Reduced Serum Zinc Ion Concentration Is Associated with Coronary Heart Disease.
Imbalances in trace element concentrations in the blood as a result of poor nutrition may affect the development of coronary heart disease. To study the relationship between zinc ion concentration in the peripheral blood and coronary heart disease, we performed multiple logistic regression and hierarchical analyses on blood measurements of 3541 patients. The experimental group comprised 1253 patients diagnosed with coronary heart disease, and the control group included 2288 healthy patients. The zinc ion concentrations were measured by a color rendering method, and the results were analyzed using SPSS software. Fifteen laboratory quality evaluation samples from the Clinical Laboratory Center of the Chinese Ministry of Health were selected for analysis. The mean values and average bias were calculated. The estimated qualified judgment standard was < 1/2 TEa (the allowable total error for zinc). A hierarchical analysis of risk factors, including smoking, age, sex, and menopause in women, was performed. The results revealed that non-smoking, aging (especially postmenopausal women), and low blood zinc concentrations were independent risk factors for the development of coronary heart disease (P ≤ 0.05, zinc ion concentration less than 13.82 ± 2.91). The findings strongly suggest that decreased zinc ion concentrations in the peripheral blood can be used as an independent risk factor for the prediction of coronary heart disease, especially in older patients, non-smokers, and women, in particular, postmenopausal women.


The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family.
The tumor-suppressive let-7 microRNA family targets various oncogene-encoding mRNAs. We identify the let-7 targets HMGA2, LIN28B and IGF2BP1 to form a let-7 antagonizing self-promoting oncogenic triangle. Surprisingly, 3'-end processing of IGF2BP1 mRNAs is unaltered in aggressive cancers and tumor-derived cells although IGF2BP1 synthesis was proposed to escape let-7 attack by APA-dependent (alternative polyadenylation) 3' UTR shortening. However, the expression of the triangle factors is inversely correlated with let-7 levels and promoted by LIN28B impairing let-7 biogenesis. Moreover, IGF2BP1 enhances the expression of all triangle factors by recruiting the respective mRNAs in mRNPs lacking AGO proteins and let-7 miRNAs. This indicates that the downregulation of let-7, largely facilitated by LIN28B upregulation, and the protection of let-7 target mRNAs by IGF2BP1-directed shielding in mRNPs synergize in enhancing the expression of triangle factors. The oncogenic potential of this triangle was confirmed in ovarian cancer (OC)-derived ES-2 cells transduced with let-7 targeting decoys. In these, the depletion of HMGA2 only diminishes tumor cell growth under permissive conditions. The depletion of LIN28B and more prominently IGF2BP1 severely impairs tumor cell viability, self-renewal and 2D as well as 3D migration. In conclusion, this suggests the targeting of the HMGA2-LIN28B-IGF2BP1 triangle as a promising strategy in cancer treatment.


JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework.
JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) and TF flexible models (TFFMs) for TFs across multiple species in six taxonomic groups. In the 2018 release of JASPAR, the CORE collection has been expanded with 322 new PFMs (60 for vertebrates and 262 for plants) and 33 PFMs were updated (24 for vertebrates, 8 for plants and 1 for insects). These new profiles represent a 30% expansion compared to the 2016 release. In addition, we have introduced 316 TFFMs (95 for vertebrates, 218 for plants and 3 for insects). This release incorporates clusters of similar PFMs in each taxon and each TF class per taxon. The JASPAR 2018 CORE vertebrate collection of PFMs was used to predict TF-binding sites in the human genome. The predictions are made available to the scientific community through a UCSC Genome Browser track data hub. Finally, this update comes with a new web framework with an interactive and responsive user-interface, along with new features. All the underlying data can be retrieved programmatically using a RESTful API and through the JASPAR 2018 R/Bioconductor package.


Multiple Influences of Mechanical Forces on Cell Competition.
Cell competition is a widespread process leading to the expansion of one cell population through the elimination and replacement of another. A large number of genetic alterations can lead to either competitive elimination of the mutated population or expansion of the mutated cells through the elimination of the neighbouring cells. Several processes have been proposed to participate in the preferential elimination of one cell population, including competition for limiting extracellular pro-survival factors, communication through direct cell-cell contact, or differential sensitivity to mechanical stress. Recent quantitative studies of cell competition have also demonstrated the strong impact of the shape of the interfaces between the two populations. Here, we discuss the direct and indirect contribution of mechanical cues to cell competition, where they act either as modulators of competitive interactions or as direct drivers of cell elimination. We first discuss how mechanics can regulate contact-dependent and diffusion-based competition by modulating the shape of the interface between the two populations. We then describe the direct contribution of mechanical stress to cell elimination and competition for space. Finally, we discuss how mechanical feedback also influences compensatory growth and triggers preferential expansion of one population.


Gastric cancer in Scotland: changing epidemiology, unchanging workload.
To determine the changes in incidence of and mortality from gastric cancer in Scotland between 1978 and 1987 and in the operative workload in Lothian between 1979 and 1988. Analysis of national incidence statistics for gastric cancer derived from the Scottish national cancer registry, deaths from gastric cancer recorded by the registrar general for Scotland, and Lothian surgical audit data. Scotland and Lothian Health Board area. Patients in Scotland with gastric cancer during 1978 to 1987 inclusive; patients in Scotland with gastric cancer recorded on their death certificate as cause of death during 1978 to 1987; patients who had an operation in Lothian for gastric cancer during 1979 to 1988. Changes in incidence of and mortality from gastric cancer in Scotland from 1978 to 1987 and in the number of operations performed for gastric cancer in Lothian from 1979 to 1988. Mortality from gastric cancer in Scotland fell by about 25% over the 10 years. The incidence and standardised incidence of gastric cancer showed a marginal decline of about 9%. The differences in trends between incidence and mortality were significant (p less than 0.05). This study shows that the surgical workload associated with gastric cancer is not declining. This is because the incidence has remained almost static, which may be due to the relative increase in the numbers of older people in the population, who are at greater risk of developing gastric cancer. Gastric cancer should not be regarded as a disease in decline. Incidence and workload should determine resources allocated to this disease rather than mortality statistics.


Costs and Efficiency of Online and Offline Recruitment Methods: A Web-Based Cohort Study.
The Internet is widely used to conduct research studies on health issues. Many different methods are used to recruit participants for such studies, but little is known about how various recruitment methods compare in terms of efficiency and costs. The aim of our study was to compare online and offline recruitment methods for Internet-based studies in terms of efficiency (number of recruited participants) and costs per participant. We employed several online and offline recruitment methods to enroll 18- to 45-year-old women in an Internet-based Danish prospective cohort study on fertility. Offline methods included press releases, posters, and flyers. Online methods comprised advertisements placed on five different websites, including Facebook and Netdoktor.dk. We defined seven categories of mutually exclusive recruitment methods and used electronic tracking via unique Uniform Resource Locator (URL) and self-reported data to identify the recruitment method for each participant. For each method, we calculated the average cost per participant and efficiency, that is, the total number of recruited participants. We recruited 8252 study participants. Of these, 534 were excluded as they could not be assigned to a specific recruitment method. The final study population included 7724 participants, of whom 803 (10.4%) were recruited by offline methods, 3985 (51.6%) by online methods, 2382 (30.8%) by online methods not initiated by us, and 554 (7.2%) by other methods. Overall, the average cost per participant was €6.22 for online methods initiated by us versus €9.06 for offline methods. Costs per participant ranged from €2.74 to €105.53 for online methods and from €0 to €67.50 for offline methods. Lowest average costs per participant were for those recruited from Netdoktor.dk (€2.99) and from Facebook (€3.44). In our Internet-based cohort study, online recruitment methods were superior to offline methods in terms of efficiency (total number of participants enrolled). The average cost per recruited participant was also lower for online than for offline methods, although costs varied greatly among both online and offline recruitment methods. We observed a decrease in the efficiency of some online recruitment methods over time, suggesting that it may be optimal to adopt multiple online methods.


The Role of Stress, Trauma, and Negative Affect in Alcohol Misuse and Alcohol Use Disorder in Women.
Recent evidence indicates that the United States is facing a public health crisis of alcohol misuse and alcohol use disorder (AUD), which has been fueled in part by dramatic rises in binge and heavy drinking and prevalence of AUD in women. Historically, alcohol misuse and AUD have been more prevalent in men than in women. However, recent evidence on data from the past decade shows increases in AUD prevalence rates that are associated with substantially higher binge and heavy drinking and AUD prevalence in women compared to men. This paper first addresses the key roles of stress, trauma, childhood maltreatment, negative affect, and mood and anxiety disorders; sex differences in the presentation of these psychosocial and psychological factors; and their contributions to alcohol misuse, escalation to binge and heavy drinking, and transition to AUD in women. Also examined are potential central and peripheral biological mechanisms by which stressors and traumatic experiences, as well as chronic stress states-including depression and anxiety-may facilitate differential pathways to alcohol misuse, escalation, and transition to AUD in women. Finally, this paper discusses major gaps in the literature on sex differences in these areas as well as the need for greater research on sex-specific pathways to alcohol misuse and transition to AUD, so as to support a more comprehensive understanding of AUD etiology and for the development of new strategies for prevention and treatment of alcohol misuse and AUD in women.


