Mechanochemical synthesis of glycine oligomers in a virtual rotational diamond anvil cell.
Mechanochemistry of glycine under compression and shear at room temperature is predicted using quantum-based molecular dynamics (QMD) and a simulation design based on rotational diamond anvil cell (RDAC) experiments. Ensembles of high throughput semiempirical density functional tight binding (DFTB) simulations are used to identify chemical trends and bounds for glycine chemistry during rapid shear under compressive loads of up to 15.6 GPa. Significant chemistry is found to occur during compressive shear above 10 GPa. Recovered products consist of small molecules such as water, structural analogs to glycine, heterocyclic molecules, large oligomers, and polypeptides including the simplest polypeptide glycylglycine at up to 4% mass fraction. The population and size of oligomers generally increases with pressure. A number of oligomeric polypeptide precursors and intermediates are also identified that consist of two or three glycine monomers linked together through C-C, C-N, and/or C-O bridges. Even larger oligomers also form that contain peptide C-N bonds and exhibit branched structures. Many of the product molecules exhibit one or more chiral centers. Our simulations demonstrate that athermal mechanical compressive shearing of glycine is a plausible prebiotic route to forming polypeptides.


Quantitative modelling of legume root nodule primordium induction by a diffusive signal of epidermal origin that inhibits auxin efflux.
Rhizobium nitrogen fixation in legumes takes place in specialized organs called root nodules. The initiation of these symbiotic organs has two important components. First, symbiotic rhizobium bacteria are recognized at the epidermis through specific bacterially secreted lipo-chitooligosaccharides (LCOs). Second, signaling processes culminate in the formation of a local auxin maximum marking the site of cell divisions. Both processes are spatially separated. This separation is most pronounced in legumes forming indeterminate nodules, such as model organism Medicago truncatula, in which the nodule primordium is formed from pericycle to most inner cortical cell layers. We used computer simulations of a simplified root of a legume that can form indeterminate nodules. A diffusive signal that inhibits auxin transport is produced in the epidermis, the site of rhizobium contact. In our model, all cells have the same response characteristics to the diffusive signal. Nevertheless, we observed the fastest and strongest auxin accumulation in the pericycle and inner cortex. The location of these auxin maxima correlates with the first dividing cells of future nodule primordia in M. truncatula. The model also predicts a transient reduction of the vascular auxin concentration rootward of the induction site as is experimentally observed. We use our model to investigate how competition for the vascular auxin source could contribute to the regulation of nodule number and spacing. Our simulations show that the diffusive signal may invoke the strongest auxin accumulation response in the inner root layers, although the signal itself is strongest close to its production site.


Robotic thumb grasp-based range of motion optimisation.
With the thumb serving an important role in the function of the human hand, improving robotic prosthetic thumb functionality will have a direct impact on the prosthesis itself. So far, no significant work exists that examines the ranges of motion a prosthetic thumb should exhibit; many myoelectric prostheses arbitrarily select them. We question this design practice as we expect a significant functional volume reduction for performing certain activities vs. the maximum obtainable workspace. To this end, we compare and contrast four anatomically-accurate thumb models. We quantify their angular ranges of motion by generating point clouds of end-effector positions, and by computing their alpha-shape bounded volumes. Examining the function of the thumb for several grasps, we identify a 76% reduction of the required workspace volume vis-a-vis the maximum volume of a "'generic'" human thumb.


Late angiotensin II receptor blockade in progressive rat mesangioproliferative glomerulonephritis: new insights into mechanisms.
Mesangioproliferative glomerulonephritis is the most common nephritis worldwide. We examined the effects of low- and high-dose telmisartan, an angiotensin II receptor blocker, in rats with progressive anti-Thy1.1 mesangioproliferative glomerulonephritis in a clinically relevant situation of established renal damage. Uninephrectomized nephritic rats were randomized on day 28 to remain untreated (control treatment; CT), or to receive low- (0.1 mg/kg/day, LT) or high-dose telmisartan (10 mg/kg/day, HT), hydrochlorothiazide + hydralazine (8 + 32 mg/kg/day, HCT + H), or atenolol (100 mg/kg/day, AT). CT and LT rats were hypertensive, whereas HT, HCT + H and AT treatment normalized blood pressures. On day 131, despite similar blood lowering effects, only HT, but not AT or HCT + H, prevented loss of renal function and reduced proteinuria compared to CT. Only HT potently ameliorated glomerulosclerosis, tubulointerstitial damage, cortical matrix deposition, podocyte damage and macrophage infiltration. HT reduced cortical expression of platelet derived growth factor receptor-α and -β as well as transforming growth factor-β1. LT exhibited minor but significant efficacy even in the absence of antihypertensive effects. Transcript array analyses revealed a four-fold down-regulation of renal cortical chemokine (C-C motif) receptor 6 (CCR6) mRNA by HT, which was confirmed at the protein level. Silencing of CCR6 did not alter podocyte function in vitro, thus indicating a predominant role in the tubulo-interstitium. In human kidney biopsies, CCR6 mRNA and mRNA of its ligand chemokine (C-C motif) ligand 20 was up-regulated in patients with progressive IgA nephropathy compared to stable disease. Thus, delayed treatment with high-dose telmisartan exerted a pronounced benefit in progressive mesangioproliferative glomerulonephritis, which extended beyond that of equivalent blood pressure lowering. We identified down-regulation of platelet-derived growth factor receptors and CCR6 as potential mediators of telmisartan-related renoprotection. CCR6 may also regulate the renal outcome in human mesangioprolfierative glomerulonephritis.


Degradation of natural toxins by phthalocyanines--example of cyanobacterial toxin, microcystin.
Phthalocyanines (Pcs) are promising photosensitizers for use in various branches of science and industry. In the presence of visible light and diatomic oxygen, phthalocyanines can react to produce singlet oxygen, a member of reactive oxygen species able to damage different molecules and tissues. The aim of this study was to investigate the ability of phthalocyanines to degrade natural toxins in the presence of visible light. As the representative of hardly degradable toxins, a group of cyanobacterial peptide toxins--microcystin-LR--was chosen for this study. According to our results, phthalocyanines are able to degrade 61.5% of microcystins within a 48-hour incubation (38% of microcystins was degraded after 24 h and 24% after 12 h of incubation). Although other oxidants like hydrogen peroxide or ozone are able to degrade microcystins within several hours, we assume that by optimizing the spectrum emitted by light source and by changing the absorption characteristics of Pcs, microcystins degradation by phthalocyanines could be more effective in the near future.


Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis.
It is well known that some intestinal bacteria, such as Escherichia coli, can produce a remarkable amount of molecular hydrogen (H(2)). Although the antioxidant effects of H(2) are well documented, the present study examined whether H(2) released from intestinally colonized bacteria could affect Concanavalin A (ConA)-induced mouse hepatitis. Systemic antibiotics significantly decreased the level of H(2) in both liver and intestines along with suppression of intestinal bacteria. As determined by the levels of AST, ALT, TNF-alpha and IFN-gamma in serum, suppression of intestinal bacterial flora by antibiotics increased the severity of ConA-induced hepatitis, while reconstitution of intestinal flora with H(2)-producing E. coli, but not H(2)-deficient mutant E. coli, down-regulated the ConA-induced liver inflammation. Furthermore, in vitro production of both TNF-alpha and IFN-gamma by ConA-stimulated spleen lymphocytes was significantly inhibited by the introduction of H(2). These results indicate that H(2) released from intestinal bacteria can suppress inflammation induced in liver by ConA.


Effects of exposure to direct and secondhand hookah and e-cigarette aerosols on ambient air quality and cardiopulmonary health in adults and children: protocol for a panel study.
Use of alternative nicotine delivery systems, such as electronic cigarettes and hookahs, has increased dramatically in the USA, but limited research has been conducted on the secondhand effects of these products, especially in children. The objective of this study is to assess the cardiopulmonary effects of e-cigarette and hookah use in vaping and smoking adults, and in non-smoking/non-vaping adults and children exposed to secondhand particles and gases. This study uses a pre/post design, with four groups: two control groups (non-smoking/non-vaping and cigarette smoking) and two test groups (hookah smoking and e-cigarette vaping). Participants will be recruited by household, so that each home includes one smoking or vaping adult and one non-smoking/non-vaping adult and/or child (5-18 years). Non-smoking/non-vaping homes include an adult and child who do not smoke or vape and do not live with individuals who do. Air quality measures will be completed during a household smoking or vaping session (ambient air for non-smoking/non-vaping group), while cardiopulmonary measures and biological samples will be taken directly before and after the smoking/vaping session, and again 24 hours later, for all participants. Air quality measures include carbon monoxide, black carbon, particulate matter, trace elements, nicotine and carbonyls; cardiopulmonary measures include heart rate variability, blood pressure, pulmonary function and exhaled carbon monoxide; biological samples will assess cotinine, inflammatory cytokines and biomarkers in urine, saliva and nasal mucosa. This study was approved by the Institutional Review Board at New York University School of Medicine (s16-02226 and s17-01143). Special attention was given to the inclusion of children, who are likely significantly impacted by the use of these products at home, and thus should be included in research. Results of the study will be distributed at conferences, in peer-reviewed journals and to relevant public health authorities for use in developing policy.


Education-based health inequalities in 18,000 Norwegian couples: the Nord-Trøndelag Health Study (HUNT).
Education-based inequalities in health are well established, but they are usually studied from an individual perspective. However, many individuals are part of a couple. We studied education-based health inequalities from the perspective of couples where indicators of health were measured by subjective health, anxiety and depression. A sample of 35,980 women and men (17,990 couples) was derived from the Norwegian Nord-Trøndelag Health Study 1995-97 (HUNT 2). Educational data and family identification numbers were obtained from Statistics Norway. The dependent variables were subjective health (four-integer scale), anxiety (21-integer scale) and depression (21-integer scale), which were captured using the Hospital Anxiety and Depression Scale. The dependent variables were rescaled from 0 to 100 where 100 was the worst score. Cross-sectional analyses were performed using two-level linear random effect regression models. The variance attributable to the couple level was 42% for education, 16% for subjective health, 19% for anxiety and 25% for depression. A one-year increase in education relative to that of one's partner was associated with an improvement of 0.6 scale points (95% confidence interval = 0.5-0.8) in the subjective health score (within-couple coefficient). A one-year increase in a couple's average education was associated with an improvement of 1.7 scale points (95% confidence interval = 1.6-1.8) in the subjective health score (between-couple coefficient). There were no education-based differences in the anxiety or depression scores when partners were compared, whereas there were substantial education-based differences between couples in all three outcome measures. We found considerable clustering of education and health within couples, which highlighted the importance of the family environment. Our results support previous studies that report the mutual effects of spouses on education-based inequalities in health, suggesting that couples develop their socioeconomic position together.


