucose utilization via GLUT1.


Up-regulation of alpha1B-adrenergic receptors with defects in G protein coupling: ligand-induced protection from receptor instability.
The biochemical basis for the unexpected agonist-induced up-regulation of the number of radioligand binding sites for two mutated alpha1B-adrenergic receptors reported previously was investigated. Up-regulation was independent of the expression vector used and was not prevented by cycloheximide or actinomycin D, eliminating several potential transcriptional mechanisms and new receptor protein synthesis. Antagonists were also able to induce up-regulation, suggesting that ligand occupancy without signal generation was sufficient to induce the increase in binding sites. Accordingly, we hypothesized that up-regulation results from ligand-induced protection from inherent instability of these mutated receptors. Studies with receptors in isolated membranes revealed that the two mutated receptors that exhibited up-regulation in intact cells also exhibited an inherent instability of their ligand binding capacity, and binding of either agonists or antagonists to these receptors could protect against the loss of binding. In contrast, the wild-type receptor and other mutated receptors that did not exhibit up-regulation in intact cells did not exhibit instability or ligand-induced protection in isolated membranes. The occurrence of instability and protection in isolated membranes for only those mutated receptors and ligands that exhibit up-regulation in intact cells provides compelling evidence that the apparent up-regulation of binding sites in intact cells results from ligand-induced protection from an inherent instability of these G protein coupling-defective receptors. Inclusion of protease inhibitors markedly reduced the loss of binding in isolated membranes, implicating membrane-localized proteolysis as the likely mechanism for the instability.


The protective effects of selenoorganic compounds against peroxynitrite-induced changes in plasma proteins and lipids.
Many selenoorganic compounds play an important role in biochemical processes and act as antioxidants, enzyme inhibitors or drugs. The effects of a new selenocompound--bis(2-aminophenyl)-diselenide on oxidative/nitrative changes in human plasma proteins induced by peroxynitrite (ONOO(-)) were studied in vitro and compared with the those of ebselen, a well-known antioxidant. We also studied the role of the tested selenocompounds in peroxynitrite-induced plasma lipid peroxidation. Exposure of the plasma to peroxynitrite (0.1 mM) resulted in an increase in the level of carbonyl groups and nitrotyrosine residues in plasma proteins (estimated using the ELISA method and Western blot analysis). In the presence of different concentrations (0.025-0.1 mM) of the tested selenocompounds, 0.1 mM peroxynitrite caused a distinct decrease in the level of carbonyl group formation and tyrosine nitration in plasma proteins. Moreover, these selenocompounds also inhibited plasma lipid peroxidation induced by ONOO(-1) (0.1 mM). The obtained results indicate that in vitro bis(2-aminophenyl)-diselenide and ebselen have very similar protective effects against peroxynitrite-induced oxidative/nitrative damage to human plasma proteins and lipids.


Trichilemmal cyst of the penis in a paediatric patient.
Paediatric penile cysts are uncommon. We report a five-year-old child with an asymptomatic progressively growing cyst on the ventral aspect of the penis after a hypospadias repair. The patient presented to the Cooper Health Clinic, Dubai, United Arab Emirates, in March 2012. A complete excision of the cyst was performed. Histology results delineated a capsulated benign trichilemmal cyst. No recurrence or complications were reported in the 26 months following the excision. We recommend an early and complete excision of all penile cysts to prevent the risk of urethral obstruction, infection, inflammation and rare malignant changes. This is the first reported case of a penile trichilemmal cyst in a child.


Tolerance and cross-tolerance in chronic alcoholics: reduced membrane binding of ethanol and other drugs.
Membrane binding of ethanol, anesthetics, and hydrophobic molecules in brain synaptosomes and liver mitochondria from rats is conspicuously reduced after long-term consumption of ethanol. The membranes are resistant to structural disordering by both ethanol and halothane. Tolerance, cross-tolerance, and dependence in chronic alcoholics may in part result from membrane alterations that inhibit the binding of ethanol and other drugs.


Hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response.
Plasma secretion of acid sphingomyelinase is a hallmark of cellular stress response resulting in the formation of membrane embedded ceramide-enriched lipid rafts and the reorganization of receptor complexes. Consistently, decompartmentalization of ceramide formation from inert sphingomyelin has been associated with signaling events and regulation of the cellular phenotype. Herein, we addressed the question of whether the secretion of acid sphingomyelinase is involved in host response during sepsis. We found an exaggerated clinical course in mice genetically deficient in acid sphingomyelinase characterized by an increased bacterial burden, an increased phagocytotic activity, and a more pronounced cytokine storm. Moreover, on a functional level, leukocyte-endothelial interaction was found diminished in sphingomyelinase-deficient animals corresponding to a distinct leukocytes' phenotype with respect to rolling and sticking as well as expression of cellular surface proteins. We conclude that hydrolysis of membrane-embedded sphingomyelin, triggered by circulating sphingomyelinase, plays a pivotal role in the first line of defense against invading microorganisms. This function might be essential during the early phase of infection leading to an adaptive response of remote cells and tissues.


Effect of water immersion methods on post-exercise recovery from simulated team sport exercise.
This study aimed to compare the efficacy of hot/cold contrast water immersion (CWI), cold-water immersion (COLD) and no recovery treatment (control) as post-exercise recovery methods following exhaustive simulated team sports exercise. Repeated sprint ability, strength, muscle soreness and inflammatory markers were measured across the 48-h post-exercise period. Eleven male team-sport athletes completed three 3-day testing trials, each separated by 2 weeks. On day 1, baseline measures of performance (10 m x 20 m sprints and isometric strength of quadriceps, hamstrings and hip flexors) were recorded. Participants then performed 80 min of simulated team sports exercise followed by a 20-m shuttle run test to exhaustion. Upon completion of the exercise, and 24h later, participants performed one of the post-exercise recovery procedures for 15 min. At 48 h post-exercise, the performance tests were repeated. Blood samples and muscle soreness ratings were taken before and immediately after post-exercise, and at 24h and 48 h post-exercise. In comparison to the control and CWI treatments, COLD resulted in significantly lower (p<0.05) muscle soreness ratings, as well as in reduced decrements to isometric leg extension and flexion strength in the 48-h post-exercise period. COLD also facilitated a more rapid return to baseline repeated sprint performances. The only benefit of CWI over control was a significant reduction in muscle soreness 24h post-exercise. This study demonstrated that COLD following exhaustive simulated team sports exercise offers greater recovery benefits than CWI or control treatments.


Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies.
Dopaminergic treatment in dementia with Lewy bodies (DLB) requires balancing risk of worsened psychosis and potential motor benefit. We assessed the effects of increased dopaminergic medication on psychosis and motor function in DLB. We studied 19 subjects fulfilling probable DLB Consensus criteria before and after increased dopaminergic medications. Standard clinical measures included: Thought Disorder score from the Unified Parkinson's disease Rating Scale (UPDRS) Part I, total motor score (UPDRS Part III), and Hoehn-Yahr (H&Y) stage. Motor benefit defined as >10% improvement over baseline UPDRS Part III score, occurred in only one-third of subjects. In this group, worsened hallucinations or psychosis developed in one-third. Considering motor benefit without exacerbation of psychosis as our aim, only 4 DLB subjects (22%) achieved this goal. Our results suggest that dopaminergic medications have limited benefit in DLB because of the low likelihood of motor improvement and the risk of psychosis exacerbation.


Polarization-independent etching of fused silica based on electrons dynamics control by shaped femtosecond pulse trains for microchannel fabrication.
We propose an approach to realize polarization-independent etching of fused silica by using temporally shaped femtosecond pulse trains to control the localized transient electrons dynamics. Instead of nanograting formation using traditional unshaped pulses, for the pulse delay of pulse trains larger than 1 ps, coherent field-vector-related coupling is not possible and field orientation is lost. The exponential growth of the periodic structures is interrupted. In this case, disordered and interconnected nanostructures are formed, which is probably the main reason of etching independence on the laser polarization. As an application example, square-wave-shaped and arc-shaped microchannels are fabricated by using pulse trains to demonstrate the advantage of the proposed method in fabricating high-aspect-ratio and three-dimensional microchannels.


Technical quality of root fillings performed by dental students at the dental teaching centre in Reims, France.
To evaluate the technical quality of root fillings performed by undergraduate students at a dental teaching centre in France. A random sample of 419 records of patients who received dental treatment at the dental service of the teaching Hospital, in Reims, France between 2005 and 2006 was investigated. Evaluation of root filled was based on radiographical criteria defined by the French National Health Service. The length of root fillings, the radiodensity and the presence of voids in the root filling or between root filling and root canal walls were recorded and scored. Chi-square analysis was used to determine statistically significant differences between the technical quality of root fillings and tooth type. Of the 304 teeth included in the study, 69% had an adequate length of root filling and 42.7% had a dense root filling without voids; only 30.3% of teeth fulfilled these criteria at the same time. The relationship between the technical quality of root fillings and tooth type was statistically significant (P < 0.001), the highest percentage of adequate root fillings occurred in single-rooted teeth (36.1%). The highest percentage of inadequate root fillings according to the criteria of root filling length and lateral adaptation was found in molar teeth (71.9%). Overall, the technical quality of root fillings performed by undergraduate students was poor.