Mutant IDH1 and seizures in patients with glioma.
Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5. Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1wt) patients and in 59%-74% of IDH1mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5. The D2HG product of IDH1mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1mut inhibitors may improve antiepileptic therapy in patients with IDH1mut gliomas.


Herbicide options for effective weed management in dry direct-seeded rice under scented rice-wheat rotation of western Indo-Gangetic Plains.
Farmers' participatory field trials were conducted at Madhuban, and Taraori, the two participatory experimental sites/locations of the Cereal Systems Initiative for South Asia (CSISA), a collaborative project of IRRI and CIMMYT in Karnal district of Haryana, India, during Kharif (wet season) 2010 and 2011. This research aimed to evaluate preemergence (PRE) and postemergence (POST) herbicides for providing feasible and economically viable weed management options to farmers for predominant scented rice varieties. Treatments with pendimethalin PRE fb bispyribac-sodium + azimsulfuron POST had lower weed biomass at 45 days after sowing (DAS). At Madhuban, highest grain yield of scented basmati rice (3.43 t ha-1) was recorded with the sequential application of pendimethalin PRE fb bispyribac-sodium + azimsulfuron POST. However, at Taraori, yields were similar with pendimethalin or oxadiargyl PRE fb bispyribac-sodium and/or azimsulfuron POST. Applying oxadiargyl by mixing with sand onto flooded field was less effective than spray applications in non-flooded field. The benefit-cost ratio of rice crop was higher with herbicide treatments at both sites as compared with the non-treated weed-free check except single PRE and POST applications and sequential application of oxadiargyl PRE fb oxadiargyl PRE. In a separate experiment conducted at Nagla and Taraori sites, scented rice cultivars' ('CSR 30' and 'Pusa 1121') tolerance to three rates of azimsulfuron (15, 25, and 35 g ai ha-1) was evaluated over two years (2010 and 2011). CSR 30 (superfine, scented) was more sensitive to higher rates (35 g ai ha-1) of azimsulfuron as compared to Pusa 1121 (fine, scented). Crop injuries were 8 and 28% in case of CSR 30; 5 and 15% in Pusa 1121 when applied with azimsulfuron 25 and 35 g ai ha-1, respectively. Azimsulfuron applied at 35 g ai ha-1 reduced yield in both cultivars but in CSR 30 yield reduction was twofold (11.5%) as that of Pusa 1121 (5.2%).


High-Resolution Genotyping of Wild Barley Introgression Lines and Fine-Mapping of the Threshability Locus thresh-1 Using the Illumina GoldenGate Assay.
Genetically well-characterized mapping populations are a key tool for rapid and precise localization of quantitative trait loci (QTL) and subsequent identification of the underlying genes. In this study, a set of 73 introgression lines (S42ILs) originating from a cross between the spring barley cultivar Scarlett (Hordeum vulgare ssp. vulgare) and the wild barley accession ISR42-8 (H. v. ssp. spontaneum) was subjected to high-resolution genotyping with an Illumina 1536-SNP array. The array enabled a precise localization of the wild barley introgressions in the elite barley background. Based on 636 informative SNPs, the S42IL set represents 87.3% of the wild barley genome, where each line contains on average 3.3% of the donor genome. Furthermore, segregating high-resolution mapping populations (S42IL-HRs) were developed for 70 S42ILs in order to facilitate QTL fine-mapping and cloning. As a case study, we used the developed genetic resources to rapidly identify and fine-map the novel locus thresh-1 on chromosome 1H that controls grain threshability. Here, the recessive wild barley allele confers a difficult to thresh phenotype, suggesting that thresh-1 played an important role during barley domestication. Using a S42IL-HR population, thresh-1 was fine-mapped within a 4.3cM interval that was predicted to contain candidate genes involved in regulation of plant cell wall composition. The set of wild barley introgression lines and derived high-resolution populations are ideal tools to speed up the process of mapping and further dissecting QTL, which ultimately clears the way for isolating the genes behind QTL effects.


Survey of the use of whole blood in current blood transfusion practice.
Limited use of whole blood has continued despite a general move to blood component therapy in recent years. This paper describes the results of a questionnaire survey which was distributed to haematologists in charge of blood banks in England and North Wales to ascertain how much and for which indications whole blood was being requested. There was a 58% response rate. More than 90% of hospitals that responded had not requested whole blood during the last 12 months. Indications for the use of whole blood were primarily in paediatric practice, mostly for neonatal exchange transfusion or paediatric surgery (cardiac or craniofacial). Infrequent use in adult practice was for "major bleeding" when whole blood was available, and in cardiac surgery, when post-operative bleeding was unresponsive to standard replacement therapy. The evidence for the use of whole blood in preference to component therapy in the massive transfusion setting was reviewed, and no compelling evidence was found for its routine use for this indication. It is worth noting that, as currently supplied in the UK, "whole blood" is not strictly "whole" as the leucocyte-depletion process removes platelets.


Persistence of specific antibody response in different experimental infections of mice with Toxocara canis larvae.
Anti-Toxocara antibody production and persistence were studied in experimental infections of BALB/c mice, according to three different schedules: Group I (GI)-25 mice infected with 200 T. canis eggs in a single dose; Group II (GII) 25 mice infected with 150 T. canis eggs given in three occasions, 50 in the 1st, 50 in the 5th and 50 in the 8th days; Group III (GIII)-25 mice also infected with 150 T. canis eggs, in three 50 eggs portions given in the 1st, 14th and 28th days. A 15 mice control group (GIV) was maintained without infection. In the 30th, 50th, 60th, 75th, 105th and 180th post-infection days three mice of the GI, GII and GIII groups and two mice of the control group had been sacrificed and exsanguinated for sera obtention. In the 360th day the remainder mice of the four groups were, in the same way, killed and processed. The obtained sera were searched for the presence of anti-Toxocara antibodies by an ELISA technique, using T. canis larvae excretion-secretion antigen. In the GI and GII, but not in the GIII, anti-Toxocara antibodies had been found, at least, up to the 180th post-infection day. The GIII only showed anti-Toxocara antibodies, at significant level, in the 30th post-infection day.


Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics.
A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.


Sulfamethazine as a model compound to assess sex hormone-dependent cytochrome P-450 activity in rats.
Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and two of its hydroxylated metabolites [5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)] were determined in male and female rats, in castrated males, and in rats pretreated with various steroid hormones. Male rats had a 2-fold higher SMZ plasma clearance than females, castrates, and males treated with flutamide (a testosterone antagonist). When castrated male rats were treated with testosterone or trenbolone, SMZ plasma clearance returned to normal values. Higher SMZ plasma clearance rates in the presence of androgens went together with higher urinary recoveries of the 6CH2OHSMZ metabolite. In hepatic microsomes of male rats lower apparent KM values, and higher Vmax values for 6CH2OHSMZ and 5OHSMZ formation were found than in microsomes of female rats. Castration or treatment of male rats with flutamide markedly reduced microsomal SMZ hydroxylation rates. Pretreatment of male or female rats with phenobarbital or triacetyl-oleandomycin had no effect on microsomal SMZ hydroxylation, whereas a continuous infusion with bovine somatotropin in male rats caused a marked decrease in SMZ hydroxylation rate. Finally, SMZ hydroxylation to 6CH2OHSMZ and 5OHSMZ in hepatic microsomes from male rats was strongly inhibited by monoclonal antibodies against P-4502C11. These results suggest that the male-specific P-4502C11 enzyme plays an important role in the hydroxylation of SMZ to 6CH2OHSMZ and 5OHSMZ in rats. SMZ seems a useful model compound to assess hormone effects on oxidative biotransformation (in vivo and in vitro) in rats.


A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals.
The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20-69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals. ClinicalTrials.gov identifier NCT01699893.


Effects of control interventions on Clostridium difficile infection in England: an observational study.
The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility. Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998-2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses. National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48-0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97-1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2). Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes. UK Clinical Research Collaboration (Medical Research Council, Wellcome Trust, National Institute for Health Research); NIHR Oxford Biomedical Research Centre; NIHR Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (Oxford University in partnership with Public Health England [PHE]), and on Modelling Methodology (Imperial College, London in partnership with PHE); and the Health Innovation Challenge Fund.


The dopamine metabolite 3-methoxytyramine is a neuromodulator.
Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1). Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated cAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause cAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia.