Metamorphosis and gonad maturation in the horn fly Haematobia irritans.
The bloodsucking horn fly, Haematobia irritans (L.) (Diptera: Muscidae), is one of the most damaging pests of pasture cattle in many areas of the world. Both male and female imagoes spend their adult stage on the host, while immature stages develop in dung. Our goal was to determine if the progress of H. irritans gonad maturation can be correlated with eye and cuticle pigmentation events that occur during development of the imago within the puparium. The progression of germline cell divisions in immature gonads was analyzed from the beginning of the third larval instar (48 hours after egg hatch) until imago ecdysis. In the developing male larval gonad, meiosis began 72 hours after egg hatch, whereas in females oogonia were premeiotic at 72 hours. Meiosis was not detected in females until the mid-pharate adult stage, 120 hours after puparium formation. Therefore, gonad maturation in females appears to be delayed 144 hours with respect to that in males. In the stages within the puparium, the timing of germline cell division events was correlated with the progress of pigmentation of the eyes and cuticle as external markers.


Disentangling the directions of associations between structural social capital and mental health: Longitudinal analyses of gender, civic engagement and depressive symptoms.
The present paper analysed the directions of associations between individual-level structural social capital, in the form of civic engagement, and depressive symptoms across time from age 16-42 years in Swedish men and women. More specifically, we asked whether civic engagement was related to changes in depressive symptoms, if it was the other way around, or whether the association was bi-directional. This longitudinal study used data from a 26-year prospective cohort material of 1001 individuals in Northern Sweden (482 women and 519 men). Civic engagement was measured by a single-item question reflecting the level of engagement in clubs/organisations. Depressive symptoms were assessed by a composite index. Directions of associations were analysed by means of gender-separate cross-lagged structural equation models. Models were adjusted for parental social class, parental unemployment, parental health, and family type at baseline (age 16). Levels of both civic engagement and depressive symptoms were relatively stable across time. The model with the best fit to data showed that, in men, youth civic engagement was negatively associated with depressive symptoms in adulthood, thus supporting the hypothesis that involvement in social networks promotes health, most likely through provision of social and psychological support, perceived influence, and sense of belonging. Accordingly, interventions to promote civic engagement in young men could be a way to prevent poor mental health for men later on in life. No cross-lagged effects were found among women. We discuss this gender difference in terms of gendered experiences of civic engagement which in turn generate different meanings and consequences for men and women, such as civic engagement not being as positive for women's mental health as for that of men. We conclude that theories on structural social capital and interventions to facilitate civic engagement for health promoting purposes need to acknowledge gendered life circumstances.


Explaining the variation between practices in the duration of new antidepressant treatment: a database cohort study in primary care.
Practices vary in the duration of newly initiated antidepressant treatment, even after adjusting for patient characteristics. It was hypothesised that this may be because of differences between practices in demographic (practice deprivation and antidepressant prescribing rates), organisational (practice size and proportion of female GPs), and clinical factors (proportion of new episodes of depression coded). To examine the effect of practice characteristics on the duration of new selective serotonin reuptake inhibitor antidepressant treatment in primary care. Database cohort study of 28 027 patients from 237 GP practices in Scotland. Prescription data were used to estimate duration of treatment for individual patients beyond three time points: 30, 90, and 180 days. Data at patient and practice level were analysed by multilevel logistic regression to quantify the variation between practices. The mean rate of diagnostic coding for depression in patients beginning a course of treatment was 29% (range 0-80%). Practice-level deprivation and rate of new antidepressant prescribing were not associated with duration of treatment. The practice level factor most strongly associated with duration of treatment at practice level was the proportion of patients coded as having depression: odds ratio for continuing beyond 30 days was 1.54 (95% confidence interval [CI] = 1.22 to 1.94); beyond 90 days, 1.37 (95% CI = 1.09 to 1.71); and beyond 180 days 1.41 (95% CI = 1.10 to 1.82). Encouraging coding and structured follow-up at the onset of treatment of depression is likely to reduce early discontinuation of antidepressant treatment and improve outcomes.


Transfer Learning for Image Segmentation by Combining Image Weighting and Kernel Learning.
Many medical image segmentation methods are based on the supervised classification of voxels. Such methods generally perform well when provided with a training set that is representative of the test images to the segment. However, problems may arise when training and test data follow different distributions, for example, due to differences in scanners, scanning protocols, or patient groups. Under such conditions, weighting training images according to distribution similarity have been shown to greatly improve performance. However, this assumes that a part of the training data is representative of the test data; it does not make unrepresentative data more similar. We, therefore, investigate kernel learning as a way to reduce differences between training and test data and explore the added value of kernel learning for image weighting. We also propose a new image weighting method that minimizes maximum mean discrepancy (MMD) between training and test data, which enables the joint optimization of image weights and kernel. Experiments on brain tissue, white matter lesion, and hippocampus segmentation show that both kernel learning and image weighting, when used separately, greatly improve performance on heterogeneous data. Here, MMD weighting obtains similar performance to previously proposed image weighting methods. Combining image weighting and kernel learning, optimized either individually or jointly, can give a small additional improvement in performance.


The Th2 cytokine environment of the placenta.
It is now accepted that local changes to the balance of Th1/Th2-type cytokines occur during pregnancy within the maternal uterus and fetoplacental unit. These changes in cytokine profiles contribute to implantation of the embryo, development of the placenta, and survival of the fetus to term. Overall within the placenta there is a bias in the ratio of Th1:Th2 cytokines towards the Th2-type cytokines. However, there are specific fluctuations in this balance at implantation and during the initiation of parturition. The predominant cytokines at each stage of gestation function both to limit maternal immune rejection of the semi-allogeneic embryo/fetus, especially at the maternofetal interface; and to facilitate the on-going physiological processes within the maternal reproductive tract. These two, at times conflicting, roles are discussed in this review, with key evidence concerning cytokine expression and function from mouse and humans.


Identifying Land Use and Land-Use Changes (LULUC): A Global LULUC Matrix.
Land use and land-use changes (LULUC) information is essential to determine the environmental impacts of anthropogenic land-use and conversion. However, existing data sets are either local-scale or they quantify land occupation per land-use type rather than providing information on land-use changes. Here we combined the strengths of the remotely sensed MODIS land cover data set and FAOSTAT land-use data to obtain a database including a collection of 231 country-specific LULUC matrixes, as suggested by the IPCC. We produced two versions of each matrix: version 1, identifying forestland based on canopy cover criteria; version 2, distinguishing primary, secondary, planted forests and permanent crops. The outcome was a first country-based, consistent set of spatially explicit LULUC matrixes. The database facilitates a more holistic assessment of land-use changes, quantifying changes that occur between land classes from 2001 to 2012, providing crucial information for assessing environmental impacts caused by LULUC. The data allow global-scale land-use change analyses, requiring a distinction between land types based not only on land cover but also on land uses. The spatially explicit data set may also serve as a starting point for further studies aiming at determining the drivers of land-use change supported by spatial statistical modeling.


Behavioral effects of pentobarbital, lorazepam, ethanol and chlorpromazine substitution in pentobarbital-dependent baboons.
Baboons were given continuous intragastric infusions of 100 mg/kg/day of pentobarbital before and during these experiments. The baboons responded under a fixed-ratio (FR) 30-response schedule of food presentation from 10:00 A.M. of one day to 8:00 A.M. of the next day. Terminating pentobarbital administration (i.e., substituting water for pentobarbital) from 8:00 A.M. of one day to 8:00 A.M. of the next day produced large decreases in the number of pellets earned. Repeated 24-h terminations of pentobarbital administration at 1-week intervals produced similar decreases in the pellets earned. In another experiment, the effects of terminating pentobarbital administration for several days were examined. The number of pellets earned decreased within 2 h of terminating pentobarbital administration was maximally suppressed during the first day, and recovered over 3 to 5 days. When different doses of pentobarbital were substituted for 24 h, the disruption of responding seen after pentobarbital termination was attenuated in a dose-dependent manner. In another experiment, the effects of substituting lorazepam, ethanol or chlorpromazine for pentobarbital for 24 h were examined. Lorazepam produced a dose-dependent attenuation of the effects of pentobarbital termination, whereas ethanol did not. Chlorpromazine did not attenuate the effects of pentobarbital termination in two of the three baboons tested, and produced erratic results in the third.


Evaluation and clinical significance of the stomach age model for evaluating aging of the stomach-a multicenter study in China.
A higher prevalence of chronic atrophic gastritis (CAG) occurs in younger adults in Asia. We used Stomach Age to examine the different mechanisms of CAG between younger adults and elderly individuals, and established a simple model of cancer risk that can be applied to CAG surveillance. Stomach Age was determined by FISH examination of telomere length in stomach biopsies. Δψm was also determined by flow cytometry. Sixty volunteers were used to confirm the linear relationship between telomere length and age while 120 subjects were used to build a mathematical model by a multivariate analysis. Overall, 146 subjects were used to evaluate the validity of the model, and 1,007 subjects were used to evaluate the relationship between prognosis and Δage (calculated from the mathematical model). ROC curves were used to evaluate the relationship between prognosis and Δage and to determine the cut-off point for Δage. We established that a tight linear relationship between the telomere length and the age. The telomere length was obvious different between patients with and without CAG even in the same age. Δψm decreased in individuals whose Stomach Age was greater than real age, especially in younger adults. A mathematical model of Stomach Age (real age + Δage) was successfully constructed which was easy to apply in clinical work. A higher Δage was correlated with a worse outcome. The criterion of Δage >3.11 should be considered as the cut-off to select the subgroup of patients who require endoscopic surveillance. Variation in Stomach Age between individuals of the same biological age was confirmed. Attention should be paid to those with a greater Stomach Age, especially in younger adults. The Δage in the Simple Model can be used as a criterion to select CAG patients for gastric cancer surveillance.