Study of brucellosis in a pastoral community and evaluation of the usefulness of clinical signs and symptoms in differentiating it from other flu-like diseases.
A study of differentials causing flu-like symptoms (malaria, typhoid, streptococcal infections and rheumatoid arthritis) in 488 patients from a pastoralist area is presented. The potential usefulness of clinical signs, symptoms and diagnostic tests in ruling-in or ruling-out these diseases was investigated in the District hospital and three outlying health dispensaries. For each patient a detailed clinical history plus diagnostic test for brucellosis, typhoid, streptococcal infections and rheumatoid arthritis, and for some patients malaria were conducted. Incidence levels of these diseases were estimated using laboratory test results; brucellosis, 13%, typhoid, 40%: streptococcal infections, 6% malaria, 9%: and rheumatoid arthritis, 10%. Brucellosis could not be differentiated clinically from the other flu-like diseases but rheumatoid arthritis could.


Management approaches to hypertension in autonomic failure.
Supine hypertension is a common finding in autonomic failure that can worsen orthostatic hypotension and predispose to end-organ damage. This review focuses on nonpharmacologic and pharmacologic approaches to manage hypertension in these patients in the face of disabling orthostatic hypotension. The hypertension of autonomic failure can be driven by sympathetic-dependent or independent mechanisms, contingent on the site of autonomic lesions. Management of supine hypertension should include simple nonpharmacologic approaches including avoiding the supine position during the daytime and sleeping in a head-up tilt position at night. Most patients, however, require pharmacologic treatment. Several antihypertensive therapies lower nighttime pressure in autonomic failure, but none improve nocturnal volume depletion or morning orthostatic tolerance. Regardless, treatment may still be beneficial in some patients but must be decided on an individual basis. Blood pressure monitoring is helpful in this regard, as well as titration of doses, as these patients are hypersensitive to depressor agents due to loss of baroreceptor reflexes. Autonomic failure provides a unique opportunity to study blood pressure regulation independent of autonomic influences. Understanding mechanisms driving supine hypertension will have important implications for the treatment of autonomic failure and will improve our knowledge of cardiovascular regulation in other populations, including essential hypertension and elderly hypertensive individuals with comorbid orthostatic hypotension.


Physical exercise and Parkinson's disease: influence on symptoms, disease course and prevention.
Parkinson's disease (PD) is a common, disabling, neurodegenerative condition, and the disease prevalence is expected to increase worldwide in the next few decades. Symptomatic therapy remains unsatisfactory, and greatly needed neuroprotective therapies have not been successfully developed so far. Physical exercise (PE) has been associated with a lower risk of developing a neurodegenerative disease. The literature has been searched, and results have been systematized and interpreted with regard to the effects of PE in PD. Published data show the following: 1) PE has been associated with a lower risk of developing PD; 2) PE has been shown to improve disease symptoms, mobility, balance, gait and quality of life (in this regard, walking training, tai-chi and tango dancing have demonstrated the highest level of evidence of efficacy); and 3) neuroprotective effects from PE could be expected in PD, although this has been suggested in animal studies only. Further research on this topic should be encouraged. Multidisciplinary cooperation between neurologists, sports physicians and researchers is paramount.


Integrating cultural diversity in patient education.
Diversity among clients in the American health care system is increasing as the population of the United States changes in composition. Health providers, educators, and supervisors are in unique positions to enhance patient education among members of diverse cultures by incorporating cultural research and health beliefs into patient and staff education. Using a culturally defined framework, health providers can more holistically assess the client and subsequently plan culturally appropriate care.


Association between peripheral blood markers and immune-related factors on tumor cells in patients with resected primary lung adenocarcinoma.
We sought to identify peripheral blood markers associated with two immune-related factors-programmed cell death-ligand-2 (PD-L2) and indoleamine 2,3-dioxygenase-1 (IDO1)-that are expressed on tumor cells in primary lung adenocarcinoma (AD) specimens. We randomly selected 448 patients (70%) from 640 consecutive patients with resected stage I-III primary lung AD, who had been treated at that point with surgery alone. Expression of PD-L2 and IDO1 in these patients was assessed by immunohistochemistry, and evaluated with respect to peripheral blood markers measured before surgery, including white blood cells, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count (AMC), absolute eosinophil count (AEC), serum C-reactive protein, and serum lactate dehydrogenase levels. Membrane PD-L2 expression and cytoplasmic IDO1 expression were defined by tumor proportion score (TPS); samples with TPS < 1% were considered negative. Logistic regression models were used to identify variables associated with the immune-related factors. Advanced stage (P = 0.0090), higher AMC (P = 0.0195), and higher AEC (P = 0.0015) were independent predictors of IDO1 expression. PD-L2 expression was not associated with any tested peripheral blood markers. Peripheral blood markers, especially AMC and AEC, could potential predict IDO1 expression in lung AD. This study should be replicated in another cohort; further efforts to explore other biomarkers that predict PD-L2 or IDO1 expression are also warranted.


Shared genetic architecture underlying sleep and weight in children.
Meta-analyses suggest shorter sleep as a risk factor for obesity in children. The prevailing hypothesis is that shorter sleep causes obesity by impacting homeostatic processes. Sleep duration and adiposity are both heritable, and the association may reflect shared genetic aetiology. We examined the association between a body mass index (BMI) genetic risk score (GRS) and objectively-measured total sleep time (TST) in a cohort of Norwegian children (enrolled at age four in 2007-2008) using cross-sectional data at age six. The analytical sample included 452 six-year old children with complete genotype and phenotype data. The outcome was actigraphic total sleep time (TST) measured at age six years. Genetic risk of obesity was inferred using a 32-single nucleotide polymorphism (SNP) weighted GRS of BMI. Covariates were BMI-Standard deviation scores (SDS) (which takes into account age and sex) and, in a sensitivity analysis socioeconomic status. Analyses consisted of Pearson's correlations and linear regressions. In our sample, 54% of participants were male; mean (SD) TST, age and BMI were 9.6 (0.8) hours, 6.0 (0.2) years and 15.3 (1.2) kg/m2, respectively. BMI and TST were not correlated, r = -0.003, p = 0.946. However, the BMI GRS was associated with TST after adjusting for BMI-SDS, standardised β = -0.11; 95% confidence interval (CI) = -0.22, -0.01. To our knowledge, this is the first study to establish a relationship between genetic risk of obesity and objective sleep duration in children. Findings suggest some shared genetic aetiology underlying these traits. Future research could identify the common biological pathways through which common genes predispose to both shorter sleep and increased risk of obesity.


Simulating confined particles with a flat density profile.
Particle simulations confined by sharp walls usually develop an oscillatory density profile. For some applications, most notably soft matter liquids, this behavior is often unrealistic and one expects a monotonic density climb instead. To reconcile simulations with experiments, we propose mirror-and-shift boundary conditions where each interface is mapped to a distant part of itself. The main result is that the particle density increases almost monotonically from zero to bulk, over a short distance of about one particle diameter. The method is applied to simulate a polymer brush in explicit solvent, grafted on a flat silicon substrate. The simulated density profile agrees favorably with neutron reflectometry measurements and self-consistent field theory results.


Replication origins: why do we need so many?
During the G1 phase of the cell cycle, replication origins are prepared to fire, a process that is referred to as origin licensing. It was often pondered what a cell's fate would be if not all of its replication origins were licensed and subsequently activated during S phase. One obvious prediction was that S phase would simply be prolonged. As it turns out, however, the consequences are much more complex. A short G1 phase enforced by premature entry into S phase, or other events that negatively affect origin licensing, will ultimately compromise the cell's ability to complete DNA replication before entering mitosis. As a result, the cell becomes genomically unstable when it attempts to repair unreplicated DNA during anaphase. Thus, the density of active replication origins in the chromosomes of eukaryotic cells determines S phase dynamics and chromosome stability during mitosis.


Redefining the pattern of age-prospective memory-paradox: new insights on age effects in lab-based, naturalistic, and self-assigned tasks.
Prospective memory (PM) involves remembering intended actions in the future, such as posting a letter when seeing a post box (event-based PM) or making a phone call at 2:00 pm (time-based PM). Studies on aging and PM have often reported negative age effects in the laboratory, but positive age effects in naturalistic tasks outside the laboratory (the so-called age-PM-paradox). The present study re-examined this pattern of the paradox by studying, for the first time, age differences in time- and event-based PM in lab-based, experimenter-generated naturalistic and self-assigned real-life PM tasks within the same sample of young and older adults. Results showed that differential age effects in and outside the laboratory were qualified by the type of PM cue. While age-related deficits were obtained for laboratory event-based tasks, no age effect was obtained for naturalistic event-based PM. Age benefits in the field were only observed for naturalistic time-based tasks, but not for participants' own self-assigned time-based tasks. These findings indicate that the age benefits for naturalistic PM tasks may have been overestimated due to the dominant use of experimenter-generated naturalistic time-based PM tasks in previous studies. Therefore, the precise pattern of the age-PM-paradox may need redefining as mostly consisting of negative age effects in lab-based PM tasks and mostly the absence of negative age effects (rather than age benefits) in naturalistic and self-assigned tasks outside the laboratory.