Ranitidine and omeprazole as adjuvant therapy to pancrelipase to improve fat absorption in patients with cystic fibrosis.
Inadequate treatment of pancreatic insufficiency in patients with cystic fibrosis (CF) causes malabsorption of nutrients with significant sequelae. The objective of this study was to measure the effect of acid suppressant therapy on fat absorption in patients with CF who received a pH-sensitive, enteric-coated microtablet enzyme product. A double-blind, placebo-controlled crossover study of 12 children and 10 adults with pancreatic insufficient CF was performed. All subjects were receiving pancrelipase therapy (Pancrease MT10 and MT16; Ortho-McNeil, Springhouse, PA, U.S.A.) and for the study also received either placebo or ranitidine (Zantac; Glaxo-Wellcome, Research Triangle Park, NC U.S.A.) 5 mg/kg or 10 mg/kg daily. The adult subjects also received omeprazole therapy (Prilosec; AstraZeneca/Merck, Wilmington, DE, U.S.A.), 20 mg daily, as adjuvant therapy to pancreatic enzymes. Serial 3-day fat-balance studies were performed in the Clinical Research Center. The data were analyzed using individual paired t tests that compared each treatment with placebo and two repeated-measures, general linear model F tests. The linear model for all subjects showed no overall adjuvant drug effect on fat absorption, P = 0.32. A second linear model F test analysis of adult subjects, comparing all four drug treatments (placebo, ranitidine 5 and 10 mg/kg daily and omeprazole), also showed no difference in fat absorption, P = 0.15. Paired t test subgroup analysis of the adults showed an improvement of 4.97% (P = 0.003) in mean fat absorption comparing low-dose ranitidine to placebo. All other t test analyses showed no significant change in fat absorption between placebo and acid suppressant treatment. There was marked intersubject and intrasubject variability in fat absorption. No overall significant improvement in fat absorption could be demonstrated with adjuvant therapy. Fat absorption measured by 3-day fat-balance studies varied greatly even when comparing the same subject for placebo and baseline treatments, despite identical dietary fat and enzyme intakes. The large variability limited our ability to test for a difference in fat absorption and has significant implication for the use of this test, considered the gold standard, for determining enzyme dosage adequacy.


Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion.
Sebocytes are highly specialized, sebum-producing epithelial cells that release their content by rupture of the cell membrane and cellular degradation (holocrine secretion). These cells are most commonly found in the skin in association with hair follicles (forming the pilosebaceous unit), where they arise from hair follicle keratinocytes, but there are also sebaceous glands (SGs) not associated with a hair follicle. The latter have special functions as secretion of pheromones or corneal protection. While the full range of sebum functions in human skin remains to be clarified, sebum forms an integral component of the epidermal barrier and the skin immune system. Sebocyte formation is controlled by multiple molecular pathways (e.g. Blimp1, Wnt, C-myc, Hedgehog) and sebum synthesis is strongly regulated by hormones, in particular by androgens. Excessive sebum production is seen in acne vulgaris, one of the most common skin diseases, while deregulated sebocyte differentiation characterizes some rare benign and malignant tumors.


Higher lipid peroxidation in former-smokers vs. never-smokers - study in postmenopausal women.
One of the most spectacular exogenous prooxidative agents is cigarette smoking, constituting a well documented risk factor for several diseases. In turn it is suggested that hormone replacement therapy (HRT) in postmenopausal women can contribute to oxidative status. The aim of the study was to evaluate the level of oxidative damage to membrane lipids in blood serum collected from never-smokers and former-smokers. The study was performed in postmenopausal women, who were or were not HRT users. Ninety (90) female volunteers, aged from 46 to 67 years, were enrolled. Two major groups were considered, i.e. never-smokers (n=44) and formersmokers (n=46), which were additionally subgrouped to HRT users (HRT+) and HRT non-users (HRT-). Anthropometric parameters related to obesity were also calculated. The main groups were well matched at baseline in terms of age. The level of malondialdehyde+4-hydroxyalkenals (MDA+4-HDA), as the index of LPO, was measured spectrophotometrically. The level of LPO was higher in former-smokers than in never-smokers, regardless of HRT use. The level of LPO did constitute the only independent factor associated with past smoking in the entire examined group, as well as after stratification to HRT users and HRT non-users. LPO level was not associated with HRT treatment. No positive correlations were found between LPO level and anthropometric parameters. Past smoking is independently associated with the increased damage to membrane lipids regardless of the use of HRT in postmenopausal women. Smoking cessation is not always associated with complete reversion of excessive oxidative damage to all biological macromolecules.


Monobloc Le Fort III Distraction Osteogenesis for Correction of Severe Fronto-orbital and Midface Hypoplasia in Pediatric Crouzon Syndrome.
In severe syndromic craniosynostosis, distraction osteogenesis (DO) provides superior segmental advancement and allows progressive clinical monitoring to ensure that adequate skeletal expansion is achieved. We report two cases of Crouzon syndrome involving a 3-year-old boy and a 4-year-old girl, who were both treated with monobloc Le Fort III DO using a combination of external and internal distraction devices (Synthes, Oberdorf, Switzerland) to treat severe orbital proptosis and obstructed nasopharyngeal airway secondary to severe hypoplastic craniofacial skeletal components. Their skeletal segments were advanced in daily increments by 27 mm and 23 mm, respectively. Results at 18 months postoperatively showed successful outcomes, as evidenced by adequate eye protection, tracheostomy tube decannulation following objective evidence of patent nasopharyngeal airway, and acceptable facial appearance. Monobloc Le Fort III DO using a combination of external and internal devices produces favorable functional and clinical outcomes for the treatment of severe orbital and airway discrepancy in Crouzon syndrome.


Serial modules in parallel: the psychological refractory period and perfect time-sharing.
The authors describe ACT-R/perceptual-motor (ACT-R/PM), an integrated theory of cognition, perception, and action that consists of the ACT-R production system and a set of perceptual-motor modules. Each module (including cognition) is essentially serial, but modules run in parallel with one another. ACT-R/PM can model simple dual tasks such as the psychological refractory period (PRP), including subtle results previously explained with executive process interactive control (EPIC, D. E. Meyer & D. E. Kieras, 1997a). The central difference between the theories is that EPIC's productions can fire in parallel, whereas in ACT-R/PM, they are serial. Results from three PRP-like experiments with more demanding cognitive requirements indicate that cognitive processing for the 2 tasks need not overlap. ACT-R's activation-based retrieval processes are critical in accounting for the timing of these tasks and for explaining the dual-task performance decrement.


CANA: A Python Package for Quantifying Control and Canalization in Boolean Networks.
Logical models offer a simple but powerful means to understand the complex dynamics of biochemical regulation, without the need to estimate kinetic parameters. However, even simple automata components can lead to collective dynamics that are computationally intractable when aggregated into networks. In previous work we demonstrated that automata network models of biochemical regulation are highly canalizing, whereby many variable states and their groupings are redundant (Marques-Pita and Rocha, 2013). The precise charting and measurement of such canalization simplifies these models, making even very large networks amenable to analysis. Moreover, canalization plays an important role in the control, robustness, modularity and criticality of Boolean network dynamics, especially those used to model biochemical regulation (Gates and Rocha, 2016; Gates et al., 2016; Manicka, 2017). Here we describe a new publicly-available Python package that provides the necessary tools to extract, measure, and visualize canalizing redundancy present in Boolean network models. It extracts the pathways most effective in controlling dynamics in these models, including their effective graph and dynamics canalizing map, as well as other tools to uncover minimum sets of control variables.


Family history of diabetes and effectiveness of lifestyle counselling on the cardio-metabolic risk profile in individuals at high risk of Type 2 diabetes: 1-year follow-up of the FIN-D2D project.
To investigate whether a positive family history of diabetes is associated with the effectiveness of lifestyle counselling on cardio-metabolic risk factors and glucose tolerance status in a 1-year follow-up in a cohort of Finnish men and women at high risk for Type 2 diabetes. Altogether, 10,149 individuals who had high risk of Type 2 diabetes participated in the implementation programme of the national diabetes prevention programme at baseline. One-year follow-up data were available for 2798 individuals without diabetes. Family history of diabetes was based on self-report. Lifestyle interventions were individual or groups sessions on lifestyle changes. The effectiveness of lifestyle intervention was measured as changes in cardiovascular risk factors, glucose tolerance status and incidence of Type 2 diabetes. Family history was associated with the effectiveness of lifestyle intervention in men, but not in women. During the 1-year follow-up, body weight, BMI, systolic blood pressure, total cholesterol, LDL cholesterol and score for 10-year risk for fatal cardiovascular disease (SCORE) decreased and glucose tolerance status improved more in men without a family history of diabetes than in men with a family history of diabetes. Of the participating men and women, 10% and 5% developed Type 2 diabetes, respectively. Family history was not related to the incidence of Type 2 diabetes in either gender. Men without a family history of diabetes were more successful in responding to lifestyle counselling with regard to cardio-metabolic measurements and glucose tolerance than those with a family history of diabetes. Similar results were not seen in women. In keeping with findings from earlier studies, the prevention of Type 2 diabetes is not influenced by a family history of diabetes.