Downward vascular translocation of a green fluorescent protein-tagged strain of Dickeya sp. (Biovar 3) from stem and leaf inoculation sites on potato.
Translocation of a green fluorescent protein (GFP)-tagged Dickeya sp. from stems or from leaves to underground parts of potato plants was studied in greenhouse experiments. Thirty days after stem inoculation, 90% of plants expressed symptoms at the stem base and 95% of plants showed browning of internal stem tissue. The GFP-tagged Dickeya sp. was detected by dilution plating in extracts of the stem interiors (100%), stem bases (90%), roots (80%), stolons (55%), and progeny tubers (24%). In roots, the GFP-tagged Dickeya sp. was found inside and between parenchyma cells whereas, in stems and stolons, the GFP-tagged Dickeya sp. was found in the xylem vessels and protoxylem cells. In progeny tubers, this strain was detected in the stolon end. Thirty days after leaf inoculation, the GFP-tagged Dickeya sp. was detected in extracts of 75% of the leaves, 88% of the petioles, 63% of the axils, and inside 25% of the stems taken 15 cm above the ground level. UV microscopy confirmed the presence of the GFP-tagged Dickeya sp. inside petioles and in the main leaf veins. No blackleg or aerial stem rot and no translocation of the GFP-tagged Dickeya sp. to underground plant parts was observed. The implications for contamination of progeny tubers are discussed.


Somatic mosaicism for chromosome X and Y aneuploidies in monozygotic twins heterozygous for sickle cell disease mutation.
Somatic genetic variation in health and disease is poorly explored. Monozygotic (MZ) twins are a suitable model for studies of somatic mosaicism since genetic differences in twins derived from the same zygote represent an irrefutable example of somatic variation. We report the analysis of a pair of generally healthy female MZ twins, discordant for somatic mosaicism for aneuploidy of chromosomes X and Y. Both twins are heterozygous carriers of sickle cell disease mutation. Genotyping of blood DNA from both twins using Illumina Human 610 SNP array revealed a copy number imbalance for chromosome X in a proportion of cells in one twin. Fluorescent in situ hybridization (FISH) analysis confirmed monosomy X (45,X) in 7% of proband nucleated blood cells. Unexpectedly, FISH analysis of cells from the other twin revealed 45,X and 46,XY lineages, both present in 1% of cells. The mechanism behind formation of these aneuploidies suggests several aberrant chromosome segregation events in meiosis and mitoses following conception. Our report contributes to the delineation of the frequency of somatic structural genomic variation in normal MZ twins. These results also illustrate the plasticity of the human genome for tolerating large copy number changes in healthy subjects and show the sensitivity of the Illumina platform for detection of aberrations that are present in a minority of the studied cells.


Structure of Staphylococcus aureus guanylate monophosphate kinase.
Nucleotide monophosphate kinases (NMPKs) are potential antimicrobial drug targets owing to their role in supplying DNA and RNA precursors. The present work reports the crystal structure of Staphylococcus aureus guanylate monophosphate kinase (SaGMK) at 1.9 A resolution. The structure shows that unlike most GMKs SaGMK is dimeric, confirming the role of the extended C-terminus in dimer formation as first observed for Escherichia coli GMK (EcGMK). One of the two SaGMK dimers within the crystal asymmetric unit has two monomers in different conformations: an open form with a bound sulfate ion (mimicking the beta-phosphate of ATP) and a closed form with bound GMP and sulfate ion. GMP-induced domain movements in SaGMK can thus be defined by comparison of these conformational states. Like other GMKs, the binding of GMP firstly triggers a partial closure of the enzyme, diminishing the distance between the GMP-binding and ATP-binding sites. In addition, the closed structure shows the presence of a potassium ion in contact with the guanine ring of GMP. The potassium ion appears to form an integral part of the GMP-binding site, as the Tyr36 side chain has significantly moved to form a metal ion-ligand coordination involving the lone pair of the side-chain O atom. The potassium-binding site might also be exploited in the design of novel inhibitors.


Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI.
Before the advent of genome-wide association studies (GWASs), hundreds of candidate genes for obesity-susceptibility had been identified through a variety of approaches. We examined whether those obesity candidate genes are enriched for associations with body mass index (BMI) compared with non-candidate genes by using data from a large-scale GWAS. A thorough literature search identified 547 candidate genes for obesity-susceptibility based on evidence from animal studies, Mendelian syndromes, linkage studies, genetic association studies and expression studies. Genomic regions were defined to include the genes ±10 kb of flanking sequence around candidate and non-candidate genes. We used summary statistics publicly available from the discovery stage of the genome-wide meta-analysis for BMI performed by the genetic investigation of anthropometric traits consortium in 123 564 individuals. Hypergeometric, rank tail-strength and gene-set enrichment analysis tests were used to test for the enrichment of association in candidate compared with non-candidate genes. The hypergeometric test of enrichment was not significant at the 5% P-value quantile (P = 0.35), but was nominally significant at the 25% quantile (P = 0.015). The rank tail-strength and gene-set enrichment tests were nominally significant for the full set of genes and borderline significant for the subset without SNPs at P < 10(-7). Taken together, the observed evidence for enrichment suggests that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits.


Evaluation of Patient- and Surgeon-Specific Variations in Patient-Reported Urinary Outcomes 3 Months After Radical Prostatectomy From a Statewide Improvement Collaborative.
Understanding variation in patient-reported outcomes following radical prostatectomy may inform efforts to reduce morbidity after this procedure. To describe patient-reported urinary outcomes following radical prostatectomy in the diverse practice settings of a statewide quality improvement program and to explore whether surgeon-specific variations in observed outcomes persist after accounting for patient-level factors. This prospective population-based cohort study included 4582 men in the Michigan Urological Surgery Improvement Collaborative who underwent radical prostatectomy as primary management of localized prostate cancer between April 2014 and July 2018 and who agreed to complete validated questionnaires prior to surgery and at 3, 6, and 12 months after surgery. Data were analyzed from 2019 to June 2019. Radical prostatectomy. Patient- and surgeon-level analyses of patient-reported urinary function 3 months after radical prostatectomy. Outcomes were measured using validated questionnaires with results standardized using previously published methods. Urinary function survey scores are reported on a scale from 0 to 100 with good function established as a score of 74 or higher. For the 4582 men undergoing radical prostatectomy within the Michigan Urological Surgery Improvement Collaborative who agreed to complete surveys, mean (SD) age was 63.3 (7.1) years. Survey response rates varied: 3791 of 4582 (83%) responded at baseline, 3282 of 4137 (79%) at 3 months, 2975 of 3770 (79%) at 6 months, and 2213 of 2882 (77%) at 12 months. Mean (SD) urinary function scores were 88.5 (14.3) at baseline, 53.6 (27.5) at 3 months, 68.0 (25.1) at 6 months, and 73.7 (23.0) at 12 months. Regression analysis demonstrated that older age, lower baseline urinary function score, body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 or higher, clinical stage T2 or higher, and lack of bilateral nerve-sparing surgery were associated with a lower probability of reporting good urinary function 3 months after surgery. When evaluating patients with good baseline function, the rate at which individual surgeons' patients reported good urinary function 3 months after surgery varied broadly (0% to 54.5%; P < .001). Patients receiving surgery from top-performing surgeons were more likely to report good 3-month function. This finding persisted after accounting for patient risk factors. In this study, patient- and surgeon-level urinary outcomes following prostatectomy varied substantially. Documenting surgeon-specific variations after accounting for patient factors may facilitate identification of surgical factors associated with superior outcomes.


The PNPLA3 Genetic Variant rs738409 Influences the Progression to Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients.
Contradictory data about the impact of the rs738409 steatosis-related polymorphism within PNPLA3 gene on liver fibrosis progression in HIV/hepatitis C virus (HIV/HCV)-coinfected patients have been reported. Our objective was to test whether this, and other polymorphisms previously related to fatty liver disease in HIV infection linked to SAMM50 or LPPR4 genes, influence liver fibrosis progression in HIV/HCV-coinfected individuals. Three hundred and thirty two HIV/HCV-coinfected patients who consecutively attended four Spanish university hospitals from November 2011 to July 2013 were included. A liver stiffness cut-off of 14.6 kPa, as determined by transient elastography, was used to diagnose cirrhosis. Liver stiffness progression was studied in 171 individuals who had two available LS determinations without anti-HCV treatment between them. Moreover, 28 HIV/HCV-coinfected patients who underwent liver transplant, as well as 19 non-cirrhotic coinfected individuals used as controls, were included in an additional study. Only rs738409 was associated with cirrhosis: 45 (29.6%) of 152 G allele carriers versus 36 (20.0%) of 180 CC carriers showed cirrhosis (multivariate p = 0.018; adjusted odds ratio = 1.98; 95% confidence interval = 1.12-3.50). Also, 21 (30.4%) of 69 G allele carriers versus 16 (15.7%) of 102 CC patients showed significant liver stiffness progression (adjusted p-value = 0.015; adjusted odds ratio = 2.89; 95% confidence interval = 1.23-6.83). Finally, the proportion of rs738409 G allele carriers was significantly higher in transplanted individuals than in controls (p = 0.044, odds ratio = 3.43; 95% confidence interval = 1.01-11.70). Our results strongly suggest that the rs738409 polymorphism is associated with liver fibrosis progression in HIV/HCV-coinfected patients.