Impact of Silanization Parameters and Antibody Immobilization Strategy on Binding Capacity of Photonic Ring Resonators.
Ring resonator-based biosensors have found widespread application as the transducing principle in "lab-on-a-chip" platforms due to their sensitivity, small size and support for multiplexed sensing. Their sensitivity is, however, not inherently selective towards biomarkers, and surface functionalization of the sensors is key in transforming the sensitivity to be specific for a particular biomarker. There is currently no consensus on process parameters for optimized functionalization of these sensors. Moreover, the procedures are typically optimized on flat silicon oxide substrates as test systems prior to applying the procedure to the actual sensor. Here we present what is, to our knowledge, the first comparison of optimization of silanization on flat silicon oxide substrates to results of protein capture on sensors where all parameters of two conjugation protocols are tested on both platforms. The conjugation protocols differed in the chosen silanization solvents and protein immobilization strategy. The data show that selection of acetic acid as the solvent in the silanization step generally yields a higher protein binding capacity for C-reactive protein (CRP) onto anti-CRP functionalized ring resonator sensors than using ethanol as the solvent. Furthermore, using the BS3 linker resulted in more consistent protein binding capacity across the silanization parameters tested. Overall, the data indicate that selection of parameters in the silanization and immobilization protocols harbor potential for improved biosensor binding capacity and should therefore be included as an essential part of the biosensor development process.


Epidemiologic methods for prospective assessment of menstrual cycle and reproductive characteristics in female semiconductor workers.
Methods were developed to assess potential adverse effects of semiconductor fabrication work in a prospective study of reproductive health. All women aged 18-44 years who worked in seven silicon-wafer fabrication sites in five companies and a frequency-matched sample of women in nonfabrication jobs were included. Among 3,480 selected for screening, 2,639 (75%) completed a self-administered questionnaire to identify women at risk of pregnancy. Among the 739 (28%) eligible women, 481 (65%) completed baseline interviews and 402 (83.6%) completed at least one menstrual cycle of follow-up by providing daily diaries and daily urine samples. Menstrual cycle characteristics were assessed from questionnaires and diaries. Urine samples were assayed for reproductive hormones to identify conceptions. The usual cycle length recalled at baseline was 28 days. The mean cycle length (MCL) recorded in diaries was 29 days, with greater dispersion than at baseline. The median of the MCL from diary data was 28 days for women reporting regular cycles at baseline but 34 days for women reporting irregular cycles at baseline, and the median standard deviation in cycle length per woman was 2.5 days and 7.5 days, respectively. The prospective method, while expensive and labor intensive, showed good compliance. Nevertheless, recall also provided reasonably accurate estimates and distinguished women with regular and irregular cycles.


Stem alignment with short tapered-wedge cementless stems affects bone mineral density continuously for at least 5 years after primary total hip arthroplasty.
This study aimed to assess the relationship between the three-dimensional (3D) alignment of short tapered-wedge cementless stems and bone mineral density (BMD) changes in patients followed up for 5 years after total hip arthroplasty (THA). We retrospectively analysed the hips of 52 patients who underwent THA using short tapered-wedge cementless stems at our institution from 2013 to 2016 with complete 5-year follow-up data. We evaluated the relationship between stem alignment, measured using a 3D-templating software, and BMD changes in the 7 Gruen zones. After 1 year, significant negative correlations between varus insertion and a decrease in BMD in zone 7 and between flexed insertion and decreases in BMD in zones 3 and 4 were noted. After 5 years, significant negative correlations between varus insertion and a decrease in BMD in zone 7 and between flexed insertion and decreases in BMD zones 2, 3, and 4 were observed. With increased amounts of varus/flexion stem alignment, the amount of BMD loss decreased. There was no correlation between anteverted stem insertion and changes in BMD levels. Our data showed that stem alignment affects BMD based on 5-year follow-up data after surgery. Careful observation is necessary, especially when using short tapered-wedge cementless stems, as stem alignment may affect changes in BMD levels more than 5 years after surgery.


Trends in ureteropelvic junction obstruction management among urologists in the United States.
To determine current practice patterns in the surgical treatment of ureteropelvic junction obstruction (UPJO) among urologists in the United States. Using the American Urological Association directory, an electronic mail survey regarding the surgical management of UPJO was sent to 1040 urologists in the United States with an electronic mail address listed in the roster. The response rate was 37.6%. Of the respondents, 67.4% were in community practice and 32.6% in academic practice. Nearly 53% of the respondents would perform a workup for a crossing vessel before definitive therapy; if no crossing vessel was found, 43.5% would consider Acucise endopyelotomy as the first-line procedure. However, if a crossing vessel was found, 57.4% would perform open pyeloplasty and 34.3% would choose laparoscopic pyeloplasty as their first-line procedure. If pyeloplasty was chosen, community urologists preferred open pyeloplasty (77.6%), and academic urologists preferred laparoscopic pyeloplasty (66.9%). The surgeon's training and experience was the most influential factor in choosing between laparoscopic and open pyeloplasty. If the patient had a failed endopyelotomy in the past, most respondents (90.8%) would perform pyeloplasty for definitive treatment of the UPJO. Demonstration of a crossing vessel remains an important factor in determining the course of management of a UPJO. During the past 5 years, a growing number of urologists in both academic and nonacademic practices have been performing laparoscopic pyeloplasty for the management of UPJO in adults. Several factors, especially the surgeon's training, have an impact on the choice of procedure. Open pyeloplasty is still performed by a significant number of urologists. These data may be useful in designing physician education programs and/or future investigations to help define standard treatment practices for UPJO.


Therapist responsiveness and patient engagement in therapy.
This study tests the hypothesis that therapist responsiveness in the first two sessions of therapy relates to three measures of early patient engagement in treatment. Using videotapes and data from the NIMH Treatment of Depression Collaborative Research Program (TDCRP), an instrument was developed to measure therapist responsiveness in the first two sessions of Cognitive Behavior Therapy and Interpersonal Psychotherapy. A factor measuring positive therapeutic atmosphere, as well as a global item of therapist responsiveness, predicted both the patient's positive perception of the therapeutic relationship after the second session and the patient's remaining in therapy for more than four sessions. A negative therapist behavior factor also predicted early termination. Factors measuring therapist attentiveness and early empathic responding did not predict the engagement variables.


Modulations of myelopoiesis in vivo by chemically pure preparations of cell wall components from gram-negative bacteria: effects at different stages.
Modulation of myelopoiesis by chemically pure preparations of different cell wall components from gram-negative bacteria was investigated in vivo. The effects of lipid A, outer membrane lipoprotein, and murein were evaluated at several distinct stages: induction of colony-stimulating activity (CSA) in the serum, increase in the number of committed splenic precursor cells (CFU-C) forming granulocyte-macrophage colonies in vitro, and triggering into the cell cycle of noncommitted hemopoietic stem cells (CFU-S) from bone marrow. The results reveal different patterns of activity of the bacterial cell wall components (BCWC) tested. (i) In C57Bl/6 mice and C3H/Bom mice, all three preparations were potent inducers of CSA. In C3H/HeJ mice, CSA was only induced by lipoprotein and murein and not by lipid A. After injection of lipid A or lipoprotein, but not murein, the number of CFU-C in spleens of C57Bl/6 mice was increased up to 100-fold. In C3H/Bom and C3H/HeJ mice, not only murein but also lipoprotein were much less potent in this respect. (iii) In C57Bl/6 mice, both lipid A and lipoprotein, but not murein, were capable of inducing the proliferation of CFU-S, as demonstrated by a hot thymidine cytocide technique. Thus, induction of CSA and changes in the pool size of splenic CFU-C after administration of BCWC may be unrelated events. On the other hand, the increase of CFU-C might reflect the mitogenicity of BCWC for CFU-S.


Modeling the effects of electrical conductivity of the head on the induced electric field in the brain during magnetic stimulation.
The objective of this document is to quantify the effect of changing conductivity within the brain in transcranial magnetic stimulation. Extreme examples of white and grey matter distributions as well as cerebral spinal fluid are analyzed with numerical boundary element methods to show that the induced E fields for these various distributions vary little from the homogeneous case. Models representative of the brain that demarcate regions of white matter and grey matter add an unnecessary level of complexity to the design and analysis of magnetic stimulators. The induced E field varies little between a precise model with exact placement of white and grey matter from that of its homogeneous counterpart. The E field will increase in white matter, and decrease in grey, but the variation is small. The contour integral of the E field around a closed path is dictated by the flux change through that contour. The maximum value of the variation of the electric field between a fully homogeneous medium, and one filled with different conductivity media is 1/2 the conductivity ratio of the media involved. Neuronal stimulation is more likely at the interface between dissimilar mediums, the greatest being between white matter and cerebral spinal fluid. The interface location where no normal electric field exists will witness a localized electric field 51% greater than the homogeneous E field on the white matter side of that interface. White-grey matter interfaces will have a maximum localized increase in the E field 22.9% greater than the homogeneous case. Variations in neural intracellular potential during a magnetic stimulation pulse will be small among patients. The most efficient modeling will follow by assuming the medium homogeneous, and noting that perturbations from this result will exist.