Sexual selection by female immunity against paternal antigens can fix loss of function alleles.
Humans lack the common mammalian cell surface molecule N-glycolylneuraminic acid (Neu5Gc) due to a CMAH gene inactivation, which occurred approximately three million years ago. Modern humans produce antibodies specific for Neu5Gc. We hypothesized that anti-Neu5Gc antibodies could enter the female reproductive tract and target Neu5Gc-positive sperm or fetal tissues, reducing reproductive compatibility. Indeed, female mice with a human-like Cmah(-/-) mutation and immunized to express anti-Neu5Gc antibodies show lower fertility with Neu5Gc-positive males, due to prezygotic incompatibilities. Human anti-Neu5Gc antibodies are also capable of targeting paternally derived antigens and mediate cytotoxicity against Neu5Gc-bearing chimpanzee sperm in vitro. Models of populations polymorphic for such antigens show that reproductive incompatibility by female immunity can drive loss-of-function alleles to fixation from moderate initial frequencies. Initially, the loss of a cell-surface antigen can occur due to drift in isolated populations or when natural selection favors the loss of a receptor exploited by pathogens, subsequently the same loss-of-function allele can come under sexual selection because it avoids being targeted by the female immune system. Thus, we provide evidence of a link between sexual selection and immune function: Antigenicity in females can select against foreign paternal antigens on sperm and rapidly fix loss-of-function alleles. Similar circumstances existed when the CMAH null allele was polymorphic in ancestral hominins, just before the divergence of Homo from australopithecines.


Growth and nutritional status of the Evenki reindeer herders of Siberia.
This study examines physical growth and nutritional status in a sample of 478 (247 males; 231 females) Evenki herders of Central Siberia. The Evenki display slow growth in stature and body weight, particularly during late childhood and adolescence. Adult males fall below the U.S. 5th percentiles for both stature and body weight. Adult females are below the 5th percentile for stature and approximate the 15th percentile for weight. Despite their diminutive size, the Evenki appear to have adequate energy reserves, as indicated by their skinfold measurements, which range between the U.S. 15th and 50th percentiles. Among adults, women are relatively heavier and fatter than men and tend to increase in weight and fatness with age. Poor growth in the Evenki does not appear to be directly attributable to limited food availability. Rather, it is hypothesized that elevated metabolic requirements, associated with adaptation to a high latitude ecosystem, are responsible for limiting the amount of energy that is allocated to growth. Relatively high levels of adiposity in adult females appear to be the product of changes in activity patterns and fertility levels that resulted after the collectivization of the Evenki. © 1994 Wiley-Liss, Inc.


The functions of the medial premotor cortex. II. The timing and selection of learned movements.
Monkeys with medial premotor cortex (MPC) lesions are impaired on a simple learned task that requires them to raise their arm at their own pace. However, they can succeed on this task if they are given tones to guide performance. In the externally paced task the tones could aid performance in several ways. They tell the animal when to act (trigger), they remind the animal that food is available and so motivate (predictor), and they remind the animal of what to do (instruction). Monkeys with MPC lesions can respond quickly to visual cues (experiment 1), and they can respond as well as normal monkeys when there is no immediate trigger (experiment 2). They are also quick to relearn a task in which external cues tell them what to do (experiment 5). However, they are poor at selecting between movements on a simple motor sequence task (experiment 3), and they are poor at changing between two movements (experiment 4). On these tasks there were cues to act as triggers and predictors, but there were no external instructions. We conclude that the reason why animals with MPC lesions perform better with external cues is that these cues act as instructions. The cues prompt retrieval of the appropriate action. This is true whether the task requires the animal to perform one action (experiments 1 and 2) or to select between actions (experiments 3 and 4).


Identification of phenolic acids and flavonoids in monofloral honey from Bangladesh by high performance liquid chromatography: determination of antioxidant capacity.
The aim of the present study was to characterize the phenolic acids, flavonoids, and antioxidant properties of monofloral honey collected from five different districts in Bangladesh. A new high performance liquid chromatography (HPLC) equipped with a UV detector method was developed for the identification of the phenolic acids and flavonoids. A total of five different phenolic acids were identified, with the most abundant being caffeic acid, benzoic acid, gallic acid, followed by chlorogenic acid and trans-cinnamic acid. The flavonoids, kaempferol, and catechin were most abundant, followed by myricetin and naringenin. The mean moisture content, total sugar content, and color characteristics of the honey samples were 18.36 ± 0.95%, 67.40 ± 5.63 g/100 g, and 129.27 ± 34.66 mm Pfund, respectively. The mean total phenolic acids, total flavonoid content, and proline content were 199.20 ± 135.23, 46.73 ± 34.16, and 556.40 ± 376.86 mg/kg, respectively, while the mean FRAP values and DPPH radical scavenging activity were 327.30 ± 231.87 μM Fe (II)/100 g and 36.95 ± 20.53%, respectively. Among the different types of honey, kalijira exhibited the highest phenolics and antioxidant properties. Overall, our study confirms that all the investigated honey samples are good sources of phenolic acids and flavonoids with good antioxidant properties.


Complications following vaginal mesh procedures for stress urinary incontinence: an 8 year study of 92,246 women.
Complications of surgical mesh procedures have led to legal cases against manufacturers worldwide and to national inquiries about their safety. The aim of this study was to investigate the rate of adverse events of these procedures for stress urinary incontinence in England over 8 years. This was a retrospective cohort study of first-time tension-free vaginal tape (TVT), trans-obturator tape (TOT) or suprapubic sling (SS) surgical mesh procedures between April 2007 and March 2015. Cases were identified from the Hospital Episode Statistics database. Outcomes included number and type of procedures, including those potentially confounded by concomitant procedures, and frequency, nature and timing of complications. 92,246 first-time surgical mesh procedures (56,648 TVT, 34,704 TOT, 834 SS and 60 combinations) were identified, including 68,002 unconfounded procedures. Peri-procedural and 30-day complication rates in the unconfounded cohort were 2.4 [2.3-2.5]% and 1.7 [1.6-1.8]% respectively; 5.9 [5.7-6.1]% were readmitted at least once within 5 years for further mesh intervention or symptoms of complications, the highest risk being within the first 2 years. Complication rates were higher in the potentially confounded cohort. The complication rate within 5 years of the mesh procedure was 9.8 [9.6:10.0]% This evidence can inform future decision-making on this procedure.


Adsorption of tetracycline from water using glutaraldehyde-crosslinked electrospun nanofibers of chitosan/poly(vinyl alcohol).
In this work, the preparation and characterization of glutaraldehyde-crosslinked electrospun nanofibers of chitosan/poly(vinyl alcohol) (GCCPN) as a new adsorbent for tetracycline (TC) is reported. Electrospun nanofibers of chitosan/poly(vinyl alcohol) (PVA) were prepared by employing a 75:25 volumetric ratio of chitosan:PVA, voltage of 30 kV, collection distance of 10 cm, and injection flow rate of 2 mL/h. Then, the nanofibers were crosslinked via applying the glutaraldehyde on them for 3 h at 40 °C. The nanofibers were characterized using scanning electron microscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction. Uniform beadless nanofibers with minimum diameters of 3-11 and 6-18 nm were obtained before and after crosslinking, respectively. Then the applicability of the synthesized GCCPN for removal of TC from aqueous solutions was investigated. The response surface method was applied to evaluate the influence of pH (6-12), TC concentration (50-250 mg/L) and the adsorbent dose (0.05-0.25 g in 20 mL solution) on the adsorption characteristics of GCCPN. The maximum adsorption capacity was 102 mg/g. The adsorption kinetics was explained most effectively by the pseudo-second-order model. The adsorption data of TC on the GCCPN surface was explained well by the Langmuir isotherm model.


Entropy Drives Calcium Carbonate Ion Association.
The understanding of the molecular mechanisms underlying the early stages of crystallisation is still incomplete. In the case of calcium carbonate, experimental and computational evidence suggests that phase separation relies on so-called pre-nucleation clusters (PNCs). A thorough thermodynamic analysis of the enthalpic and entropic contributions to the overall free energy of PNC formation derived from three independent methods demonstrates that solute clustering is driven by entropy. This can be quantitatively rationalised by the release of water molecules from ion hydration layers, explaining why ion association is not limited to simple ion pairing. The key role of water release in this process suggests that PNC formation should be a common phenomenon in aqueous solutions.


A decision tree for the treatment of caries in posterior teeth.
Because of a better understanding of the caries process, a decrease in the prevalence of caries, and the rapid development of dental materials, a renewed approach to the treatment of dental caries in the posterior region is possible. A decision tree for the treatment of caries in posterior teeth, taking into account some of the most recent tooth substance-saving treatment options, is presented. These possibilities gradually evolve from nondestructive to conventional cavity preparations. In addition, the "preventive Class II restoration" is introduced. The application of this conservative attitude toward invasive techniques offers great advantages for both the patient and the dentist. Unfortunately, this approach is time-consuming. Long-term clinical evaluation of the application of the proposed decision tree on a wide scale is needed to confirm its potential benefits or to modify and improve treatment options.