Will the olympics survive?.
The United States of America dominated 58 events in athletics, field and swimming, which between them accounted for 35 per cent of all events in the Munich Olympiad. 1972; these events favour taller individuals. But, in 25 per cent of other events (1) cycling, (2) fencing, (3) gymnastics, (4) judo, (5) weightlifting and (6) Graeco Roman wrestling the U.S.A. did not win a single medal. The failure of the U.S.A. to maintain her lead in Munich was largely due to weaknesses in these other events in many of which the potential medallists can be derived from the lower half of the height distribution (events 3 to 6). These weaknesses are Russia's strength and they continued to remain unstrengthened at Montreal. Also, the domination held by the U.S.A. in swimming was seriously challenged by East Germany. The present trends indicate that the U.S.A.'s ranking is likely to slip further to the third position in Moscow 1980. Factors inhibiting the survival of the Olympics are pointed.


Mothers with disabilities: in their own voice.
The purpose of this study was to gain an understanding of the personal experience of women with disabilities engaged in the occupation of mothering and their perceptions of their interpersonal environment, including interaction with family, professional caregivers, and the community. In this qualitative study, in-depth interviews were conducted with a diverse sample (n = 8) of mothers with disabilities or chronic illnesses to uncover the nature of their mothering experience. Data were analyzed for themes with the constant comparison approach of grounded theory. The quality of the participants' experience varied with the degree of perceived similarity or dissimilarity with other mothers and acceptance of these differences. In addition, their perception of the supportive or nonsupportive nature of their interpersonal environment had an impact on their mothering experience. The results suggest that mothers with disabilities tend to value the importance of performing maternal occupations according to a perceived culturally common way, although self-acceptance of their own unique differences in performing these occupations facilitates maternal engagement as well.


Serial diffusion MRI to monitor and model treatment response of the targeted nanotherapy CRLX101.
Targeted nanotherapies are being developed to improve tumor drug delivery and enhance therapeutic response. Techniques that can predict response will facilitate clinical translation and may help define optimal treatment strategies. We evaluated the efficacy of diffusion-weighted magnetic resonance imaging to monitor early response to CRLX101 (a cyclodextrin-based polymer particle containing the DNA topoisomerase I inhibitor camptothecin) nanotherapy (formerly IT-101), and explored its potential as a therapeutic response predictor using a mechanistic model of tumor cell proliferation. Diffusion MRI was serially conducted following CRLX101 administration in a mouse lymphoma model. Apparent diffusion coefficients (ADCs) extracted from the data were used as treatment response biomarkers. Animals treated with irinotecan (CPT-11) and saline were imaged for comparison. ADC data were also input into a mathematical model of tumor growth. Histological analysis using cleaved-caspase 3, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, Ki-67, and hematoxylin and eosin (H&E) were conducted on tumor samples for correlation with imaging results. CRLX101-treated tumors at day 2, 4, and 7 posttreatment exhibited changes in mean ADC = 16 ± 9%, 24 ± 10%, 49 ± 17%, and size (TV) = -5 ± 3%, -30 ± 4%, and -45 ± 13%, respectively. Both parameters were statistically greater than controls [p(ADC) ≤ 0.02, and p(TV) ≤ 0.01 at day 4 and 7], and noticeably greater than CPT-11-treated tumors (ADC = 5 ± 5%, 14 ± 7%, and 18 ± 6%; TV = -15 ± 5%, -22 ± 13%, and -26 ± 8%). Model-derived parameters for cell proliferation obtained using ADC data distinguished CRLX101-treated tumors from controls (P = 0.02). Temporal changes in ADC specified early CRLX101 treatment response and could be used to model image-derived cell proliferation rates following treatment. Comparisons of targeted and nontargeted treatments highlight the utility of noninvasive imaging and modeling to evaluate, monitor, and predict responses to targeted nanotherapeutics.


Phenotypic analysis and gamma delta-T cell receptor repertoire of murine T cells associated with the vaginal epithelium.
T cells expressing alpha beta- and gamma delta-TCR are associated with the murine vaginal epithelium. A combination of phenotypic analysis of cell surface Ag and molecular analysis of the gamma- and delta-genes was used to demonstrate that vaginal gamma delta-T cells have several features that distinguish them from gamma delta-T cells present in other tissues. Three color flow cytofluorometric analysis demonstrated that freshly isolated vaginal gamma delta-T cells are CD4-CD8- and their expression of Thy-1 is strain dependent. Furthermore, specific differences in CD5, CD28, and p55IL-2 receptor expression were found between alpha beta- and gamma delta-T cells isolated from vaginal tissue. The vaginal gamma delta-T cells are predominantly CD45+, pgp-1+, HSA-, Ly-6C-, and MEL-14-. Both alpha beta- and gamma delta-T cells were absent in vaginal tissue from nude mice, although Thy-1-positive cells are present. It was also demonstrated that V gamma 4 and V delta 1 are the only gamma- and delta-genes that are expressed by vaginal cells. Sequence analysis of their junctions revealed that they express the V gamma 4 and V delta 1 sequences also found in fetal thymocytes. Furthermore, the V delta 1 sequence is identical in the vaginal cells and the gamma delta-T cells from the epidermal epithelium. We conclude that the vagina, like the skin, is a site where gamma delta-T cells with an invariant TCR exist.


Arrhythmogenic Hearts in PKD2 Mutant Mice Are Characterized by Cardiac Fibrosis, Systolic, and Diastolic Dysfunctions.
Autosomal dominant polycystic kidney disease (PKD) is a hereditary disorder affecting multiple organs, including the heart. PKD has been associated with many cardiac abnormalities including the arrhythmogenic remodeling in clinical evaluations. In our current study, we hypothesized that Pkd2 gene mutation results in structural and functional defects in the myocardium. The structural and functional changes of Pkd2 mutant hearts were analyzed in the myocardial-specific Pkd2 knockout (KO) mouse. We further assessed a potential role of TGF-b1 signaling in the pathology of Pkd2-KO hearts. Hearts from age-matched 6-month-old MyH6•Pkd2 wt/wt (control or wild-type) and MyH6•Pkd2 flox/flox (mutant or Pkd2-KO) mice were used to study differential heart structure and function. Cardiac histology was used to study structure, and the "isolated working heart" system was adapted to mount and perfuse mouse heart to measure different cardiac parameters. We found that macrophage1 (M1) and macrophage 2 (M2) infiltration, transforming growth factor (TGF-b1) and TGF-b1 receptor expressions were significantly higher in Pkd2-KO, compared to wild-type hearts. The increase in the extracellular matrix in Pkd2-KO myocardium led to cardiac hypertrophy, interstitial and conduction system fibrosis, causing cardiac dysfunction with a predisposition to arrhythmia. Left ventricular (LV) expansion or compliance and LV filling were impaired in fibrotic Pkd2-KO hearts, resulted in diastolic dysfunction. LV systolic contractility and elastance decreased in fibrotic Pkd2-KO hearts, resulted in systolic dysfunction. Compared to wild-type hearts, Pkd2-KO hearts were less responsive to the pharmacological stress-test and changes in preload. In conclusion, Pkd2-KO mice had systolic and diastolic dysfunction with arrhythmogenic hearts.


Evolutionary entanglement of mobile genetic elements and host defence systems: guns for hire.
All cellular life forms are afflicted by diverse genetic parasites, including viruses and other types of mobile genetic elements (MGEs), and have evolved multiple, diverse defence systems that protect them from MGE assault via different mechanisms. Here, we provide our perspectives on how recent evidence points to tight evolutionary connections between MGEs and defence systems that reach far beyond the proverbial arms race. Defence systems incur a fitness cost for the hosts; therefore, at least in prokaryotes, horizontal mobility of defence systems, mediated primarily by MGEs, is essential for their persistence. Moreover, defence systems themselves possess certain features of selfish elements. Common components of MGEs, such as site-specific nucleases, are 'guns for hire' that can also function as parts of defence mechanisms and are often shuttled between MGEs and defence systems. Thus, evolutionary and molecular factors converge to mould the multifaceted, inextricable connection between MGEs and anti-MGE defence systems.


Chaotic ultra-wideband radio generator based on an optoelectronic oscillator with a built-in microwave photonic filter.
We induce a microwave photonic bandpass filter into an optoelectronic oscillator to generate a chaotic ultra-wideband signal in both the optical and electrical domain. The theoretical analysis and numerical simulation indicate that this system is capable of generating band-limited high-dimensional chaos. Experimental results coincide well with the theoretical prediction and show that the power spectrum of the generated chaotic signal basically meets the Federal Communications Commission indoor mask. The generated chaotic carrier is further intensity modulated by a 10 MHz square wave, and the waveform of the output ultra-wideband signal is measured for demonstrating the chaotic on-off keying modulation.


Genetic rescue of small inbred populations: meta-analysis reveals large and consistent benefits of gene flow.
Many species have fragmented distribution with small isolated populations suffering inbreeding depression and/or reduced ability to evolve. Without gene flow from another population within the species (genetic rescue), these populations are likely to be extirpated. However, there have been only ~ 20 published cases of such outcrossing for conservation purposes, probably a very low proportion of populations that would potentially benefit. As one impediment to genetic rescues is the lack of an overview of the magnitude and consistency of genetic rescue effects in wild species, I carried out a meta-analysis. Outcrossing of inbred populations resulted in beneficial effects in 92.9% of 156 cases screened as having a low risk of outbreeding depression. The median increase in composite fitness (combined fecundity and survival) following outcrossing was 148% in stressful environments and 45% in benign ones. Fitness benefits also increased significantly with maternal ΔF (reduction in inbreeding coefficient due to gene flow) and for naturally outbreeding versus inbreeding species. However, benefits did not differ significantly among invertebrates, vertebrates and plants. Evolutionary potential for fitness characters in inbred populations also benefited from gene flow. There are no scientific impediments to the widespread use of outcrossing to genetically rescue inbred populations of naturally outbreeding species, provided potential crosses have a low risk of outbreeding depression. I provide revised guidelines for the management of genetic rescue attempts.