Temporal and tight hepatitis C virus gene activation in cultured human hepatoma cells mediated by a cell-permeable Cre recombinase.
Conditional gene expression has greatly facilitated the examination of the functions of particular gene products. Using the Cre/lox P switching expression system, we plan to develop efficient conditional transgene activation of hepatitis C virus core protein (HCV-C) cDNA (nucleotide 342-914) in the transgenic mice to overcome "immune tolerance" formed during the embryonic period and "immune escape" against hepatitis virus antigen in our project. To use this system in vivo, the dormant transgenic construct, i.e., pApoE-SCS-EGFP-HCV-C, was generated using techniques of standard molecular biology. The liverspecific human apoE promoter was here used to target expression of genes of interest (EGFP and HCV-C) to murine liver. Prior to generating the transgenic mice, the availability of Cre/lox P system and construct functionality were successfully verified by a cell-free recombination system and via checking the expression of EGFP and HCV-C in the human hepatoma cells at the mRNA and protein levels. These results suggest that the Cre/lox P system could tightly control expression of EGFP and HCV-C in vitro, which laid a solid foundation to conditionally activate expression of target gene(s) in transgenic mice by Cre-mediated site-specific recombination.


Unravelling Motor Learning Processes in Theater Performers.
Theater performers, more than common actors, experience high physical loadings. This study aimed at analyzing the motor behavior of novice performers (dancers/actors who were introduced to the acting method of Jan Fabre) by investigating the kinematics of a physical acting exercise in a prospective study. Two measurement sessions were organized: before and after the novice performers (N = 13) took part in seven workshops. Total body kinematics were registered using a three-dimensional motion capture system. Using a principal component analysis, six factors were disseminated out of 30 kinematic parameters: Pelvic Motion, Speed of Progression, Lower Limb Position, Foot Motion, Lower Limb Motion, and Trunk Posture. Although no main effect of training was found for any of the factors (.429 < p < .964), Trunk Posture showed a higher consistency after the workshops. This study succeeded in providing insights in the motor behavior of theater performers and revealed recognizable features of motor learning.


[Effect of resveratrol on cognitive functions in older adults: a systematic review and meta-analysis].
Introduction: resveratrol has multiple beneficial effects on different body systems, including the central nervous system, however, the results reported on the effect on cognitive functions in older adults are inconsistent. Therefore, the purpose of this systematic review is to present a synthesis of knowledge about the effect of resveratrol on cognitive functions in older adults. Method: a systematic review was carried out according to the PRISMA-2009 criteria. The search for articles was carried out until September 7, 2021 in PubMed, Scopus, Web of Science, PsycINFO, SciELO, and TESIUNAM. The outcome variables were delayed, immediate, and working memory, and processing speed. The standardized mean difference (SMD) was estimated to assess the effect. Results: one thousand sixty-five studies were found, of which six met the eligibility criteria for the systematic review and meta-analysis. No significant effect was found on delayed memory (SMD = 0.69, 95 % CI: 0.85-2.23, p = 0.38), immediate memory (SMD = 0.56, 95 % CI: -0.20-1.31, p = 0.15), working memory (SMD = -0.21, 95 % CI: -0.74-0.32, p = 0.43) and processing speed (SMD = 0.25, 95 % CI: -0.58-1.07, p = 0.55). Conclusion: our results suggest that resveratrol does not have an effect on cognitive functions in older adults, however, it is necessary to carry out more studies with different doses, type of nutraceutical formulation and treatment time.


Use of inhaled iloprost in an infant with bronchopulmonary dysplasia and pulmonary artery hypertension.
Pulmonary artery hypertension is a common cardiovascular complication in preterm infants with bronchopulmonary dysplasia which is associated with increased morbidity and mortality. Inhaled iloprost is used as a therapeutic option in pulmonary hypertension, especially in adults. There have been but a few reports on the use of iloprost for neonates and infants. We report the case of a 5 month-old-male infant who received neonatal intensive care for 4 months due to respiratory distress syndrome and prematurity, during which he developed bronchopulmonary dysplasia. Echocardiography showed severe pulmonary hypertension. The initial treatment included respiratory support with high frequency oscillatory ventilation (HFOV); however, his clinical condition did not improve. Inhaled iloprost with sildenafil, an oral phosphodiesterase-5 inhibitor, was thus used. With the administration of iloprost and sildenafil, his condition improved and he was weaned from oxygen. Our clinical experience suggests that iloprost is a promising therapy for pulmonary hypertension, especially when inhaled nitric oxide is unavailable.


Ultrasharp h-BN Nanocones and the Origin of Their High Mechanical Stiffness and Large Dipole Moment.
We report on experimental synthesis and theoretical studies of ultrasharp BN-nanocones. Using scanning and transmission electron microscopy, the cone-like morphology of synthesized products was confirmed. Theoretical analysis of the dipole moment nature in h-BN nanocones reveals that the moment has contributions from the polarity of B-N bonds and electronic flexoelectric effect associated with a curved h-BN lattice. The latter phenomenon is predicted on the basis of the extension of the theory of flexoelectric effects in the h-BN lattice through establishing universality of the linear dependence of flexoelectric dipole moments on local curvature in various nano- h-BN networks (nanotubes and fullerenes). Our study of the atomic structure response and its polarization under deformation of nanocones with different apex angles shows the advantageous properties of cones with the smallest angles.


Optimising streptozotocin dosing to minimise renal toxicity and impairment of stomach emptying in male 129/Sv mice.
The streptozotocin (STZ)-induced diabetic mouse model has been extensively used as a model for diabetes and diabetic nephropathy, but it is still influenced by many off-target toxic effects and large variation in diabetes induction. Therefore, the aim of this study was to compare different STZ dosing regimens to optimise animal welfare and minimise unwanted effects of STZ measured by acute renal toxicity, impairment of stomach emptying and weight loss. Male 129/Sv mice were injected with 1 × 50, 1 × 100, 1 × 125, 1 × 150, 1 × 200, 5 × 50, 2 × 100 and 2 × 125 mg/kg STZ or vehicle and euthanized 24 hours after the last injection. All STZ doses were found to induce significant enlargement of the stomach. All multiple doses of STZ increased the albumin:creatinine ratio significantly, and immunohistochemical staining of KIM-1 and Ki-67 was increased by 5 × 50 and 2 × 100 mg/kg STZ. Renal gene expression of Cdkn1a, KIM-1, NGAL and MCP-1 was increased by most of the STZ doses. No difference was found between the double intermediate dose of 2 × 100 mg/kg and the multiple low dose of 5 × 50 mg/kg regarding either stomach enlargement or kidney injury. However, the reduced fasting periods and injections in the 2 × 100 mg/kg STZ group could have lowered the impact on the general condition measured as change in body weight. This shows that the double intermediate dose is a good alternative to the recommended multiple low dose for diabetes induction in these mice. The STZ-induced mouse model has again proven to be a model with large variations affecting both animal welfare and model robustness.


A correlative neurobehavioral-morphological model of acrylamide neuropathy.
Sprague-Dawley rats were intoxicated with 50 mg/kg/day of acrylamide monomer given by daily intraperitoneal injections. The progression of disease was studied in intoxicated animals and unintoxicated controls using a functionally-oriented behavioral battery focusing on sensory-motor behaviors. Correlative morphological examination focused on neuronal cell bodies and nerve fibers at early time points. The results were compared with previous results from animals intoxicated with another prototype neurotoxin, 2,5-hexanedione (2,5-HD), and studied with the identical behavioral battery. With both toxins behavioral changes slightly preceded observed structural damage at the sites examined. Broadly similar behavioral patterns occurred with both toxins, i.e., more-complex functions showed the earliest deficits; hindlimb functions deteriorated before forelimb functions; grasp reflex deteriorated before place reflex. This pattern correlates with the established pattern of selective vulnerability of long and large axons. Although the patterns of behavioral toxicities were broadly similar, the functionally-oriented battery succeeded in detecting differences which corresponded with established neuropathological subtleties in the two dying-back processes. We discuss potential difficulties in correlating behavioral/clinical results with morphological data but stress the importance of such correlations.


[Surveillance of case findings of pulmonary tuberculosis].
As a result of the changing epidemic situation of tuberculosis, collective chest fluoroscopy as a method to detect pulmonary tuberculosis is becoming increasingly inadequate, and "symptom-dependent case finding" should be taken as the chief means for detection of the disease in our district. However, in collective units with high detected rates and in populations of high prevalence or in combination with general survey of lung cancer, regular fluoroscopic chest examination is an important route to discover patients with pulmonary tuberculosis.