The frequency and outcome of lupus nephritis: results from an international inception cohort study.
To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort. Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores. There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P < 0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P ≤ 0.02) scores compared to patients with normal values. LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN.


Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis.
Haptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic response to VitE in nonalcoholic steatohepatitis (NASH) is unknown. Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH. A post hoc analysis of 228 patients receiving VitE or placebo in 2 clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1-1, 2-1, or 2-2), on histologic features and laboratory markers of nonalcoholic fatty liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype. Hp 2-2 patients treated with VitE versus placebo showed significant histologic improvement (51% vs. 20%; OR=4.2; P=0.006), resolution of steatohepatitis (44% vs. 12%; OR=6.2; P=0.009), decrease in nonalcoholic fatty liver disease Activity Score (NAS) (-2.2 vs. -0.6; P=0.001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Hp 2-1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1-1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2-2 or 2-1 versus 1-1 for all liver enzyme. Hp 2 allele is associated with greater histologic and biological improvement in NASH with VitE treatment compared with the Hp 1 allele.


The Functional Anatomy of the Carpometacarpal Complex in Anthropoids and Its Implications for the Evolution of the Hominoid Hand.
Previously, we described several features of the carpometacarpal joints in extant large-bodied apes that are likely adaptations to the functional demands of vertical climbing and suspension. We observed that all hominids, including modern humans and the 4.4-million-year-old hominid Ardipithecus ramidus, lacked these features. Here, we assess the uniqueness of these features in a large sample of monkey, ape, and human hands. These new data provide additional insights into the functional adaptations and evolution of the anthropoid hand. Our survey highlights a series of anatomical adaptations that restrict motion between the second and third metacarpals (MC2 and MC3) and their associated carpals in extant apes, achieved via joint reorganization and novel energy dissipation mechanisms. Their hamate-MC4 and -MC5 joint surface morphologies suggest limited mobility, at least in Pan. Gibbons and spider monkeys have several characters (angled MC3, complex capitate-MC3 joint topography, variably present capitate-MC3 ligaments) that suggest functional convergence in response to suspensory locomotion. Baboons have carpometacarpal morphology suggesting flexion/extension at these joints beyond that observed in most other Old World monkeys, probably as an energy dissipating mechanism minimizing collision forces during terrestrial locomotion. All hominids lack these specializations of the extant great apes, suggesting that vertical climbing was never a central feature of our ancestral locomotor repertoire. Furthermore, the reinforced carpometacarpus of vertically climbing African apes was likely appropriated for knuckle-walking in concert with other novel potential energy dissipating mechanisms. The most parsimonious explanation of the structural similarity of these carpometacarpal specializations in great apes is that they evolved independently.


Impact of HLA-B*81-associated mutations in HIV-1 Gag on viral replication capacity.
HIV-1 attenuation resulting from immune escape mutations selected in Gag may contribute to slower disease progression in HIV-1-infected individuals expressing certain HLA class I alleles. We previously showed that the protective allele HLA-B*81 and the HLA-B*81-selected Gag T186S mutation are strongly associated with a lower viral replication capacity of recombinant viruses encoding Gag-protease derived from individuals chronically infected with HIV-1 subtype C. In the present study, we directly tested the effect of this mutation on viral replication capacity. In addition, we investigated potential compensatory effects of various polymorphisms, including other HLA-B*81-associated mutations that significantly covary with the T186S mutation. Mutations were introduced into a reference subtype B backbone and into patient-derived subtype C sequences in subtype B and C backbones by site-directed mutagenesis. The exponential-phase growth of mutant and wild-type viruses was assayed by flow cytometry of a green fluorescent protein reporter T cell line or by measurement of HIV-1 reverse transcriptase activity in culture supernatants. Engineering of the T186S mutation alone into all patient-derived subtype C sequences failed to yield replication-competent viruses, while in the subtype B sequence, the T186S mutation resulted in impaired replication capacity. Only the T186S mutation in combination with the T190I mutation yielded replication-competent viruses for all virus backbones tested; however, these constructs replicated slower than the wild type, suggesting that only partial compensation is mediated by the T190I mutation. Constructs encoding the T186S mutation in combination with other putative compensatory mutations were attenuated or defective. These results suggest that the T186S mutation is deleterious to HIV-1 subtype C replication and likely requires complex compensatory pathways, which may contribute to the clinical benefit associated with HLA-B*81.


MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2.
Serum levels of miR-194 have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion, and epithelial-mesenchymal transition in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts. Conversely, inhibition of miR-194 activity suppressed the invasive capacity of prostate cancer cell lines in vitro and in vivo Mechanistic investigations identified the ubiquitin ligase suppressor of cytokine signaling 2 (SOCS2) as a direct, biologically relevant target of miR-194 in prostate cancer. Low levels of SOCS2 correlated strongly with disease recurrence and metastasis in clinical specimens. SOCS2 downregulation recapitulated miR-194-driven metastatic phenotypes, whereas overexpression of a nontargetable SOCS2 reduced miR-194-stimulated invasion. Targeting of SOCS2 by miR-194 resulted in derepression of the oncogenic kinases FLT3 and JAK2, leading to enhanced ERK and STAT3 signaling. Pharmacologic inhibition of ERK and JAK/STAT pathways reversed miR-194-driven phenotypes. The GATA2 transcription factor was identified as an upstream regulator of miR-194, consistent with a strong concordance between GATA2 and miR-194 levels in clinical specimens. Overall, these results offer new insights into the molecular mechanisms of metastatic progression in prostate cancer. Cancer Res; 77(4); 1021-34. ©2016 AACR.


Hb G-Waimanalo [A1] [α64(E13)Asp→Asn; HBA1: c.193 G > A] with Decreased Oxygen Affinity.
A clinically asymptomatic 12-year-old girl showed microcytosis in routine examination. Cation exchange high performance liquid chromatography (HPLC), revealed two additional peaks eluting after Hb A and DNA sequencing uncovered a novel heterozygous mutation at codon 64 of the α1-globin gene. The hemoglobin (Hb) variant was annotated as Hb G-Waimanalo [A1]. Further analyses demonstrated a decreased oxygen affinity Hb compared to the normal Hb configuration.


Linkage analysis and map construction in genetic populations of clonal F1 and double cross.
In this study, we considered four categories of molecular markers based on the number of distinguishable alleles at the marker locus and the number of distinguishable genotypes in clonal F1 progenies. For two marker loci, there are nine scenarios that allow the estimation of female, male, and/or combined recombination frequencies. In a double cross population derived from four inbred lines, five categories of markers are classified and another five scenarios are present for recombination frequency estimation. Theoretical frequencies of identifiable genotypes were given for each scenario, from which the maximum likelihood estimates of one or more of the three recombination frequencies could be estimated. If there was no analytic solution, then Newton-Raphson method was used to acquire a numerical solution. We then proposed to use an algorithm in Traveling Salesman Problem to determine the marker order. Finally, we proposed a procedure to build the two haploids of the female parent and the two haploids of the male parent in clonal F1. Once the four haploids were built, clonal F1 hybrids could be exactly regarded as a double cross population. Efficiency of the proposed methods was demonstrated in simulated clonal F1 populations and one actual maize double cross. Extensive comparisons with software JoinMap4.1, OneMap, and R/qtl show that the methodology proposed in this article can build more accurate linkage maps in less time.


Widespread genetic incompatibility in C. elegans maintained by balancing selection.
Natural selection is expected to eliminate genetic incompatibilities from interbreeding populations. We have discovered a globally distributed incompatibility in the primarily selfing species Caenorhabditis elegans that has been maintained despite its negative consequences for fitness. Embryos homozygous for a naturally occurring deletion of the zygotically acting gene zeel-1 arrest if their sperm parent carries an incompatible allele of a second, paternal-effect locus, peel-1. The two interacting loci are tightly linked, with incompatible alleles occurring in linkage disequilibrium in two common haplotypes. These haplotypes exhibit elevated sequence divergence, and population genetic analyses of this region indicate that natural selection is preserving both haplotypes in the population. Our data suggest that long-term maintenance of a balanced polymorphism has permitted the incompatibility to persist despite gene flow across the rest of the genome.