[Semantic equivalence of the Brazilian Portuguese version of the "Body Change Inventory"].
With the increase in research on the components of Body Image, validated instruments are needed to evaluate its dimensions. The Body Change Inventory (BCI) assesses strategies used to alter body size among adolescents. The scope of this study was to describe the translation and evaluation for semantic equivalence of the BCI in the Portuguese language. The process involved the steps of (1) translation of the questionnaire to the Portuguese language; (2) back-translation to English; (3) evaluation of semantic equivalence; and (4) assessment of comprehension by professional experts and the target population. The six subscales of the instrument were translated into the Portuguese language. Language adaptations were made to render the instrument suitable for the Brazilian reality. The questions were interpreted as easily understandable by both experts and young people. The Body Change Inventory has been translated and adapted into Portuguese. Evaluation of the operational, measurement and functional equivalence are still needed.


Do Periodontal Pathogens or Associated Virulence Factors Have a Deleterious Effect on the Blood-Brain Barrier, Contributing to Alzheimer's Disease?
The central nervous system (CNS) is protected by a highly selective barrier, the blood-brain barrier (BBB), that regulates the exchange and homeostasis of bloodborne molecules, excluding xenobiotics. This barrier forms the first line of defense by prohibiting pathogens from crossing to the CNS. Aging and chronic exposure of the BBB to pathogens renders it permeable, and this may give rise to pathology in the CNS such as Alzheimer's disease (AD). Researchers have linked pathogens associated with periodontitis to neuroinflammation and AD-like pathology in vivo and in vitro. Although the presence of periodontitis-associated bacteria has been linked to AD in several clinical studies as DNA and virulence factors were confirmed in brain samples of human AD subjects, the mechanism by which the bacteria traverse to the brain and potentially influences neuropathology is unknown. In this review, we present current knowledge about the association between periodontitis and AD, the mechanism whereby periodontal pathogens might provoke neuroinflammation and how periodontal pathogens could affect the BBB. We suggest future studies, with emphasis on the use of human in vitro models of cells associated with the BBB to unravel the pathway of entry for these bacteria to the CNS and to reveal the molecular and cellular pathways involved in initiating the AD-like pathology. In conclusion, evidence demonstrates that bacteria associated with periodontitis and their virulence factors are capable of inflecting damage to the BBB and have a role in giving rise to pathology similar to that found in AD.


An adversarial training framework for mitigating algorithmic biases in clinical machine learning.
Machine learning is becoming increasingly prominent in healthcare. Although its benefits are clear, growing attention is being given to how these tools may exacerbate existing biases and disparities. In this study, we introduce an adversarial training framework that is capable of mitigating biases that may have been acquired through data collection. We demonstrate this proposed framework on the real-world task of rapidly predicting COVID-19, and focus on mitigating site-specific (hospital) and demographic (ethnicity) biases. Using the statistical definition of equalized odds, we show that adversarial training improves outcome fairness, while still achieving clinically-effective screening performances (negative predictive values >0.98). We compare our method to previous benchmarks, and perform prospective and external validation across four independent hospital cohorts. Our method can be generalized to any outcomes, models, and definitions of fairness.


Bifurcating spatially heterogeneous solutions in a chemotaxis model for biological pattern generation.
We consider a simple cell-chemotaxis model for spatial pattern formation on two-dimensional domains proposed by Oster and Murray (1989, J. exp. Zool. 251, 186-202). We determine finite-amplitude, steady-state, spatially heterogeneous solutions and study the effect of domain growth on the resulting patterns. We also investigate in-depth bifurcating solutions as the chemotactic parameter varies. This numerical study shows that this deceptively simple-chemotaxis model can produce a surprisingly rich spectrum of complex spatial patterns.


Epidermal growth factor-like domain multiple 7 (EGFL7): Expression and possible effect on biliary epithelium growth in cholangiocarcinoma.
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. The intrahepatic subtype comprises two forms: mucin-iCCA and mixed-iCCA. Epidermal growth factor-like domain multiple (EGFL7) is overexpressed in less differentiated liver tumors. The aim of this study was to assess the presence of EGFL7 due to its possible role in the growth of CCA. Hematoxylin and Eosin and periodic acid-Schiff staining were used to evaluate the morphological aspects and glycogen deposition. Immunohistochemistry and immunofluorescence were performed to identify the presence of EGFL7 both in tumor sections ex vivo and in appropriate cell lines in culture. We found that EGFL7 is expressed in malignant cholangiocytes of mixed-iCCA and absent in mucin-iCCA. In conclusion the expression of EGFL7 might be useful in the classification of CCA subtypes.


Discovery of Compounds Inhibiting the ADP-Ribosyltransferase Activity of Pertussis Toxin.
The targeted pathogen-selective approach to drug development holds promise to minimize collateral damage to the beneficial microbiome. The AB5-topology pertussis toxin (PtxS1-S5) is a major virulence factor of Bordetella pertussis, the causative agent of the highly contagious respiratory disease whooping cough. Once internalized into the host cell, PtxS1 ADP-ribosylates α-subunits of the heterotrimeric Gαi-superfamily, thereby disrupting G-protein-coupled receptor signaling. Here, we report the discovery of the first small molecules inhibiting the ADP-ribosyltransferase activity of pertussis toxin. We developed protocols to purify milligram-levels of active recombinant B. pertussis PtxS1 from Escherichia coli and an in vitro high throughput-compatible assay to quantify NAD+ consumption during PtxS1-catalyzed ADP-ribosylation of Gαi. Two inhibitory compounds (NSC228155 and NSC29193) with low micromolar IC50-values (3.0 μM and 6.8 μM) were identified in the in vitro NAD+ consumption assay that also were potent in an independent in vitro assay monitoring conjugation of ADP-ribose to Gαi. Docking and molecular dynamics simulations identified plausible binding poses of NSC228155 and in particular of NSC29193, most likely owing to the rigidity of the latter ligand, at the NAD+-binding pocket of PtxS1. NSC228155 inhibited the pertussis AB5 holotoxin-catalyzed ADP-ribosylation of Gαi in living human cells with a low micromolar IC50-value (2.4 μM). NSC228155 and NSC29193 might prove to be useful hit compounds in targeted B. pertussis-selective drug development.


Do "mudsplashes" induce tactile change blindness?
The phenomenon of change blindness (the surprising inability of people to correctly perceive changes between consecutively presented displays), primarily reported in vision, has recently been shown to occur for positional changes presented in tactile displays as well. Here, we studied people's ability to detect changes in the number of tactile stimuli in successively presented displays composed of one to three stimuli distributed over the body surface. In Experiment 1, a tactile mask consisting of the simultaneous activation of all seven possible tactile stimulators was sometimes presented between the two to-be-discriminated tactile displays. In Experiment 2, a "mudsplash" paradigm was used, with a brief irrelevant tactile distractor presented at the moment of change of the tactile display. Change blindness was demonstrated in both experiments, thus showing that the failure to detect tactile change is not necessarily related to (1) the physical disruption between consecutive events, (2) the effect of masking covering the location of the change, or (3) the erasure or resetting of the information contained within an internal representation of the tactile display. These results are interpreted in terms of a limitation in the number of spatial locations/events that can be consciously accessed at any one time. This limitation appears to constrain change-detection performance, no matter the sensory modality in which the stimuli are presented.


DNA methylation of the MAPT gene in Parkinson's disease cohorts and modulation by vitamin E in vitro.
Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methylation levels were determined by pyrosequencing of bisulfite-treated DNA in a leukocyte cohort (358 PD patients and 1084 controls) and in two brain cohorts (Brain1, comprising 69 cerebellum controls; and Brain2, comprising 3 brain regions from 28 PD patients and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. In normal leukocytes, the MAPT H1/H2 diplotype and sex were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed that the H1 haplotype had higher methylation than the H2 haplotype in normal leukocytes and brain tissues. MAPT methylation was negatively associated with MAPT expression in the Brain1 cohort and in transfected cells. Methylation levels differed between three normal brain regions (Brain2 cohort, putamen < cerebellum < anterior cingulate cortex). In PD samples, age at onset was positively associated with MAPT methylation in leukocytes. Moreover, there was hypermethylation in the cerebellum and hypomethylation in the putamen of PD patients compared with controls (Brain2 cohort). Finally, leukocyte methylation status was positively associated with blood vitamin E levels, and the effect was more significant in H2 haplotype carriers; this result was confirmed in cells that were exposed to 100 μM vitamin E. The significant effects of sex, diplotype, and brain region suggest that hypermethylation of the MAPT gene is neuroprotective by reducing MAPT expression. The effect of vitamin E on MAPT represents a possible gene-environment interaction.


Oxidant and antioxidant status in children with subacute sclerosing panencephalitis.
We analyzed serum alpha-tocopherol, beta-carotene, retinol, and ascorbic acid levels and malondialdehyde and reduced glutathione concentrations on erythrocyte and cerebrospinal fluid in 30 patients with subacute sclerosing panencephalitis to evaluate oxidant and antioxidant status. Serum alpha-tocopherol, beta-carotene, retinol, ascorbic acid levels, and erythrocyte and cerebrospinal fluid reduced glutathione concentrations were decreased; however, erythrocyte and cerebrospinal fluid malondialdehyde levels were increased in the patients. Cerebrospinal fluid malondialdehyde levels were different between clinical stages of the disease (P < .05). Higher cerebrospinal fluid malondialdehyde level was associated with the more severe clinical stage. A positive correlation was found between cerebrospinal fluid malondialdehyde level and clinical stages (r = 0.42; P < .05) and between erythrocyte malondialdehyde level and clinical stages (r = 0.40; P < .05). Our findings showed presence of oxidative damage in subacute sclerosing panencephalitis and that antioxidants were increased as defense mechanisms of the organism against oxidative damage.