Connexin-43 gap junctions are involved in multiconnexin-expressing stromal support of hemopoietic progenitors and stem cells.
Gap junctions (GJs) provide for a unique system of intercellular communication (IC) allowing rapid transport of small molecules from cell to cell. GJs are formed by a large family of proteins named connexins (Cxs). Cx43 has been considered as the predominantly expressed Cx by hematopoietic-supporting stroma. To investigate the role of the Cx family in hemopoiesis, we analyzed the expression of 11 different Cx species in different stromal cell lines derived from murine bone marrow (BM) or fetal liver (FL). We found that up to 5 Cxs are expressed in FL stromal cells (Cx43, Cx45, Cx30.3, Cx31, and Cx31.1), whereas only Cx43, Cx45, and Cx31 were clearly detectable in BM stromal cells. In vivo, the Cx43-deficient 14.5- to 15-day FL cobblestone area-forming cells (CAFC)-week 1-4 and colony-forming unit contents were 26%-38% and 39%-47% lower than in their wild-type counterparts, respectively. The reintroduction of the Cx43 gene into Cx43-deficient FL stromal cells was able to restore their diminished IC to the level of the wild-type FL stromal cells. In addition, these Cx43-reintroduced stromal cells showed an increased support ability (3.7-fold) for CAFC-week 1 in normal mouse BM and 5-fold higher supportive ability for CAFC-week 4 in 5-fluorouracil-treated BM cells as compared with Cx43-deficient FL stromal cells. These findings suggest that stromal Cx43-mediated IC, although not responsible for all GJ-mediated IC of stromal cells, plays a role in the supportive ability for hemopoietic progenitors and stem cells. (Blood. 2000;96:498-505)


Triiodothyroacetic Acid Cross-Reacts With Measurement of Triiodothyronine (T3) on Various Immunoassay Platforms.
Thyroid hormone analog 3,5,3'-triiodothyroacetic acid (TRIAC) is effective in reducing the hypermetabolism in monocarboxylate transporter 8 (MCT8)-deficient individuals. Because of the structural similarity between TRIAC and 3,3',5'-triiodothyronine (T3), we sought to investigate the degree of cross-reactivity of TRIAC with various commercially available total and free T3 assays. Varying concentrations (50-1,000 ng/dL) of TRIAC (Sigma Aldrich) were added to pooled serum and assayed for total T3 (TT3) and free T3 (FT3) on the following platforms: e602 (Roche Diagnostics), Architect (Abbott Diagnostics), Centaur (Siemens Healthcare Diagnostics), IMMULITE (Siemens Healthcare Diagnostics), DxI (Beckman Coulter), and Vitros (Ortho Clinical Diagnostics). TT3 competition assay with TRIAC was performed by adding increasing amounts of T3 to pooled serum samples that contained a constant concentration of TRIAC (250 ng/dL). Significant overestimation of TT3 and FT3 assays were observed across all platforms corresponding to increasing concentrations of TRIAC. The TRIAC effect at 250 ng/dL showed a constant interference of approximately 190 ng/dL TT3. All commercial TT3 and FT3 assays tested in this work cross-react significantly with TRIAC. Therefore, patients undergoing TRIAC therapy should have T3 hormone response monitored using alternative nonimmunoassay-based methods to avoid misinterpretation of thyroid function profiles.


Impact of curcumin on ferroptosis-related genes in colorectal cancer: Insights from in-silico and in-vitro studies.
Colorectal cancer (CRC) is responsible for a significant number of cancer-related fatalities worldwide. Researchers are investigating the therapeutic potential of ferroptosis, a type of iron-dependent controlled cell death, in the context of CRC. Curcumin, a natural compound found in turmeric, exhibits anticancer properties. This study explores the effects of curcumin on genes related to ferroptosis (FRGs) in CRC. To gather CRC data, we used the Gene Expression Profiling Interactive Analysis (GEPIA) and Gene Expression Omnibus (GEO) databases, while FRGs were obtained from the FerrDb database and PubMed. We identified 739 CRC differentially expressed genes (DEGs) in CRC and discovered 39 genes that were common genes between FRGs and CRC DEGs. The DEGs related to ferroptosis were enriched with various biological processes and molecular functions, including the regulation of signal transduction and glucose metabolism. Using the Drug Gene Interaction Database (DGIdb), we predicted drugs targeting CRC-DEGs and identified 17 potential drug targets. Additionally, we identified eight essential proteins related to ferroptosis in CRC, including MYC, IL1B, and SLC1A5. Survival analysis revealed that alterations in gene expression of CDC25A, DDR2, FABP4, IL1B, SNCA, and TFAM were associated with prognosis in CRC patients. In SW480 human CRC cells, treatment with curcumin decreased the expression of MYC, IL1B, and EZH2 mRNA, while simultaneously increasing the expression of SLCA5 and CAV1. The findings of this study suggest that curcumin could regulate FRGs in CRC and have the potential to be utilized as a therapeutic agent for treating CRC.


Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse.
In the mouse olfactory system, each olfactory sensory neuron (OSN) expresses only one odorant receptor (OR) gene in a monoallelic and mutually exclusive manner. Such expression forms the genetic basis for OR-instructed axonal projection of OSNs to the olfactory bulb of the brain during development. Here, we identify an upstream cis-acting DNA region that activates the OR gene cluster in mouse and allows the expression of only one OR gene within the cluster. Deletion of the coding region of the expressed OR gene or a naturally occurring frame-shift mutation allows a second OR gene to be expressed. We propose that stochastic activation of only one OR gene within the cluster and negative feedback regulation by that OR gene product are necessary to ensure the one receptor-one neuron rule.


Hepatitis B and liver transplantation: 2008 update.
The ultimate goal of treatment is suppression of viral replication to undetectable HBV-DNA levels prior to and after liver transplantation (LT) to prevent infection of the newly transplanted liver. Most published data are available from therapy with lamivudine (LAM) in pre- and post-transplant HBV patients. Add-on therapy with adefovir dipivoxil (ADV) in pre-transplant LAM-resistant patients has been shown to represent an effective antiviral strategy leading to hepatic recompensation in many cases and, eventually, removal from the waiting list. Newer nucleos(t)ide analogues such as entecavir, tenofovir and telbivudine have shown lower resistance rates than LAM and more antiviral potency in studies in the non-transplant setting. Combined hepatitis B immune globulin (HBIG) and nucleos(t)ide analogue therapy have been widely adopted as the most effective treatment strategy against recurrent HBV disease after LT. Many programs have evaluated lower doses or a shorter duration of HBIG and intramuscular versus intravenous routes of administration. Active immunisation using recombinant HBV vaccines, including the S, pre-S1 and pre-S2 regions, and those with immunostimulatory adjuvants, seem to be more immunogenic than the currently available vaccines and have been used in studies to replace HBIG. Furthermore, it has been shown that immune memory against HBV can be adoptively transferred from organ donors to transplant recipients. Nucleos(t)ide analogue combination therapies might provide an alternative to the current treatment paradigm with costly HBIG; however, experience with this new treatment regimen is very limited and controlled clinical studies are urgently warranted to investigate its safety and efficacy and to determine which nucleos(t)ide analogue combinations will be the most promising in the long term after LT.


A biomechanical mathematical model for the collagen bundle distribution-dependent contraction and subsequent retraction of healing dermal wounds.
A continuum hypothesis-based, biomechanical model is presented for the simulation of the collagen bundle distribution-dependent contraction and subsequent retraction of healing dermal wounds that cover a large surface area. Since wound contraction mainly takes place in the dermal layer of the skin, solely a portion of this layer is included explicitly into the model. This portion of dermal layer is modeled as a heterogeneous, orthotropic continuous solid with bulk mechanical properties that are locally dependent on both the local concentration and the local geometrical arrangement of the collagen bundles. With respect to the dynamic regulation of the geometrical arrangement of the collagen bundles, it is assumed that a portion of the collagen molecules are deposited and reoriented in the direction of movement of (myo)fibroblasts. The remainder of the newly secreted collagen molecules are deposited by ratio in the direction of the present collagen bundles. Simulation results show that the distribution of the collagen bundles influences the evolution over time of both the shape of the wounded area and the degree of overall contraction of the wounded area. Interestingly, these effects are solely a consequence of alterations in the initial overall distribution of the collagen bundles, and not a consequence of alterations in the evolution over time of the different cell densities and concentrations of the modeled constituents. In accordance with experimental observations, simulation results show furthermore that ultimately the majority of the collagen molecules ends up permanently oriented toward the center of the wound and in the plane that runs parallel to the surface of the skin.


The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients.
BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.


Hepatic lesions associated with intrahepatic arterioportal fistulae in dogs.
Seven cases of hepatic arterioportal fistulae in young dogs (mean age 6 months) are described. All cases were presumed to be congenital in origin. The onset of clinical signs, which frequently included gastrointestinal and neurological disturbances, was usually sudden. All dogs had clinical evidence of portal hypertension in the form of ascites, and all developed multiple extrahepatic portacaval venous shunts consequential to portal hypertension. The neurological disturbances were likely the result of portacaval shunting. The arterial and venous vessels involved in the fistulae had markedly altered wall structure. Hepatic regions adjacent to the fistulae frequently evidenced marked bile duct proliferation. Hepatic parenchymal atrophy, relative collapse of distributing portal veins, dilatation of hepatic arterial branches and proliferation of hepatic arterioles were seen throughout the liver; these changes closely resembled those present with portacaval shunting in the absence of hepatic arterioportal fistulae. The importance of recognizing that hepatic arterioportal fistulae and multiple extrahepatic portacaval shunts usually coexist and separately influence the morphological appearance of the liver is stressed.