Autonomous Expansion of Grasshopper Wings Reveal External Forces Contribute to Final Adult Wing Shape.
Ecydsis, the transformation from juvenile to adult form in insects, is time-consuming and leaves insects vulnerable to predation. For winged insects the process of wing expansion during ecdysis, the unfurling and expanding the wings, is a critical bottleneck in achieving sexual maturity. Internal and external forces play a role in wing expansion. Vigorous abdominal pumping during wing expansion allow insects to pressurize and inflate their wings, filling them with hemolymph. In addition, many insects adopt expansion-specific postures, and if inhibited, do not expand their wings normally, suggesting that external forces such as gravity may play a role. However two previous studies over 40 years ago reported that the forewings of swarming locusts can expand autonomously when removed from the emerging insect and laid flat on a saline solution. Termed "autoexpansion," we replicated previous experiments of autoexpansion on flat liquid media, documenting changes in both wing length and area over time while also focusing on the role of gravity in autoexpansion. Using the North American bird grasshopper Schistocerca americana, we tested four autoexpansion treatments of varying surface tension and hydrophobicity (gravity, deionized water, buffer, and mineral oil) while simultaneously observing and measuring intact, normal wing expansion. Finally, we constructed a simple model of a viscoelastic expanding wing subjected to gravity, to determine whether it could capture aspects of wing expansion. Our data confirmed that wing autoexpansion does occur in S. americana, but autoexpanding wings, especially hindwings, failed to increase to the same final length and area as intact wings. We found that gravity plays an important role in wing expansion, early in the expansion process. Combined with the significant mass increase we documented in intact wings, it suggests that hydraulic pumping of hemolymph into the wings plays an important role in increasing the area of expanding wings, especially in driving expansion of the large, pleated hindwings. Autoexpansion in a non-swarming orthopteran suggests that local cues driving wing autoexpansion may serve a broader purpose, reducing total expansion time and costs by shifting some processes from central to local control. Documenting wing autoexpansion in a widely studied model organism and demonstrating a mathematical model provides a tractable new system for exploring higher level questions about the mechanisms of wing expansion and the implications of autoexpansion, as well as potential bioinspiration for future technologies applicable to micro-air vehicles, space exploration, or medical and prosthetic devices.


Effects of electroacupuncture on intraoperative and postoperative analgesic requirement.
Acupuncture has been shown to be effective in experimental and clinical acute pain settings. This study aims to evaluate the effect of preoperative electroacupuncture (EA) on intraoperative and postoperative analgesic (alfentanil and morphine) requirement in patients scheduled for gynaecologic lower abdominal surgery. Ninety patients were randomly assigned to one of three groups: Group I (control group)--received placebo EA for 45 minutes before induction of general anaesthesia (GA); Group II--preoperative EA instituted 45 minutes before induction of GA; Group III--45 minutes of postoperative EA. The Bispectral Index monitor was used intraoperatively to monitor the hypnotic effect of anaesthetic drugs, and alfentanil was titrated to maintain the blood pressure and pulse rate within +/- 15% of basal values. Postoperative pain was managed by intravenous morphine via a patient-controlled analgesia (PCA) device. Patients in Group II (0.44 +/- .15microg/kg/min) received less alfentanil than those in Group III (0.58 +/- .22 microg/kg/min) (p = p.024), but not significantly less than those in Group I 10.51 +/- 0.21 microg/kg/min) (p = 0.472). Postoperative morphine consumption was numerically lower in Group II compared with the other groups; however, the difference was statistically significant only during the period of 6-12 hours between Group II [0.03 (0.05) mg/kg] and Group I [0.10 (0.11) mg/kg] (p = 0.015), and Group II and Group III [0.08 (0.10) mg/kg] (p = 0.010). The 24-hour cumulative morphine consumption for Group II (0.52 +/- .19mg/kg) was less than that for either Group I I0.68 +/- 38mg/kg) or Group III (0.58 +/- .27mg/kg), but the difference did not reach significance. In conclusion, preoperative EA leads to a reduced intraoperative alfentanil consumption, though this effect may not be specific, and has a morphine sparing effect during the early postoperative period.


Acute exposure to Catha edulis depresses contractility and induces myocardial infarction in spontaneously contracting, isolated rabbit's heart.
Khat chewing is a recreational habit known to pose major socio-economic and medical problems in countries of Southern Arabia and the Horn of Africa. Among other adverse health effects, khat chewing has been associated with an increased risk of myocardial infarction (MI) in heavy consumers. This study was carried out to examine the direct effects of Catha edulis extract on contractility of spontaneously contracting, isolated rabbit heart and to investigate its mechanism of action. Isolated six rabbit's hearts attached to a Langendorff apparatus were perfused with extract at a constant flow rate and continuously bubbled with a 95% O2/5% CO2 gas mixture. Each heart served as its own control, as responses were recorded before and after administration of C. edulis extract. Varying concentrations of extract (50, 100 and 250 mg/ml) were loaded in the perfusate, their effects recorded and effluent fluid collected for assay of cardiac enzymes. Histological examination of the cardiac tissue was performed at the end of perfusion with 250 mg/ml extract. This study revealed that acute exposure to C. edulis extract exerted negative inotropic and chronotropic effects on isolated hearts. The extract also had a vasoconstrictor effect on coronary vessels, independent of α1 adrenergic receptor stimulation. Histological examination of hearts perfused with 250 mg/ml C. edulis extract revealed the presence of histological changes unique to myocardial infarction, a finding consistent with observed increased levels of cardiac enzymes in perfusates. Thus, we have demonstrated experimentally a direct cardiac depressant- and MI inducing effects of C. edulis extract. These results are consistent with the earlier reported deleterious effects of khat on cardiovascular function among khat chewers.


Immediate dentin sealing for indirect bonded restorations.
The aim of this article is to review available literature on the clinical procedure of immediate dentine sealing for indirect bonded restorations. More than 40 articles reporting the technique, studies, outcomes, etc. were reviewed after PUBMED/MEDLINE search, most of them addressing the specific situation of dentin bonding for indirect restorations. It is known that tooth preparation for indirect bonded restorations can result in significant dentin exposures. Immediate application and polymerization of the dentin bonding agent to the freshly cut dentin, prior to impression making is therefore recommended by some authors. Literature indicates that this procedure, immediate dentine sealing (IDS), appears to achieve improved bond strength, fewer gap formations, decreased bacterial leakage, and reduces post-cementation sensitivity. This rational approach to adhesion is also reported to have a positive influence on tooth structure preservation, patient comfort, and long term survival of indirect bonded restorations. In the extensive literature regarding advantages of using IDS technique significant differences have been shown when compared to Delayed Dentine Sealing. Although more research is required in this field, presently there are NO scientific reasons not to recommend IDS in routine practice.


Retrospective analysis of the prognostic significance of DNA content and proliferative activity in large bowel carcinoma.
In the present study we have evaluated the prognostic significance of ploidy levels and proliferative activity in 279 cases of large bowel carcinomas which were included in a surgical prospective randomized trial. Ploidy levels and proliferative activity were determined on nuclei isolated from paraffin-embedded tissues of 279 colorectal carcinoma patients, with a mean follow-up of 51.9 months. Product limit survival analysis demonstrated a borderline significant association (P = 0.0689 by generalized Breslow; P = 0.0336 by generalized Savage) between ploidy and survival, with a 75th quantile survival of 49.8 months for patients with diploid tumors and 35.9 months for patients with aneuploid tumors. After stratification for staging, Dukes' C cases showed a statistically significant association between tumor ploidy and survival (P = 0.0224 by generalized Breslow, P = 0.0110 by generalized Savage). Product limit survival analysis for proliferative activity and survival showed a similar outcome with the strongest association in Dukes's C stage of disease (75th quantile survival of 38.9 months for low proliferative and 18.0 months for high proliferative tumors).


Damsel in distress: captured damselfish prey emit chemical cues that attract secondary predators and improve escape chances.
In aquatic environments, many prey animals possess damage-released chemical alarm cues that elicit antipredator behaviours in responsive con- and heterospecifics. Despite considerable study, the selective advantage of alarm cues remains unclear. In an attempt to investigate one of the more promising hypotheses concerning the evolution of alarm cues, we examined whether the cue functions in a fashion analogous to the distress vocalizations emitted by many terrestrial animals. Our results suggest that chemical alarm cues in damselfish (Pomacentridae) may have evolved to benefit the cue sender by attracting secondary predators who disrupt the predation event, allowing the prey a greater chance to escape. The coral reef piscivore, the dusky dottyback (Pseudochromis fuscus), chemically eavesdrops on predation events and uses chemical alarm cues from fish prey (lemon damselfish; Pomacentrus moluccensis) in an attempt to find and steal prey from primary predators. Field studies showed that Ps. fuscus aggregate at sites where prey alarm cue has been experimentally released. Furthermore, secondary predators attempted to steal captured prey of primary predators in laboratory trials and enhanced prey escape chances by 35-40%. These results are the first, to the best of our knowledge, to demonstrate a mechanism by which marine fish may benefit from the production and release of alarm cues, and highlight the complex and important role that semiochemicals play in marine predator-prey interactions.


Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses.
Natural killer (NK) cells are lymphocytes involved in antimicrobial and antitumoral immune responses. Using N-ethyl-N-nitrosourea mutagenesis in mice, we identified a mutant with increased resistance to viral infections because of the presence of hyperresponsive NK cells. Whole-genome sequencing and functional analysis revealed a loss-of-function mutation in the Ncr1 gene encoding the activating receptor NKp46. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. NKp46 was critical for the subsequent development of antiviral and antibacterial T cell responses, which suggests that the regulation of NK cell function by NKp46 allows for the optimal development of adaptive immune responses. NKp46 blockade enhanced NK cell reactivity in vivo, which could enable the design of immunostimulation strategies in humans.