Selection of reversions and suppressors of a mutation in the CBF binding site of a lymphomagenic retrovirus.
The retrovirus SL3 induces T-cell lymphomas in mice. The transcriptional enhancer in the long terminal repeat (LTR) of SL3 contains two 72-bp repeats. Each repeat contains a binding site for the transcription factor CBF (also called AML1). The CBF binding sites are called core elements. SAA is a mutant that is identical to SL3 except for the presence of a single-base-pair substitution in each of the two core elements. This mutation significantly attenuates viral lymphomagenicity. Most lymphomas that occur in SAA-infected mice contain proviruses with reversions or second-site suppressor mutations within the core element. We examined the selective pressures that might account for the predominance of the reversions and suppressor mutations in tumor proviruses by analyzing when proviruses with altered core sequences became abundant during the course of lymphomagenesis. Altered core sequences were easily detected in thymus DNAs by 4 to 6 weeks after SAA infection of mice, well before lymphomas were grossly evident. This result is consistent with the hypothesis that viruses with the core sequence alterations emerged because they replicated more effectively in mice than SAA. The number of 72-bp tandem, repeats in the viral LTR was found to vary, presumably as a consequence of reverse transcriptase slippage during polymerization. Proviruses with two repeats predominated in the thymuses of SAA- and SL3-infected mice before lymphomas developed, although LTRs with one or three repeats were also present. This suggested that two was the optimal number of 72-bp repeats for viral replication. However, in lymphomas, proviruses with three or four repeats usually predominated. This suggested that a late step in the process of lymphomagenesis led to the abundance of proviruses with additional repeats. We hypothesize that proviruses with additional 72-bp repeats endowed the cells containing them with a selective growth advantage.


THE CONSUMPTION OF ACAI PULP CHANGES THE CONCENTRATIONS OF PLASMINOGEN ACTIVATOR INHIBITOR-1 AND EPIDERMAL GROWTH FACTOR (EGF) IN APPARENTLY HEALTHY WOMEN.
obesity, characterized by adiposity excess, is associated with endothelial dysfunction and possible inflammatory state with release of cytokines that determine endothelial function and can trigger chronic diseases. The dietary pattern are associated with the synthesis these cytokines. Fruits as the acai, which is rich in flavonoids, have a direct and beneficial effect on the control of this inflammatory process through the exercised antioxidant capacity. to evaluate the effect of acai pulp consumption on the inflammatory markers, anthropometric measurements, body composition, biochemical and dietary parameters in healthy women. forty women, were divided in 25 eutrophic and 15 with overweight. They intaked 200 g of acai pulp during 4 weeks. Anthropometric measurements, body composition, inflammatory markers, biochemical data, dietary intake and dietary antioxidants capacity were evaluated before and after the intervention. after the intervention, there was significant increase of EGF (p = 0.021) and PAI- 1(p = 0.011) in overweight women. Moreover, there was increase in body weight (p = 0.031), body mass index (p = 0.028), percentage of truncal fat (p = 0.003) and triceps skinfold thickness (p = 0.046) in eutrophic women. However, the skinfold thickness (p = 0.018) and total body fat (p = 0.016) decreased in overweight women. There was reduction of total protein (p = 0.049) due to the globulin reduction (p = 0.005), but the nutritional status was maintained in eutrophic group. the intake of 200g acai pulp, modulated the EGF and PAI-1 expression, possibly by modulation of acai on the parameters of body composition, dietary, clinical, biochemical and inflammatory, led to a redistribution and resizing of body fat of the trunk area, and presumably increased visceral fat.


Modulation of mismatch repair and genomic stability by miR-155.
Inactivation of mismatch repair (MMR) is the cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10-40% of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability [microsatellite instability (MSI)] are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer. Here we show that overexpression of miR-155 significantly down-regulates the core MMR proteins, hMSH2, hMSH6, and hMLH1, inducing a mutator phenotype and MSI. An inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer. Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis.


Determination of minimum clinically important difference (MCID) in pain, disability, and quality of life after revision fusion for symptomatic pseudoarthrosis.
Spinal surgical outcome studies rely on patient reported outcome (PRO) measurements to assess the effect of treatment. A shortcoming of these questionnaires is that the extent of improvement in their numerical scores lacks a direct clinical meaning. As a result, the concept of minimum clinically important difference (MCID) has been used to measure the critical threshold needed to achieve clinically relevant treatment effectiveness. Post hoc anchor-based MCID methods have not been applied to the surgical treatment for pseudoarthrosis. To determine the most appropriate MCID values for visual analog scale (VAS), Oswestry Disability Index (ODI), Short Form (SF)-12 physical component score (PCS), and European Quality of Life 5-Dimensions (EQ-5D) in patients undergoing revision lumbar arthrodesis for symptomatic pseudoarthrosis. STUDY DESIGN/ SETTING: Retrospective cohort study. In 47 patients undergoing revision fusion for pseudoarthrosis-associated back pain, PRO measures of back pain (BP-VAS), ODI, physical quality of life (SF-12 PCS), and general health utility (EQ-5D) were assessed preoperatively and 2 years postoperatively. Four subjective post hoc anchor-based MCID calculation methods were used to calculate MCID (average change; minimum detectable change; change difference; and receiver operating characteristic curve analysis) for two separate anchors (health transition index (HTI) of SF-36 and satisfaction index). All patients were available for a 2-year PRO assessment. Two years after surgery, a significant improvement was observed for all PROs; Mean change score: BP-VAS (2.3±2.6; p<.001), ODI (8.6%±13.2%; p<.001), SF-12 PCS (4.0±6.1; p=.01), and EQ-5D (0.18±0.19; p<.001). The four MCID calculation methods generated a wide range of MCID values for each of the PROs (BP-VAS: 2.0-3.2; ODI: 4.0%-16.6%; SF-12 PCS: 3.2-6.1; and EQ-5D: 0.14-0.24). There was no difference in response between anchors for any patient, suggesting that HTI and satisfaction anchors are equivalent in this patient population. The wide variations in calculated MCID values between methods precluded any ability to reliably determine what the true value is for meaningful change in this disease state. Using subjective post hoc anchor-based methods of MCID calculation, MCID after revision fusion for pseudoarthrosis varies by as much as 400% per PRO based on the calculation technique. MCID was suggested to be as low as 2 points for ODI and 3 points for SF-12. These wide variations and low values of MCID question the face validity of such calculation techniques, especially when applied to heterogeneous disease and patient groups with a multitude of psychosocial confounders such as failed back syndromes. The variability of MCID thresholds observed in our study of patients undergoing revision lumbar fusion for pseudoarthrosis raises further questions to whether ante hoc or Delphi methods may be a more valid and consistent technique to define clinically meaningful, patient-centered changes in PRO measurements.


Influence of familiar features on diagnosis: instantiated features in an applied setting.
Medical diagnosis can be viewed as a categorization task. There are two mechanisms whereby humans make categorical judgments: "analytical reasoning," based on explicit consideration of features and "nonanalytical reasoning," an unconscious holistic process of matching against prior exemplars. However, there is evidence that prior experience can also operate at the level of individual "instantiated" features (Brooks & Hannah, 2006). The present studies examined instantiated features in medical diagnosis. Four "pseudopsychiatric" conditions, each described by four characteristic features, were taught to undergraduate psychology students. They practiced on additional cases, then were tested on new cases with features from two conditions. In Experiment 1, diagnoses associated with familiar features presented one or three times during practice were assigned a higher probability than those with novel features. Experiment 2 showed that the impact of feature frequency was dependent on its consistency with the case diagnosis. Experiment 3 showed that the effect of feature familiarity was not confined to cases with two equiprobable diagnoses. Experiment 4 showed that the effect remained after a 24 hour delay. These four studies demonstrated that features seen in practice have a greater influence on diagnosis than novel synonyms. In fact, seeing a feature once within the appropriate context (a patient case in which it is a member of the primary diagnosis) was sufficient to form a diagnostic association equivalent to instantiations seen four times in a different context. The results of these studies have implications for theories of categorization and for teaching clinical reasoning.


Plasma concentrations of cyclic volatile methylsiloxanes (cVMS) in pregnant and postmenopausal Norwegian women and self-reported use of personal care products (PCPs).
Dermal application of personal care products (PCPs) is considered an important human exposure route for siloxanes. Their presence as minor or major constituents in many personal care products (PCPs) and cosmetics is of concern for human exposure. The aim of this study was to quantify cyclic volatile methylsiloxanes (cVMS) in blood plasma of pregnant and postmenopausal women, and to investigate possible links to self-reported use of PCPs for the latter group. Participants were recruited from two studies, namely the Norwegian Women and Cancer Study (NOWAC) and the North Norwegian Mother-and-child Study (MISA). For the NOWAC cohort, 94 plasma samples from postmenopausal women were analyzed (blood drawn in 2005) and information about PCP use and breast implants was derived from a self-administered questionnaire. In the MISA study, the collection of the plasma samples (blood drawn in 2009) constituted a re-sampling because the original serum vacutainers used were contaminated with cVMS. D4 (octamethylcyclotetrasiloxane) was the dominant compound in plasma for both cohorts. For the NOWAC samples, more than 85% of the women had D4 concentrations above the LOQ (2.74 ng/mL), while the detection frequency was only 18% for the MISA participants. The highest cVMS plasma concentrations were observed for D4: 12.7 ng/mL (NOWAC) and 2.69 ng/mL (MISA). For the other cVMS, decamethylcyclopentasiloxane (D5) and dodecamethylcyclohexasiloxane (D6) concentrations were below the detection limit in most samples. There was no significant correlation between the concentrations of D4 and the reported total body cream use. Sampling time (2005 versus 2009) and age of the donors could explain the differences between the two cohorts.