Functional changes in astroglial cells in epilepsy.
Epilepsy comprises a group of disorders characterized by the periodic occurrence of seizures, and pathologic specimens from patients with temporal lobe epilepsy demonstrate marked reactive gliosis. Since recent studies have implicated glial cells in novel physiological roles in the CNS, such as modulation of synaptic transmission, it is plausible that glial cells may have a functional role in the hyperexcitability characteristic of epilepsy. Indeed, alterations in distinct astrocyte membrane channels, receptors and transporters have all been associated with the epileptic state. This review integrates the current evidence regarding astroglial dysfunction in epilepsy and the potential underlying mechanisms of hyperexcitability. Functional understanding of the cellular and molecular alterations of astroglia-dependent hyperexcitability will help to clarify the physiological role of astrocytes in neural function as well as lead to the identification of novel therapeutic targets.


Single-cell transcriptomic analysis of SARS-CoV-2 reactive CD4 + T cells.
The contribution of CD4 + T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4 + T cells from 32 COVID-19 patients. In patients with severe disease compared to mild disease, we found increased proportions of cytotoxic follicular helper (T FH ) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2 reactive regulatory T cells. Importantly, the CD4-CTLs were highly enriched for the expression of transcripts encoding chemokines that are involved in the recruitment of myeloid cells and dendritic cells to the sites of viral infection. Polyfunctional T helper (T H )1 cells and T H 17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4 + T cells compared to influenza-reactive CD4 + T cells. Together, our analyses provide so far unprecedented insights into the gene expression patterns of SARS-CoV-2 reactive CD4 + T cells in distinct disease severities.


A rapid, small scale method for characterization of plasmid insertions in the Dictyostelium genome.
A rapid, simple method for characterization of plasmid insertions in the Dictyostelium discoideum genome was developed. It is based on the capability of linear plasmid multimers in the insertions to recircularize efficiently in Escherichia coli cells. This recombinational recircularization of plasmid multimers provides a highly sensitive and reliable tool for determining whether individual Dictyostelium transformants resulted from restriction enzyme-mediated integration (REMI) or from recombinational integration of plasmid (RIP). The method also reveals any rearrangements in RIP insertions and provides an estimate of the vector copy number in any particular transformant.


Coordination of the contractile activity of bile canaliculi. Evidence from calcium microinjection of triplet hepatocytes.
The discovery that bile canaliculi are capable of spontaneous contractile activity has led to their use in the investigation of the physiology of the liver cell. The contraction of a bile canaliculus is dependent on the network of actin, which is found in the pericanalicular region of the hepatocyte, and agents that inhibit actin filaments interfere with canalicular contraction. Injection of calcium directly into the cytoplasm of one hepatocyte of a cell pair results in contraction. Injection of calcium directly into the cytoplasm of one hepatocyte of a cell pair results in contraction of the canaliculus. To determine whether the contractile activity of adjacent bile canaliculi was coordinated, calcium was injected into one cell of a group of three hepatocytes that formed two neighboring bile canaliculi. Calcium microinjection resulted in contraction of the bile canaliculus contiguous with the microinjected cell and was followed by a contraction of the second, adjacent canaliculus. These secondary contractions occurred after an interval of approximately 45 seconds. The finding that bile canalicular contractions are coordinated with contractions occurring in a sequential fashion supports the hypothesis that, within the liver lobule, transport of bile within the canalicular network results from the coordinated contractions of the canaliculi.


Pyrogenic synthetic amorphous silica (NM-203): Genotoxicity in rats following sub-chronic oral exposure.
The genotoxicity of nano-structured synthetic amorphous silica (SAS), a common food additive, was investigated in vivo in rats. A 90-day oral toxicity study was performed according to OECD test guideline 408 and the genotoxicity of pyrogenic SAS nanomaterial NM-203 was assessed in several organs, using complementary tests. Adult Sprague-Dawley rats of both sexes were treated orally for 90 days with 0, 2, 5, 10, 20, or 50 mg SAS/kg bw per day. Dose levels were selected to approximate expected human dietary exposures to SAS. DNA strand breaks were evaluated by the comet assay in blood, bone marrow, liver, and spleen according to OECD test guideline 489; mutations induced in bone marrow precursors of erythrocytes were assessed by the Pig-a assay and chromosome/ genome damage by the micronucleus assay in blood (OECD test guideline 474) and colon. No treatment-related increases of gene (Pig-a) or chromosome/genome (micronucleus) mutations were detected in the blood. The percentage of micronucleated cells was not increased in the colon of treated rats. Among the organs analyzed by the comet assay, the spleen was the only target showing a weak but biologically relevant genotoxic effect.


Giant adrenal myelolipoma associated with 21-hydroxylase deficiency: unusual association mimicking an androgen-secreting adrenocortical carcinoma.
The objective of this study was to describe a case of giant myelolipoma associated with undiagnosed congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency. Five seven year-old male patient referred with abdominal ultrasound revealing a left adrenal mass. Biochemical investigation revealed hyperandrogenism and imaging exams characterized a large heterogeneous left adrenal mass with interweaving free fat tissue, compatible with the diagnosis of myelolipoma, and a 1.5 cm nodule in the right adrenal gland. Biochemical correlation has brought concerns about differential diagnosis with adrenocortical carcinoma, and surgical excision of the left adrenal mass was indicated. Anatomopathologic findings revealed a myelolipoma and multinodular hyperplasic adrenocortex. Further investigation resulted in the diagnosis of CAH due to 21OH deficiency. Concluded that CAH has been shown to be associated with adrenocortical tumors. Although rare, myelolipoma associated with CAH should be included in the differential diagnosis of adrenal gland masses. Moreover, CAH should always be ruled out in incidentally detected adrenal masses to avoid unnecessary surgical procedures.


Chronic active liver disease with common variable hypogammaglobulinemia.
Progressive liver injury in chronic active liver disease is usually associated with elevation of serum immunoglobulin levels. However, the role of immunoglobulins in the pathogenesis of this disease is still obscure. We report here the case of a 41-year-old man with hypogammaglobulinemia since at least 1964 in whom chronic active liver disease later developed. From 1954 he had had frequent respiratory tract infections, and these continued, along with diarrhea, despite regular gamma-globulin therapy. Studies in 1969 showed absent serum IgA and IgM and an abnormally low level of IgG. In 1974, liver enzyme abnormalities were recorded and a diagnosis of chronic active liver disease was made. A liver biopsy showed cirrhosis with active hepatitis. Lymphocyte function studies revealed that the T cells suppressed B-cell maturation and production of immunoglobulins. He was treated with azathioprine and prednisone, and this therapy has been associated with a decrease in both the elevation in liver enzymes and the frequency of infections. This case suggests that liver cell injury in chronic active liver disease is independent of the elevation of immunoglobulins and that immunosuppressive therapy may be well tolerated by patients with hypogammaglobulinemia.


Enuresis in Children: Common Questions and Answers.
Nocturnal enuresis is defined as nighttime urinary incontinence occurring at least twice weekly in children five years and older. Approximately 14% of children have spontaneous resolution each year without treatment. Subtypes of nocturnal enuresis include nonmonosymptomatic enuresis and primary and secondary monosymptomatic nocturnal enuresis. Monosymptomatic enuresis is characterized by nighttime bedwetting without daytime urinary incontinence. Pathophysiology of primary monosymptomatic nocturnal enuresis may be due to sleep arousal disorder, overproduction of urine, small bladder storage capacity, or detrusor overactivity. Children with nonmonosymptomatic enuresis have daytime and nighttime symptoms resulting from a variety of underlying etiologies. An in-depth history is an integral component of the initial evaluation. For all types of enuresis, a comprehensive physical examination and urinalysis should be performed to help identify the cause. It is important to reiterate to the family that bedwetting is not the child's fault. Treatment should begin with behavioral modification, which then progresses to enuresis alarm therapy and oral desmopressin. Enuresis alarm therapy is more likely to produce long-term success; desmopressin yields earlier symptom improvement. Treatment of secondary monosymptomatic nocturnal enuresis and nonmonosymptomatic enuresis should primarily focus on the underlying etiology. Pediatric urology referral should be made for refractory cases in which underlying genitourinary anomalies or neurologic disorders are more likely. .