Ureteroscopy in pregnant women with complicated colic pain: Is there any risk of premature labor?
Clinical presentation of ureteral stones during pregnancy is generally with renal colic pain. The aim of this study is to present our experience in the management of renal colic during pregnancy in emergency settings. 208 pregnant patients who presented to emergency department with renal colic pain and underwent ureteroscopy (URS) due to failed conservative therapy were enrolled in the study. Urinary tract stones were diagnosed either with ultrasound (US) examination or during URS. Laser lithotripsy and double J (DJ) stent placement were routinely done in all patients with ureteral stones. The incidence of infective complications and premature uterine contractions (PUC) due to URS were compared. No stone was identified in 36.1% (n = 75) of patients with using US and diagnostic URS. Of the remaining 133 patients, 30 (22.6%) had no stone at US but stones were diagnosed during diagnostic URS. The type of anesthesia had no significant effect on PUC. An increased risk of sepsis and PUC was found in patients with fever at the initial presentation. Interestingly, PUC was more frequent in patients with lower serum magnesium levels. There was a significant correlation with time delay until the intervention and the risk of urosepsis and PUC, individually. Ureteroscopy is a safe option for evaluation of pregnant patients with unresolved renal colic. According to the current findings, timing of the operation is the most important factor affecting the septic risks and abortion threat. Surgical intervention with URS must be planned as soon as possible.


Aesthetic and Functional Evaluation of Total Nasal Reconstructions.
The loss of a portion or the totality of the nose has great relevance on the perception of the beauty of a face and can result in a catastrophic quality of life impairment. Several surgical techniques are currently available for the reconstruction of the nasal pyramid. However, there are very few nasal reconstruction quality evaluation protocols that allow the surgeon to choose objectively the best technique for each kind of defects. Six total nasal reconstruction performed in University of Sassari Maxillofacial Unit were evaluated with a protocol that investigate objectively and subjectively the surgical aesthetic and functional outcome. Sensitivity recovery on the reconstructive flaps was also assessed. Patients reported a satisfactory nasal reconstruction both functionally and aesthetically. Sensitivity recovery on the forehead flap was always present even after pedicle resection or in case of traumatic section of the infraorbital nerve. The use of a three layer reconstruction has proved a viable technique both aesthetically and functionally. In particular the use of the forehead flap to reconstruct the outer layer of the nose allows to carry a tissue with very similar characteristics to the original with a recovery of the sensitivity almost complete.


Ammonotely in a neotropical frugivorous bat as energy intake decreases.
We tested the role of increased ammonia in urine as an energy- and/or nitrogen (N)-saving mechanism in the great fruit-eating bat Artibeus lituratus (Phyllostomidae). We compared N excretion in two groups of bats fed energy-rich (2.75 kJ g(-1) wet mass) or energy-poor diets (0.7 kJ g(-1) wet mass). Within each diet, bats were assigned to different N contents. In order to function as an energy-saving mechanism, ammonia production should increase with decreasing energy intake. To function as an N-saving mechanism, ammonia production should increase with decreasing N intake. Because we varied both diet energy density and N content, our study design allowed us to test these two possibilities simultaneously. Bats had higher food intake rate and, consequently, higher N intake rate on the energy-poor diet, but energy intake rate was lower. Most bats on the energy-rich diet were ureotelic whereas on the energy-poor diet bats were ureotelic, ammonotelic or ureo-ammonotelic. Bats fed the energy-poor diet had a higher excretion rate of ammonia and a higher percent of N excreted as ammonia. Percent N ammonia and ammonia excretion rate were inversely related to energy intake, but they were not related to N intake. By favoring ammonia production over urea, bats on the energy-poor diet may save up to 1% of their basal metabolic rate. Consumption of energy-dilute fruits by fruit bats might affect the way in which N wastes are excreted, favoring the excretion of ammonia N when food intake is accompanied by the ingestion of large volumes of water.


Influence of disorder on generation and probability of extreme events in Salerno lattices.
Extreme events (EEs) in nonlinear and/or disordered one-dimensional photonic lattice systems described by the Salerno model with on-site disorder are studied. The goal is to explain particular properties of these phenomena, essentially related to localization of light in the presence of nonlinear and/or nonlocal couplings in the considered systems. Combining statistical and nonlinear dynamical methods and measures developed in the framework of the theory of localization phenomena in disordered and nonlinear systems, particularities of EEs are qualitatively clarified. Findings presented here indicate that the best environment for EEs' creation are disordered near-integrable Salerno lattices. In addition, it is been shown that the leading role in the generation and dynamical properties of EEs in the considered model is played by modulation instability, i.e., by nonlinearities in the system, although EEs can be induced in linear lattices with on-site disorder too.


Transcriptional regulation via nuclear receptor crosstalk required for the Drosophila circadian clock.
Circadian clocks in large part rely on transcriptional feedback loops. At the core of the clock machinery, the transcriptional activators CLOCK/BMAL1 (in mammals) and CLOCK/CYCLE (CLK/CYC) (in Drosophila) drive the expression of the period (per) family genes. The PER-containing complexes inhibit the activity of CLOCK/BMAL1 or CLK/CYC, thereby forming a negative feedback loop [1]. In mammals, the ROR and REV-ERB family nuclear receptors add positive and negative transcriptional regulation to this core negative feedback loop to ensure the generation of robust circadian molecular oscillation [2]. Despite the overall similarities between mammalian and Drosophila clocks, whether comparable mechanisms via nuclear receptors are required for the Drosophila clock remains unknown. We show here that the nuclear receptor E75, the fly homolog of REV-ERB α and REV-ERB β, and the NR2E3 subfamily nuclear receptor UNF are components of the molecular clocks in the Drosophila pacemaker neurons. In vivo assays in conjunction with the in vitro experiments demonstrate that E75 and UNF bind to per regulatory sequences and act together to enhance the CLK/CYC-mediated transcription of the per gene, thereby completing the core transcriptional feedback loop necessary for the free-running clockwork. Our results identify a missing link in the Drosophila clock and highlight the significance of the transcriptional regulation via nuclear receptors in metazoan circadian clocks.


Manganese induced immune suppression of the lobster, Nephrops norvegicus.
Manganese (Mn) is one of the most abundant elements on earth, particularly in the soft bottom sediments of the oceans. As a micronutrient Mn is essential in the metabolic processes of organisms. However, at high concentrations the metal becomes a neurotoxin with well-documented effects. As a consequence of euthrophication, manganese is released from bottom sediments of coastal areas and the Norway lobsters, Nephrops norvegicus, can experience high levels of bioavailable Mn(2+). Here, we present the first report showing that Mn also affects several fundamental processes in the mobilisation and activation of immunoactive haemocytes. When N. norvegicus was exposed to a realistic [Mn(2+)] of 20 mg l(-1) for 10 days 24.1 microg ml(-1) was recorded in the haemolymph. At this concentration the total haemocyte count was reduced by ca. 60%. By using BrdU as a tracer for cell division, it was shown that the proliferation rate in the haematopoietic tissue did not increase, despite the haemocytepenia. A gene coding for a Runt-domain protein, known to be involved in maturation of immune active haemocytes in a variety of organisms, was identified also in haemocytes of N. norvegicus. The expression of this gene was >40% lower in the Mn-exposed lobsters as judged by using a cDNA probe and the in situ hybridisation technique. In response to non-self molecules, like lipopolysaccharide (LPS), the granular haemocytes of arthropods are known to degranulate and thereby release and activate the prophenoloxidase system, necessary for their immune defence. A degranulation assay, tested on isolated granular haemocytes, showed about 75% lower activity in the Mn-exposed lobsters than that for the unexposed. Furthermore, using an enzymatic assay, the activation per se of prophenoloxidase by LPS was found blocked in the Mn-exposed lobsters. Taken together, these results show that Mn exposure suppressed fundamental immune mechanisms of Norway lobsters. This identifies a potential harm that also exists for other organisms and should be considered when increasing the distribution of bioavailable Mn, as has been done through recently introduced applications of the metal.


Dok-4 is a novel negative regulator of T cell activation.
Dok-4 (downstream of tyrosine kinase-4) is a recently identified member of the Dok family of adaptor proteins, which are characterized by an amino-terminal pleckstrin homology domain, a phosphotyrosine-binding domain, and a carboxyl-terminal region containing several tyrosines and poly-proline-rich motifs. Two members of the Dok family, Dok-1 and Dok-2, have already been described as negative regulators in T cells. However, the function of Dok-4, which is also expressed in T cells, remains unknown. In this study, we report that Dok-4 is phosphorylated after TCR engagement and shuttled within the cytoplasm of T cells before being recruited to the polarized microtubule organizing center after the formation of the immunological synapse. Loss-of-function experiments using RNA interference constructs show that Dok-4 is a negative regulator of ERK phosphorylation, IL-2 promoter activity, and T cell proliferation. Exogenous expression of wild-type Dok-4 induces a significant activation of Rap1, which is involved in the regulation of ERK. The pleckstrin homology domain of Dok-4 is required both for its cytoplasmic shuttling and relocalization as well as for its inhibitory properties on T cell activation. Thus, Dok-4 represents a novel negative regulator of T cells.