Improved glucose homeostasis in male obese Zucker rats coincides with enhanced baroreflexes and activation of the nucleus tractus solitarius.
Young adult male obese Zucker rats (OZR) develop insulin resistance and hypertension with impaired baroreflex-mediated bradycardia and activation of nucleus tractus solitarius (NTS). Because type 1 diabetic rats also develop impaired baroreflex-mediated NTS activation, we hypothesized that improving glycemic control in OZR would enhance compromised baroreflexes and NTS activation. Fasting blood glucose measured by telemetry was comparable in OZR and lean Zucker rats (LZR) at 12-17 wk. However, with access to food, OZR were chronically hyperglycemic throughout this age range. By 15-17 wk of age, tail samples yielded higher glucose values than those measured by telemetry in OZR but not LZR, consistent with reports of exaggerated stress responses in OZR. Injection of glucose (1g/kg ip) produced larger rises in glucose and areas under the curve in OZR than LZR. Treatment with metformin (300 mg·kg-1·day-1) or pioglitazone (5 mg·kg-1·day-1) in drinking water for 2-3 wk normalized fed glucose levels in OZR with no effect in LZR. After metformin treatment, area under the curve for blood glucose after glucose injection was reduced in OZR and comparable to LZR. Hyperinsulinemia was slightly reduced by each treatment in OZR, but insulin was still greatly elevated compared with LZR. Neither treatment reduced hypertension in OZR, but both treatments significantly improved the blunted phenylephrine-induced bradycardia and NTS c-Fos expression in OZR with no effect in LZR. These data suggest that restoring glycemic control in OZR enhances baroreflex control of heart rate by improving the response of the NTS to raising arterial pressure, even in the presence of hyperinsulinemia and hypertension.


A retrospective chart review to identify perinatal factors associated with food allergies.
Gut flora are important immunomodulators that may be disrupted in individuals with atopic conditions. Probiotic bacteria have been suggested as therapeutic modalities to mitigate or prevent food allergic manifestations. We wished to investigate whether perinatal factors known to disrupt gut flora increase the risk of IgE-mediated food allergies. Birth records obtained from 192 healthy children and 99 children diagnosed with food allergies were reviewed retrospectively. Data pertaining to delivery method, perinatal antibiotic exposure, neonatal nursery environment, and maternal variables were recorded. Logistic regression analysis was used to assess the association between variables of interest and subsequent food allergy diagnosis. Retrospective investigation did not find perinatal antibiotics, NICU admission, or cesarean section to be associated with increased risk of food allergy diagnosis. However, associations between food allergy diagnosis and male gender (66 vs. 33; p=0.02) were apparent in this cohort. Additionally, increasing maternal age at delivery was significantly associated with food allergy diagnosis during childhood (OR, 1.05; 95% CI, 1.017 to 1.105; p=0.005). Gut flora are potent immunomodulators, but their overall contribution to immune maturation remains to be elucidated. Additional understanding of the interplay between immunologic, genetic, and environmental factors underlying food allergy development need to be clarified before probiotic therapeutic interventions can routinely be recommended for prevention or mitigation of food allergies. Such interventions may be well-suited in male infants and in infants born to older mothers.


Late acquisition of literacy in a native language.
With event-related functional MRI (fMRI) and with behavioral measures we studied the brain processes underlying the acquisition of native language literacy. Adult dialect speakers were scanned while reading words belonging to three different conditions: dialect words, i.e., the native language in which subjects are illiterate (dialect), German words, i.e., the second language in which subjects are literate, and pseudo-words. Investigating literacy acquisition of a dialect may reveal how novel readers of a language build an orthographic lexicon, i.e., establish a link between already available semantic and phonological representations and new orthographic word forms. The main results of the study indicate that a set of regions, including the left anterior hippocampal formation and subcortical nuclei, is involved in the buildup of orthographic representations. The repeated exposure to written dialect words resulted in a convergence of the neural substrate to that of the language in which these subjects were already proficient readers. The latter result is compatible with a "fast" brain plasticity process that may be related to a shift of reading strategies.


HTRIdb: an open-access database for experimentally verified human transcriptional regulation interactions.
The modeling of interactions among transcription factors (TFs) and their respective target genes (TGs) into transcriptional regulatory networks is important for the complete understanding of regulation of biological processes. In the case of experimentally verified human TF-TG interactions, there is no database at present that explicitly provides such information even though many databases containing human TF-TG interaction data have been available. In an effort to provide researchers with a repository of experimentally verified human TF-TG interactions from which such interactions can be directly extracted, we present here the Human Transcriptional Regulation Interactions database (HTRIdb). The HTRIdb is an open-access database that can be searched via a user-friendly web interface and the retrieved TF-TG interactions data and the associated protein-protein interactions can be downloaded or interactively visualized as a network through the web version of the popular Cytoscape visualization tool, the Cytoscape Web. Moreover, users can improve the database quality by uploading their own interactions and indicating inconsistencies in the data. So far, HTRIdb has been populated with 284 TFs that regulate 18302 genes, totaling 51871 TF-TG interactions. HTRIdb is freely available at http://www.lbbc.ibb.unesp.br/htri. HTRIdb is a powerful user-friendly tool from which human experimentally validated TF-TG interactions can be easily extracted and used to construct transcriptional regulation interaction networks enabling researchers to decipher the regulation of biological processes.


Neoadjuvant radiotherapy/chemoradiotherapy in locally advanced non-small cell lung cancer.
Locally advanced non-small cell lung cancer (NSCLC) consists of a heterogeneous group of patients, and the optimal treatment is still controversial. The current standard of care is concurrent chemoradiotherapy. The prognosis is still poor, with high rates of local and distant failure despite multimodality treatment. One of the efforts to improve outcomes in these patients is to use neoadjuvant treatment to improve resectability, and downstaging the nodal disease, which has a clear impact on prognosis. Radiotherapy as the sole neoadjuvant modality has been used historically without any survival benefit, but with increased toxicity. After the demonstrating a survival benefit by combining radiotherapy and chemotherapy, phase II studies were started to determine the neoadjuvant administration of these two modalities together. Although the results of these studies revealed a heterogeneous postinduction pathologic complete response, tumor and nodal down-staging can be achieved at the cost of a slightly higher morbidity and mortality. Subsequent phase III trials also failed to show a survival benefit to surgery, but indicated that there may be a subset of patients with locally advanced disease who can benefit from resection unless pneumonectomy is not provided. In order to increase the efficacy of radiotherapy, hyperfractionated-accelerated schedules have been used with promising complete pathologic response rates, which might improve prognosis. Recently, studies applying high radiotherapy doses in the neoadjuvant setting demonstrated the safety of resection after radiotherapy, with high nodal clearance rates and encouraging long-term survival results. In conclusion, neoadjuvant treatment of locally advanced NSCLC is one of the most challenging issues in the treatment of this disease, but it can be offered to appropriately selected patients, and should be done by a multidisciplinary team. Individual risk profiles, definite role of radiotherapy with optimal timing, and dose need to be clarified by carefully designed clinical trials.


Treatment of food waste digestate using microalgae-based systems with low-intensity light-emitting diodes.
Anaerobic digestion of food wastes coupled with digestate post-treatment using microalgae-based systems could recover large amounts of energy and nutrients worldwide. However, the development of full-scale implementations requires overcoming microalgae inhibition by high ammonia concentrations and low light transmittances affecting photosynthesis. This study evaluated the potential of microalgae-based reactors supplied with red light-emitting diodes (LEDs) at low intensity (660 nm and 15 µmol·m-2·s-1) to treat food waste digestate. LED reactors were compared with control reactors exposed to solar radiation. From a range of species in the inoculum, Chlorella vulgaris showed high adaptation to both lighting regimes and digestate environmental conditions, characterized by a C:N:P ratio of 74:74:1. Removal efficiencies for control and LED reactors were 84.0% and 95.8% for soluble chemical oxygen demand (COD) and 89.4% and 53.0% for ammonia, respectively. Approximately 50% of ammonia in control reactor and 15% in LED reactor was lost from the systems, whereas 17% and 36% of ammonia was transformed to organic nitrogen in control and LED reactors, respectively. Low-intensity LEDs maintained microalgae growth in levels similar to solar radiation and supported efficient digestate treatment, showing a potential for further application in optimization of full scale reactors at a relatively low energy cost.


A strategy for the conservation of biodiversity on mid-ocean ridges from deep-sea mining.
Mineral exploitation has spread from land to shallow coastal waters and is now planned for the offshore, deep seabed. Large seafloor areas are being approved for exploration for seafloor mineral deposits, creating an urgent need for regional environmental management plans. Networks of areas where mining and mining impacts are prohibited are key elements of these plans. We adapt marine reserve design principles to the distinctive biophysical environment of mid-ocean ridges, offer a framework for design and evaluation of these networks to support conservation of benthic ecosystems on mid-ocean ridges, and introduce projected climate-induced changes in the deep sea to the evaluation of reserve design. We enumerate a suite of metrics to measure network performance against conservation targets and network design criteria promulgated by the Convention on Biological Diversity. We apply these metrics to network scenarios on the northern and equatorial Mid-Atlantic Ridge, where contractors are exploring for seafloor massive sulfide (SMS) deposits. A latitudinally distributed network of areas performs well at (i) capturing ecologically important areas and 30 to 50% of the spreading ridge areas, (ii) replicating representative areas, (iii) maintaining along-ridge population connectivity, and (iv) protecting areas potentially less affected by climate-related changes. Critically, the network design is adaptive, allowing for refinement based on new knowledge and the location of mining sites, provided that design principles and conservation targets are maintained. This framework can be applied along the global mid-ocean ridge system as a precautionary measure to protect biodiversity and ecosystem function from impacts of SMS mining.


Simple general method of generating non-oxo, non-amavadine model octacoordinated vanadium(IV) complexes of some tetradentate ONNO chelating ligands from various oxovanadium(IV/V) compounds and structural characterization of one of them.
A simple general route of obtaining very stable octacoordinated non-oxovanadium(IV) complexes of the general formula VL2 (where H2L is a tetradentate ONNO donor) is presented. Six such complexes (1-6) are adequately characterized by elemental analysis, mass spectrometry, and various spectroscopic techniques. One of these compounds (1) has been structurally characterized. The molecule has crystallographic symmetry and has a dodecahedral structure existing in a tetragonal space group Pn2. The non-oxo character and VL2 stoichiometry for all of the complexes are established from analytical and mass spectrometric data. In addition, the non-oxo character is clearly indicated by the complete absence of the strong nuV=O band in the 925-1025 cm-1 region, which is a signature of all oxovanadium species. The complexes are quite stable in open air in the solid state and in solution, a phenomenon rarely observed in non-oxovanadium(IV) or bare vanadium(IV) complexes.


Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.
Huntingtin protein is mutated in Huntington disease. We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wild-type huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.


Motivational Interviewing to Encourage Quit Attempts Among Smokers Not Ready to Quit: A Trial-Based Economic Analysis.
This study used data from a randomized controlled trial evaluating the efficacy of motivational interviewing (MI) relative to health education (HE) and brief advice (BA) to encourage quit attempts and cessation in order to determine their relative cost-effectiveness. Urban community residents (n = 255) with low desire to quit smoking were randomized to MI, HE, or BA which differed in communication style and/or number of treatment sessions. Incremental cost-effectiveness ratios were used to compare the intensive interventions (MI and HE) to BA for facilitating quit attempts and smoking cessation. Costs were calculated from the perspective of an agency that might engage in program delivery. Sensitivity analysis examined different assumptions for MI training and pharmacotherapy costs. Total intervention delivery time costs per participant for MI, HE, and BA were $46.63, $42.87, and $2.4, respectively. Cost-effectiveness ratios per quit attempt at 24 weeks were $380 for MI, $272 for HE, and $209 for BA. The cost per additional quit attempt for MI and HE relative to BA was $508 and $301, respectively. The cost per additional quit for MI and HE relative to BA was $2030 and $752, respectively. Four separate sensitivity analyses conducted in our study did not change the conclusion the HE had a lower Incremental Cost-Effectiveness Ratio for both quit attempts and cessation. HE was the most cost-effective of the three types of smoking cessation induction therapies and therefore may be preferable for smokers who are less motivated to quit. Providing valuable cost information in choosing different clinical methods for motivating smokers to quit. All direct costs and activity-based time costs associated with delivering the intervention were analyzed from the perspective of an agency that may wish to replicate these strategies. A randomized controlled trial evaluating the efficacy of MI relative to HE and BA to encourage quit attempts and cessation determined their relative cost-effectiveness. HE was the most cost-effective of the three types of smoking cessation induction therapies and therefore may be preferable. Despite guideline recommendations, MI may not be the best approach to encourage quit attempts in diverse populations. Rather, a structured, intensive HE intervention might be the most cost-effective alternative.


Optimal visuotactile integration for velocity discrimination of self-hand movements.
Illusory hand movements can be elicited by a textured disk or a visual pattern rotating under one's hand, while proprioceptive inputs convey immobility information (Blanchard C, Roll R, Roll JP, Kavounoudias A. PLoS One 8: e62475, 2013). Here, we investigated whether visuotactile integration can optimize velocity discrimination of illusory hand movements in line with Bayesian predictions. We induced illusory movements in 15 volunteers by visual and/or tactile stimulation delivered at six angular velocities. Participants had to compare hand illusion velocities with a 5°/s hand reference movement in an alternative forced choice paradigm. Results showed that the discrimination threshold decreased in the visuotactile condition compared with unimodal (visual or tactile) conditions, reflecting better bimodal discrimination. The perceptual strength (gain) of the illusions also increased: the stimulation required to give rise to a 5°/s illusory movement was slower in the visuotactile condition compared with each of the two unimodal conditions. The maximum likelihood estimation model satisfactorily predicted the improved discrimination threshold but not the increase in gain. When we added a zero-centered prior, reflecting immobility information, the Bayesian model did actually predict the gain increase but systematically overestimated it. Interestingly, the predicted gains better fit the visuotactile performances when a proprioceptive noise was generated by covibrating antagonist wrist muscles. These findings show that kinesthetic information of visual and tactile origins is optimally integrated to improve velocity discrimination of self-hand movements. However, a Bayesian model alone could not fully describe the illusory phenomenon pointing to the crucial importance of the omnipresent muscle proprioceptive cues with respect to other sensory cues for kinesthesia.


Use of Mass-Participation Outdoor Events to Assess Human Exposure to Tickborne Pathogens.
Mapping the public health threat of tickborne pathogens requires quantification of not only the density of infected host-seeking ticks but also the rate of human exposure to these ticks. To efficiently sample a high number of persons in a short time, we used a mass-participation outdoor event. In June 2014, we sampled ≈500 persons competing in a 2-day mountain marathon run across predominantly tick-infested habitat in Scotland. From the number of tick bites recorded and prevalence of tick infection with Borrelia burgdoferi sensu lato and B. miyamotoi, we quantified the frequency of competitor exposure to the pathogens. Mass-participation outdoor events have the potential to serve as excellent windows for epidemiologic study of tickborne pathogens; their concerted use should improve spatial and temporal mapping of human exposure to infected ticks.


Ensemble clustering of phosphoproteomic data identifies differences in protein interactions and cell-cell junction integrity of HER2-overexpressing cells.
Overexpression of HER2, a receptor tyrosine kinase of the ERBB family, in breast cancer is related to increased cancer progression and aggressiveness. A breast epithelial cell model with the single perturbation of HER2 overexpression is capable of replicating the increased aggressiveness of HER2 overexpressing cancers. In previous work, Wolf-Yadlin and colleagues (Wolf-Yadlin et al., Mol. Syst. Biol., 2006, 2) measured the proximal tyrosine phosphorylation dynamics of the parental and HER2 overexpressing cells (24H) in response to EGF. Here, we apply an ensemble clustering approach to dynamic phosphorylation measurements of the two cell models in order to identify signaling events that explain the increased migratory potential of HER2 overexpressing cells. The use of an ensemble approach for identifying relationships within a dataset and how these relationships change across datasets uncovers relationships that cannot be found by the direct comparison of dynamic responses in the two conditions. Of particular note is a drastic change in the clustering of SHC1 phosphorylation (on site Y349) from an EGFR-MAPK module in parental cells to a module consisting of an E-cadherin junction protein phosphorylation site, catenin delta-1 Y228, in HER2 overexpressing (24H) cells. Given the importance of E-cadherin junctions in healthy epithelial wound healing and migration, we chose to test the computationally-derived identification of altered cell junctions and CTNND1:SHC1 relationships. Our cell and molecular biology experiments demonstrate that SHC and CTNND1 interact in an EGF- and HER2-dependent manner and that the cell junctions are phenotypically affected by HER2, breaking down in response to EGF and yet avoiding apoptosis as a result of cell junction loss. The results suggest a mechanism by which HER2 alters the localization of the SHC-MAPK signaling axis and a phenotypic effect on cell junction integrity.


Furosemide augments the effects of captopril on nuclear studies in renovascular stenosis.
Captopril facilitates detection of unilateral renovascular hypertension by selectively reducing glomerular filtration rate in affected kidneys. To determine if volume depletion augments this response, we compared the effects of captopril, furosemide, and combined furosemide plus captopril on individual kidney computer-derived clearances of 99mTc-diethylenetriamine pentaacetic acid (DTPA) and [131I]o-iodohippurate in two-kidney, one clip Goldblatt hypertensive rats and normal controls. In clipped kidneys, captopril reduced DTPA clearance significantly from baseline (from 0.31 +/- 0.02 to 0.19 +/- 0.04 ml/min/100 g; p less than 0.02) whereas furosemide alone had no effect (0.28 +/- 0.03 ml/min/100 g). Combined furosemide plus captopril further reduced clipped kidney DTPA clearance to a level significantly less than captopril alone (0.10 +/- 0.02 ml/min/100 g; p less than 0.02). Clipped kidney o-iodohippurate clearance was not changed from baseline by any treatment. In contralateral unclipped and normal kidneys, DTPA clearance did not decline from baseline following either captopril or furosemide plus captopril treatment. Since the dose of captopril used (3 mg/kg by intraperitoneal injection) did not reduce systolic blood pressure of hypertensive rats significantly, these changes probably reflect intrarenal rather than systemic hemodynamic effects of converting enzyme inhibition and are consistent with the hypothesis that captopril interferes with glomerular filtration in stenotic kidneys by reducing efferent arteriolar vascular resistance. Prior volume depletion accentuates the effect of captopril on stenotic kidney glomerular filtration rate, providing improved functional discrimination of stenotic kidneys from contralateral unclipped and normal kidneys. These results indicate that furosemide-induced volume depletion may increase the diagnostic sensitivity of captopril-enhanced 99mTc-DTPA renography in the detection of unilateral renovascular hypertension.


Persistent/Recurrent syringomyelia after Chiari decompression-natural history and management strategies: a systematic review.
Study Design Systematic review. Study Rationale One of the most consistent indications for a Chiari decompression is tonsillar descent meeting the radiographic criteria and an associated syrinx in a symptomatic patient. In counseling patients about surgery, it would be advantageous to have information regarding the expected outcome with regard to the syrinx and other possible treatments available if the result is suboptimal. Clinical Questions The clinical questions include: (1) What is the average rate of recurrent or residual syringomyelia following posterior fossa decompression as a result of Chiari malformation with associated syringomyelia? (2) What treatment methods have been reported in the literature for managing recurrent or residual syringomyelia after initial posterior fossa decompression? Materials and Methods Available search engines were utilized to identify publications dealing with recurrent or residual syrinx after Chiari decompression and/or management of the syrinx. Rates of residual or recurrent syrinx were extracted and management strategies were recorded. Overall strength of evidence was quantified. Results Of the 72 citations, 11 citations met inclusion criteria. Rates of recurrent/residual syringomyelia after decompression in adults range from 0 to 22% with an average of 6.7%. There were no studies that discussed specifically management of the remaining syrinx. Conclusion Rates of recurrent/residual syringomyelia after Chiari decompression in adults range from 0 to 22% (average 6.7%). Although no studies describing the optimal management of residual syrinx were found, there is general agreement that the aim of the initial surgery is to restore relatively unimpeded flow of cerebrospinal across the craniocervical junction. Large holocord syrinx may induce a component of spinal cord injury even with adequate decompression and reduction in the caliber of the syrinx, resulting in permanent symptoms of injury.