Immunological reactions to neural grafts in the central nervous system.
Immunological rejection is a lasting, although highly variable, threat to allo- and xenogeneic neural tissue grafted to the CNS of rodents, monkeys and man. One major determinant for rejection of intracerebral CNS grafts appears to be induction of major histocompatibility complex (MHC) antigens on the donor CNS cells. We have previously examined the cellular immune response against neural mouse xenografts undergoing rejection in the adult rat brain. In this study we focus on the astro- and microglial reactions within and around the graft, and the potential of individual host rat and donor mouse brain cells to express MHC antigens. Previous light microscopical observations of expression of rat MHC antigen class I by endothelial cells, microglial cells, and invading leukocytes were extended to the ultrastructural level and found to include a few astrocytes. Rat and mouse MHC antigen class II was only detected on leukocytes and activated microglial cells. The findings imply that within grafts of brain or spinal cord tissue donor astrocytes, microglial cells and endothelial cells can be induced to act as target cells for class I specific host T cytotoxic cells, while only (graft and host) microglial cells can be induced to express MHC antigen class II and present antigen to sensitized (and possibly also resting) host T helper cells.


Blockade of angiotensin II type 2 receptor by PD123319 inhibits osteogenic differentiation of human mesenchymal stem cells via inhibition of extracellular signal-regulated kinase signaling.
Recent evidence indicates that the vasculature contains mesenchymal stem cells (MSCs). We hypothesized that angiotensin II (Ang II) type 2 receptors (AT2Rs) play a role in the osteogenesis of MSCs and may have a role in vascular calcification. Human MSCs were differentiated into osteoblasts. Expression of AT2R was significantly increased during osteogenesis, whereas the expression of Ang II type 1 receptors was not significantly changed. Incubation with the AT2R blocker PD123319 with or without Ang II significantly inhibited calcium deposition, whereas type 1 receptor blocker valsartan had no significant effect. PD123319 inhibited extracellular signal-regulated kinase (ERK) phosphorylation in the osteogenic process, whereas valsartan had no effect. Furthermore, PD123319 combined with Ang II also inhibited acute ERK phosphorylation in MSCs induced by insulin. In conclusion, AT2R is upregulated during osteogenesis. Blockade of AT2R inhibits osteogenesis and ERK phosphorylation of human MSCs. These results provide a novel insight into the pathophysiology of calcific vascular disease.


Plant perception of β-aminobutyric acid is mediated by an aspartyl-tRNA synthetase.
Specific chemicals can prime the plant immune system for augmented defense. β-aminobutyric acid (BABA) is a priming agent that provides broad-spectrum disease protection. However, BABA also suppresses plant growth when applied in high doses, which has hampered its application as a crop defense activator. Here we describe a mutant of Arabidopsis thaliana that is impaired in BABA-induced disease immunity (ibi1) but is hypersensitive to BABA-induced growth repression. IBI1 encodes an aspartyl-tRNA synthetase. Enantiomer-specific binding of the R enantiomer of BABA to IBI1 primed the protein for noncanonical defense signaling in the cytoplasm after pathogen attack. This priming was associated with aspartic acid accumulation and tRNA-induced phosphorylation of translation initiation factor eIF2α. However, mutation of eIF2α-phosphorylating GCN2 kinase did not affect BABA-induced immunity but relieved BABA-induced growth repression. Hence, BABA-activated IBI1 controls plant immunity and growth via separate pathways. Our results open new opportunities to separate broad-spectrum disease resistance from the associated costs on plant growth.


Lipiodol: a potential direct surrogate for cone-beam computed tomography image guidance in radiotherapy of liver tumor.
To investigate the feasibility of using lipiodol as a direct surrogate for target localization using cone-beam CT (CBCT) image guidance in radiotherapy (RT) of patients with unresectable liver tumors after transarterial chemoembolization. Forty-six patients with an unresectable solitary liver tumor were enrolled for RT using active breathing control (ABC) and CBCT image guidance after transarterial chemoembolization. Each patient had pre- and posttreatment CBCT in the first 10 fractions of treatment. Lipiodol retention was evaluated using daily CBCT scans, and volume of lipiodol retention in the liver was calculated and compared between planning CT and post-RT CT. Influence of lipiodol on dosimetry was evaluated by measuring doses using an ion chamber with and without the presence of lipiodol. Margin analysis was performed on the basis of both inter- and intrafractional target localization errors. Twenty-eight patients successfully completed the study. The shape and size of lipiodol retention did not vary substantially during the course of treatment. The mean Dice similarity coefficient for the lipiodol volume in pretreatment CT and that in posttreatment CT was 0.836 (range, 0.817-0.885). The maximum change (ratio of the lipiodol volume in pretreatment CT to that in posttreatment CT) was 1.045. The mean dose changes with the presence of <10 mL lipiodol were -1.44% and 0.13% for 6 MV and 15 MV, respectively. With ABC and online CBCT image guidance, clinical target volume-planning target volume margins were determined to be 2.5 mm in the mediolateral direction, 2.9 mm in the anteroposterior direction, and 4.0 mm in the craniocaudal direction. Lipiodol could be used as a direct surrogate for CBCT image guidance to improve the localization accuracy for RT of liver tumors. Combination of ABC and CBCT image guidance with lipiodol can potentially reduce the clinical target volume-planning target volume margin.


Barriers to access for Canadians who use cannabis for therapeutic purposes.
There is increased interest in the therapeutic potential of cannabis in recent decades. Canada, the Netherlands, Israel and some states in the United States have developed programs to allow access to cannabis for therapeutic purposes (CTP). In Canada, enrollment in the federal CTP program represents fewer than 5% of the estimated users of CTP. The discrepancy between the number of Canadians who report using CTP and the rate of utilization of the federal CTP program suggests the existence of barriers to access to this program. In the present study we employ a health services analytical framework to examine barriers to access to CTP among 628 current CTP users. We define barriers to access as areas of poor fit between clients and services. We use five dimensions of accommodation, accessibility, availability, affordability, and acceptability to examine access to CTP. Our findings reveal that it is difficult for Canadians to find a physician to support their application to access CTP. Accessing CTP from unauthorized sources was common; only 7% of respondents accessed CTP exclusively from authorized sources. Access to CTP was positively associated with the presence of medical cannabis dispensaries, which were not included in the regulatory regime. Access to CTP varied by medical condition and general quality of health. Affordability of CTP was a substantial barrier to access. Strategies need to be developed to encourage scientific inquiry into CTP and address the barriers to access to CTP and the stigma and controversy that surround CTP and strain patient-physician relationships.


Asymmetric synthesis of the aminocyclitol pactamycin, a universal translocation inhibitor.
An asymmetric total synthesis of the aminocyclopentitol pactamycin is described. The title compound is delivered in 15 steps from 2,4-pentanedione. Critical to this approach was the exploitation of a complex symmetry-breaking reduction strategy to assemble the C1, C2, and C7 relative stereochemistry within the first four steps of the synthesis. Multiple iterations of this reduction strategy are described, and a thorough analysis of stereochemical outcomes is detailed. In the final case, an asymmetric Mannich reaction was developed to install a protected amine directly at the C2 position. Symmetry-breaking reduction of this material gave way to a remarkable series of stereochemical outcomes leading to the title compound without recourse to nonstrategic downstream manipulations. This synthesis is immediately accommodating to the preparation of structural analogs.


Crosstalk of EDA-A2/XEDAR in the p53 signaling pathway.
We recently identified X-linked ectodermal dysplasia receptor (XEDAR, also known as TNFRSF27 or EDA2R) as a direct p53 target that was frequently downregulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations. However, the role of the posttranslational regulation of XEDAR protein in colorectal carcinogenesis was not well clarified thus far. Here, we report that the extracellular NH(2) terminus of XEDAR protein was cleaved by a metalloproteinase and released into culture media. The remaining COOH-terminal membrane-anchored fragment was rapidly degraded through the ubiquitin-proteasome pathway. Interestingly, ectopic p53 expression also transactivated an XEDAR ligand, EDA-A2, together with XEDAR. Moreover, EDA-A2 blocked the cleavage of XEDAR and subsequently inhibited cell growth. We also found a missense mutation of the XEDAR gene in NCI-H716 colorectal cancer cells, which caused the translocation of XEDAR protein from cell membrane to cytoplasm. This mutation attenuated the growth-suppressive effect of XEDAR, indicating that membrane localization is critical for physiologic XEDAR function. Thus, our findings clearly revealed the crucial role of EDA-A2/XEDAR interaction in the p53-signaling pathway.