A new design tool for feature extraction in noisy images based on grayscale hit-or-miss transforms.
The hit-or-miss transform (HMT) is a well-known morphological transform capable of identifying features in digital images. When image features contain noise, texture, or some other distortion, the HMT may fail. Various researchers have extended the HMT in different ways to make it more robust to noise. The most successful, and most recent extensions of the HMT for noise robustness, use rank-order operators in place of standard morphological erosions and dilations. A major issue with the proposed methods is that no technique is provided for calculating the parameters that are introduced to generalize the HMT, and, in most cases, these parameters are determined empirically. We present here, a new conceptual interpretation of the HMT which uses a percentage occupancy (PO) function to implement the erosion and dilation operators in a single pass of the image. Further, we present a novel design tool, derived from this PO function that can be used to determine the only parameter for our routine and for other generalizations of the HMT proposed in the literature. We demonstrate the power of our technique using a set of very noisy images and draw a comparison between our method and the most recent extensions of the HMT.


Packing fractal Sierpiński triangles into one-dimensional crystals via a templating method.
Crystalline structures with Sierpiński triangles as building blocks were constructed via a templating method in an ultra-high vacuum and studied by low-temperature scanning tunneling microscopy. Cobalt atoms and 4,4''-dicyano-1,1':3',1''-terphenyl molecules were used to build the Sierpiński triangles. The Au(100)-(hex), Au(111)-22 ×, and stepped Au(111) surfaces were used as templates to guide the packing of Sierpiński triangles. One-dimensional double chains and two-dimensional small domains of Sierpiński triangles were successfully prepared using the method in experiments.


Protective immune response against foot-and-mouth disease.
The causative agents of foot-and-mouth disease (FMD) are small icosahedral viruses of the Aphthovirus group within the Picornaviridae family. There is no evidence that these viruses infect cells of the immune system or otherwise interfere detrimentally with their function; additionally, it has not been possible to relate cytotoxicity reactions against virus-infected cells to the efficacy of the immune response against FMD virus infection. In contrast, there is a close association between FMD virus antibody and the protective immune response (10, 14, 15, 20, 24, 25, 29-32). Induction of this antibody is dependent on the structure of the viral antigenic sites (7-9, 11, 18) and on the concomitant presence of Th-lymphocyte epitopes (4, 5, 7, 8), although a Th-lymphocyte-independent response has been reported (2). Recent work by Piatti et al. (26) showed that the immune response induced by FMD virus was only Th-lymphocyte dependent when low doses of antigen were used. This latter work was performed in mice, and it is not certain that a similar situation would be found in cattle. As for the major effector immune defense, this relies on the interaction between antibody-virus complexes and the phagocytic cells of the reticuloendothelial system (17, 19).


Unusual Dyslipidemia in Patients with Chronic Kidney Diseases.
Chronic Kidney Disease (CKD) is a major and globally increasing health problem in the general population arising from a spectrum of diseases. Majority of the patients die even before reaching End Stage Renal Disease (ESRD) due to cardiovascular complications which arise due to altered lipoprotein compositions. Present study was aimed at evaluating the serum lipid profile in CKD patients and to find the pattern of its alteration in both haemodialyzed and conservatively treated CKD patients. Seventy one randomly selected CKD patients attending a tertiary care hospital of Assam during one year of time frame (40 haemodialyzed and 31 conservatively treated) along with 50 apparently healthy controls were included in the study. Test for serum lipid profile, urea creatinine, FBS, PPBS, total protein and albumin were carried out in all the cases and controls. The results were analyzed and compared with the controls using Microsoft Excel software. Triglyceride Level (TGL) of CKD group 157.88±61.82, controls 96.98±37.52, Very Low Density Lipoprotein (VLDL) of CKD group 31.58±12.36, controls 19.39±7.50 was marginally elevated and High Density Lipoprotein (HDL) of CKD group 33.40±9.06, controls 45.95±10.35 was significantly reduced in the patient group as compared to the controls and the results were statistically highly significant with p-value<0.001. Total cholesterol (CKD group 128.2±53.57, controls 142.53±31.44) and LDL (CKD group 63.23±46.47, controls 77.35±26.81) were lower in the patient group as compared to the controls, however the difference was statistically not significant (p value 0.09 and 0.059 respectively). There was no statistically significant difference of lipid profile between hemodialyzed and conservatively treated CKD groups and there was no gender related variation of lipid profile too. Increased TGL and reduced HDL, rather than increased total cholesterol and increased LDL are responsible for the high incidence of cardiovascular complications in CKD patients. Hypolipidemic drugs and low fat diet may be helpful in impeding the progression of cardiovascular complications and decrease mortality and morbidity in those patients.


PBDEs in US and German clothes dryer lint: a potential source of indoor contamination and exposure.
Polybrominated diphenyl ethers (PBDEs) are emerging persistent organic pollutants (POPs). Since the 1970s, PBDEs have been widely used as additive flame retardants in furniture and electronic equipment. Due to their wide use and persistent nature, these chemicals are found in the environment, human blood, breast milk and other tissues in increasing levels in recent decades. PBDEs are similar to polychlorinated biphenyls (PCBs) in structure and toxicity. However, unlike PCBs and PCDDs/PCDFs, the route of PBDE exposure is not almost exclusively through food. PBDE levels in US food are not markedly higher than in Europe, although US human blood and milk levels are an order of magnitude higher. For these reasons, other possible routes of PBDE exposure have been investigated to understand PBDE intake into humans. PBDE contaminated clothes dryer lint and household dust are indicators of indoor contamination and may be sources of human exposure through hand-to-mouth contact or dermal absorption. There are very few publications about PBDEs in US or European lint. Household dryer lint from 12 US and seven German homes were analyzed for PBDEs by gas chromatography coupled to high-resolution mass spectrometry. We found the median US total PBDE levels were more than 10 times higher than median German levels and the mean US levels were two times higher than mean German levels. The US levels ranged from 321 to 3073ngg(-1) (median: 803ngg(-1), mean: 1138ngg(-1)) and the German levels were from 330 to 2069ngg(-1) (median: 71ngg(-1), mean: 361ngg(-1)). PBDE contamination of lint was found in all samples; the source of the PBDEs may be from dryer electrical components and/or dust deposition onto clothing.


Mechanism of ammonia transport by Amt/MEP/Rh: structure of AmtB at 1.35 A.
The first structure of an ammonia channel from the Amt/MEP/Rh protein superfamily, determined to 1.35 angstrom resolution, shows it to be a channel that spans the membrane 11 times. Two structurally similar halves span the membrane with opposite polarity. Structures with and without ammonia or methyl ammonia show a vestibule that recruits NH4+/NH3, a binding site for NH4+, and a 20 angstrom-long hydrophobic channel that lowers the NH4+ pKa to below 6 and conducts NH3. Favorable interactions for NH3 are seen within the channel and use conserved histidines. Reconstitution of AmtB into vesicles shows that AmtB conducts uncharged NH3.


Interval training based on ventilatory anaerobic threshold improves aerobic functional capacity and metabolic profile: a randomized controlled trial in coronary artery disease patients.
Exercise training has been an essential component of cardiac rehabilitation. However, it is not known if interval training (IT) based on the ventilatory anaerobic threshold (VAT) could be effective in improving aerobic functional capacity and metabolic profile in patients without or with coronary artery disease (CAD). To investigate the effects of an IT program, based-intensity between 70-110% of workload reached at the VAT, on the aerobic functional capacity and metabolic profile of patients with and without CAD. Randomized controlled trial. Outpatients from a cardiac rehabilitation. A sample was composed of 32 patients with CAD (CAD group) and 32 patients without CAD (noCAD group) that were randomized into a trained or control groups. Submaximal cardiopulmonary exercise test on the cycle ergometer and blood samples were realized at baseline and post 16 weeks of IT program. The cardiorespiratory variables were obtained at the VAT level. Trained groups (CAD-T, N.=15; noCAD-T, N.=15) underwent a supervised three-week session IT program (30-40 minutes each exercise session, at the intensity workloads equivalent to %VAT [70-110%]) for 16 weeks. After 16 weeks of IT program, there were a significant increase of VO(2VAT) and workload in the trained groups (P<0.05), while in the control groups VO(2VAT) and heart rate decreased (P<0.05). Body mass and body index mass decreased in trained groups (P<0.05), and low-density lipoprotein increased only in noCAD group after 16 weeks (P<0.05). The magnitude of the improvement in VO(2VAT) was related to VO(2VAT) (r=-0.57, P<0.05) and workload (r=-0.52, P<0.05) at baseline. The IT program prescribed with intensities based on VAT improved the aerobic functional capacity and decreased body mass and body index mass loss in patients with and without CAD. IT program based on VAT provides new possibilities for cardiac rehabilitation in relation to individualized exercise prescription of the interval training.