An integrated RNAseq-1H NMR metabolomics approach to understand soybean primary metabolism regulation in response to Rhizoctonia foliar blight disease.
Rhizoctonia solani AG1-IA is a devastating phytopathogen causing Rhizoctonia foliar blight (RFB) of soybean worldwide with yield losses reaching 60%. Plant defense mechanisms are complex and information from different metabolic pathways is required to thoroughly understand plant defense regulation and function. Combining information from different "omics" levels such as transcriptomics, metabolomics, and proteomics is required to gain insights into plant metabolism and its regulation. As such, we studied fluctuations in soybean metabolism in response to R. solani infection at early and late disease stages using an integrated transcriptomics-metabolomics approach, focusing on the regulation of soybean primary metabolism and oxidative stress tolerance. Transcriptomics (RNAseq) and metabolomics (1H NMR) data were analyzed individually and by integration using bidirectional orthogonal projections to latent structures (O2PLS) to reveal possible links between the metabolome and transcriptome during early and late infection stages. O2PLS analysis detected 516 significant transcripts, double that reported in the univariate analysis, and more significant metabolites than detected in partial least squares discriminant analysis. Strong separation of treatments based on integration of the metabolomes and transcriptomes of the analyzed soybean leaves was revealed, similar trends as those seen in analyses done on individual datasets, validating the integration method being applied. Strong fluctuations of soybean primary metabolism occurred in glycolysis, the TCA cycle, photosynthesis and photosynthates in response to R. solani infection. Data were validated using quantitative real-time PCR on a set of specific markers as well as randomly selected genes. Significant increases in transcript and metabolite levels involved in redox reactions and ROS signaling, such as peroxidases, thiamine, tocopherol, proline, L-alanine and GABA were also recorded. Levels of ethanol increased 24 h post-infection in soybean leaves, and alcohol dehydrogenase (ADH) loss-of-function mutants of Arabidopsis thaliana had higher necrosis than wild type plants. As a proof-of-concept, this study offers novel insights into the biological correlations and identification of candidate genes and metabolites that can be used in soybean breeding for resistance to R. solani AG1-IA infection. Additionally, these findings imply that alcohol and its associated gene product ADH may have important roles in plant resistance to R. solani AG1-IA causing foliar blight.


A lion in the room: youth living with HIV.
This qualitative study conducted in rural and urban Georgia was designed to understand the experience of youth living with HIV who received health care from community-based and AIDS service organizations. The interview guide was developed by the authors within a health improvement context, and data analysis focused on thematic content. Twenty-nine youth, 13 to 24 years of age, volunteered to be interviewed, either in focus groups or independently. The major thematic findings were taking pills, how they look at you, being healthy, keeping it private, a lion next to you, they can help me, and life goes on. Physical and psychosocial benefits were achieved from trusting relationships with professional and personal caregivers, personal control, and self-esteem. This study identified a need for more intense, reliable, and continuous attention to social and family support.


Effectiveness of monovalent rotavirus vaccine in Bolivia: case-control study.
To evaluate the effectiveness of two doses of a monovalent rotavirus vaccine (RV1) against hospital admission for rotavirus in Bolivia. Case-control study. Six hospitals in Bolivia, between March 2010 and June 2011. 400 hospital admissions for rotavirus, 1200 non-diarrhea hospital controls, and 718 rotavirus negative hospital controls. Odds of antecedent vaccination between case patients and controls; effectiveness of vaccination ((1-adjusted odds ratio)×100), adjusted for age and other confounders; and stratified effectiveness by dose, disease severity, age group, and serotype. In comparison with non-diarrhea controls, case patients were more likely to be male and attend day care but less likely to have chronic underlying illness, higher level maternal education, and telephones and computers in their home. Rotavirus negative controls were somewhat more similar to case patients but also were more likely to be male and attend day care and less likely to have higher level maternal education and computers in their homes. The adjusted effectiveness of RV1 against hospital admission for rotavirus was 69% (95% confidence interval 54% to 79%) with rotavirus negative controls and 77% (65% to 84%) with non-diarrhea controls. The effectiveness of one dose of RV1 was 36% and 56%, respectively. With both control groups, protection was sustained through two years of life, with similar efficacy against hospital admission among children under 1 year (64% and 77%) and over 1 year of age (72% and 76%). RV1 provided significant protection against diverse serotypes, partially and fully heterotypic to the G1P[8] vaccine. Effectiveness using the two control groups was 80% and 85% against G9P[8], 74% and 93%% against G3P[8], 59% and 69% against G2P[4], and 80% and 87% against G9P[6] strains. The monovalent rotavirus vaccine conferred high protection against hospital admission for diarrhea due to rotavirus in Bolivian children. Protection was sustained through two years of life against diverse serotypes different from the vaccine strain.


A model for DNA polymerase translocation: worm-like movement of DNA within the binding cleft.
On the basis of recent results, we propose a model for DNA polymerase translocation along DNA. Human immunodeficiency virus reverse transcriptase is taken as an example. According to the model, movement of the enzyme is the result of transition of the enzyme-bound DNA from the A- to B-form which is accompanied by lengthening of DNA within the binding channel. The driving force of this transition is the increase in water accessibility to the DNA-binding cleft after dNTP binding. dNTP hydrolysis proceeding during the following chemical step supplies the energy for the reverse B-->A transition of DNA. Translocation is considered to be an integral part of the stage of conformational change preceding catalysis and can be described as a worm-like movement of DNA within the DNA-binding cleft.


Unhelpful thoughts and beliefs linked to social anxiety in stuttering: development of a measure.
Those who stutter have a proclivity to social anxiety. Yet, to date, there is no comprehensive measure of thoughts and beliefs about stuttering that represent the cognitions associated with that anxiety. The present paper describes the development of a measure to assess unhelpful thoughts and beliefs about stuttering. The Unhelpful Thoughts and Beliefs about Stuttering (UTBAS) self-report measure contains 66 items that assess the frequency of unhelpful thoughts and beliefs. Items were constructed from a comprehensive file audit of all stuttering cases seen in a cognitive-behavior therapy based treatment programme over a ten-year period. Preliminary investigations indicate that the UTBAS has high levels of test-retest reliability (r = 0.89) and internal consistency (Chronbach's alpha = 0.98). It has good known-groups validity, being able to discriminate between stuttering and non-stuttering participants on items that contain no reference to stuttering [t(38) = 8.06, p<0.0001], with a large effect size (d = 2.3). It has good convergent validity (r = 0.53-0.72) and discriminant validity (r = 0.24-0.27). The UTBAS sensitivity to change was supported by improvements in thoughts and beliefs related to social anxiety following cognitive-behavioural treatment for anxiety in stuttering [t(25) = 10.13, p<0.0001]. The effect size was large (d = 2.5). Implications for the use of the UTBAS as an outcome measure and a clinical tool are discussed, along with the potential value of the UTBAS to explore the well-documented social anxiety experienced by those who stutter.


Scaling-Up Simulations of Diffusion in Microporous Materials.
We introduce and demonstrate the coarse-graining of static and dynamical properties of host-guest systems constituted by methane in two different microporous materials. The reference systems are mapped to occupancy-based pore-scale lattice models. Each coarse-grained model is equipped with an appropriate coarse-grained potential and a local dynamical operator, which represents the probability of interpore molecular jumps between different cages. Coarse-grained thermodynamics and dynamics are both defined based on small-scale atomistic simulations of the reference systems. We considered two host materials: the widely studied ITQ-29 zeolite and the LTA-zeolite-templated carbon, which was recently theorized. Our method allows for representing with satisfactory accuracy and a considerably reduced computational effort the reference systems while providing new interesting physical insights in terms of static and diffusive properties.


Ultrasound-assisted hydrogen peroxide-ascorbic acid method to degrade sweet corncob polysaccharides can help treat type 2 diabetes via multiple pathways in vivo.
In this study, we aimed to investigate the impact of various ultrasound durations on the structure and bioactivity of sweet corncob polysaccharides treated with ultrasound-assisted degradation using hydrogen peroxide and ascorbic acid (H2O2-Vc). We subjected sweet corncob polysaccharides to ultrasound treatment for 0, 30, 60, and 90 min alongside the H2O2-Vc method. We then analyzed their chemical composition and structure. Additionally, we administered these polysaccharides to mice with type 2 diabetes (T2DM) through gavage at a dosage of 200 mg/kg/day. The results indicated a significant reduction in the molecular weight of the degraded sweet corncob polysaccharides, while their composition remained relatively stable. However, the basic structure of the polysaccharides was retained. In vivo experiments demonstrated that ultrasound-assisted degradation of these polysaccharides had a positive impact on T2DM, particularly the 60-minute ultrasound treatment (UH-DSCBP-60 min), which effectively controlled blood glucose levels by regulating glycolipid metabolism in the livers of mice with T2DM. This approach also reduced inflammation and oxidative stress levels and inhibited disaccharide activity in the small intestine. We demonstrated that ultrasound can positively affect the sweet corncob polysaccharides hypoglycemic activity. The findings of our study provide a theoretical foundation for the valuable utilization of sweet corncob polysaccharides.


Contrasting within- and between-host immune selection shapes Neisseria Opa repertoires.
Pathogen evolution is influenced strongly by the host immune response. Previous studies of the effects of herd immunity on the population structure of directly transmitted, short-lived pathogens have primarily focused on the impact of competition for hosts. In contrast, for long-lived infections like HIV, theoretical work has focused on the mechanisms promoting antigenic variation within the host. In reality, successful transmission requires that pathogens balance both within- and between-host immune selection. The Opa adhesins in the bacterial Neisseria genus provide a unique system to study the evolution of the same antigens across two major pathogens: while N. meningitidis is an airborne, respiratory pathogen colonising the nasopharynx relatively transiently, N. gonorrhoeae can cause sexually transmitted, long-lived infections. We use a simple mathematical model and genomic data to show that trade-offs between immune selection pressures within- and between-hosts can explain the contrasting Opa repertoires observed in meningococci and gonococci.