Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid.
Maleic acid is a multi-functional chemical widely used in the field of industrial chemistry for producing food additives and food contact materials. As maleic acid may contaminate food by the release from food packages or intentional addition, it raises the concern about the effects of excessive dietary exposure to maleic acid on human health. However, the influence of maleic acid on human health has not been thoroughly studied. In silico toxicogenomics approaches have found the association between maleic acid and nervous system disease in human. The aim of this study is to experimentally explore the effects of maleic acid on human neuronal cells. A microarray-based transcriptome profiling was performed to offer a better understanding of the effects of maleic acid on human health. Gene expression profiles of human neuroblastoma SH-SY5Y cells exposed to three concentrations of maleic acid (10, 50, and 100 μM) for 24 h were analyzed. Genes which were differentially expressed in dose-dependent manners were identified and further analyzed with an enrichment analysis. The expression profile of selected genes related to the inferred functional changes was validated using quantitative polymerase chain reaction (qPCR). Specific fluorescence probes were applied to observe the inferred functional changes in maleic acid-treated neuronal cells. A total of 316 differentially expressed genes (141 upregulated and 175 downregulated) were identified in response to the treatment of maleic acid. The enrichment analysis showed that DNA binding and metal ion binding were the significant molecular functions (MFs) of the neuronal cells affected by maleic acid. Maleic acid exposure decreased the expression of genes associated with calcium and thiol levels of the cells in a dose-dependent manner. The levels of intracellular calcium and thiol levels were also affected by maleic acid dose-dependent. The exposure to maleic acid is found to decrease the cellular calcium and thiol levels in human neuronal cells at both transcriptional and functional levels. This study reported the first transcriptomic profiling of human neuronal cells treated with maleic acid. It is also the first experimental validation of chemical effects predicted by in silico toxicogenomics approaches. The proposed approach may be useful in understanding the potential effects of other poorly characterized chemicals on human health.


Assessment of the psychometrics of a PROMIS item bank: self-efficacy for managing daily activities.
The aim of this study is to investigate the psychometrics of the Patient-Reported Outcomes Measurement Information System self-efficacy for managing daily activities item bank. The item pool was field tested on a sample of 1087 participants via internet (n = 250) and in-clinic (n = 837) surveys. All participants reported having at least one chronic health condition. The 35 item pool was investigated for dimensionality (confirmatory factor analyses, CFA and exploratory factor analysis, EFA), item-total correlations, local independence, precision, and differential item functioning (DIF) across gender, race, ethnicity, age groups, data collection modes, and neurological chronic conditions (McFadden Pseudo R (2) less than 10 %). The item pool met two of the four CFA fit criteria (CFI = 0.952 and SRMR = 0.07). EFA analysis found a dominant first factor (eigenvalue = 24.34) and the ratio of first to second eigenvalue was 12.4. The item pool demonstrated good item-total correlations (0.59-0.85) and acceptable internal consistency (Cronbach's alpha = 0.97). The item pool maintained its precision (reliability over 0.90) across a wide range of theta (3.70), and there was no significant DIF. The findings indicated the item pool has sound psychometric properties and the test items are eligible for development of computerized adaptive testing and short forms.


Characterisation of sphingolipids in the human lens by thin layer chromatography-desorption electrospray ionisation mass spectrometry.
The lipidome of the human lens is unique in that cholesterol and dihydrosphingomyelin are the dominant classes. Moreover, the lens lipidome is not static with dramatic changes in several sphingolipid classes associated with both aging and cataract. Accordingly, there is a clear need to expand knowledge of the molecular species that constitute the human lens sphingolipidome. In this study, human lens lipids have been extracted and separated by thin-layer chromatography (TLC). Direct analysis of the TLC plates by desorption electrospray ionisation-mass spectrometry (DESI-MS) allowed the detection over 30 species from 11 classes of sphingolipids. Significantly, novel classes of lens lipids including sulfatides, dihydrosulfatides, lactosylceramide sulfates and dihydrolactosylceramide sulfates were identified.


Changing ideas about eukaryotic origins.
The origin of eukaryotic cells is one of the most fascinating challenges in biology, and has inspired decades of controversy and debate. Recent work has led to major upheavals in our understanding of eukaryotic origins and has catalysed new debates about the roles of endosymbiosis and gene flow across the tree of life. Improved methods of phylogenetic analysis support scenarios in which the host cell for the mitochondrial endosymbiont was a member of the Archaea, and new technologies for sampling the genomes of environmental prokaryotes have allowed investigators to home in on closer relatives of founding symbiotic partners. The inference and interpretation of phylogenetic trees from genomic data remains at the centre of many of these debates, and there is increasing recognition that trees built using inadequate methods can prove misleading, whether describing the relationship of eukaryotes to other cells or the root of the universal tree. New statistical approaches show promise for addressing these questions but they come with their own computational challenges. The papers in this theme issue discuss recent progress on the origin of eukaryotic cells and genomes, highlight some of the ongoing debates, and suggest possible routes to future progress.


Risk Perceptions of Wastewater Use for Urban Agriculture in Accra, Ghana.
Poor food hygiene is a significant risk to public health globally, but especially in low and middle-income countries where access to sanitation, and general hygiene remain poor. Food hygiene becomes even more pertinent when untreated, or poorly treated wastewater is used in agriculture. In such circumstances the WHO recommends the adoption of a multiple-barrier approach that prescribes health protective measures at different entry points along the food chain. This study sought to assess the knowledge and awareness of wastewater use for crop production, its related health risks, and adoption of health protective measures by farmers, market salespersons and consumers using questionnaires and focus group discussions. In the period from September 2012 to August 2013, 490 respondents were interviewed during two cropping seasons. The study found that awareness of the source of irrigation water was low among consumers and street food vendors, though higher among market vendors. In contrast, health risk awareness was generally high among salespersons and consumers, but low among farmers. The study found that consumers did not prioritize health indicators when buying produce from vendors but were motivated to buy produce, or prepared food based on taste, friendship, cost, convenience and freshness of produce. Similarly, farmers' awareness of health risk did not influence their adoption of safer farm practices. The study recommends the promotion of interventions that would result in more direct benefits to both producers and vendors, together with hygiene education and enforcement of food safety byelaws in order to influence behaviour change, and increase the uptake of the multiple-barrier approach.


Production of specific antisera to human B lymphocytes.
Antisera have been prepared, in mice and rabbits, to membrane and sub-membrane fractions of human B lymphocyte derived lymphoid lines. Antisera to a protein subfraction were, after only minimal absorption, specific for human peripheral B lymphocytes, monocytes and B cell derived lymphoid lines. The antigen(s) recognised by these antisera were not the same as the previously described B-cell markers; immunoglobulin, Fc receptor, complement receptor and Ia antigens. The antigen(s) could not be removed from cells by lysostrip with anti- beta2 microglobulin.


Comparative quantitation of human cytomegalovirus DNA in blood leukocytes and plasma of transplant and AIDS patients.
A new method for the quantitation of human cytomegalovirus (HCMV) DNA was used to determine the levels of viral DNA in parallel in 120 blood leukocyte (leukoDNAemia) and plasma (plasmaDNAemia) samples from 8 heart or heart-lung transplant patients and 17 AIDS patients with disseminated HCMV infection. PlasmaDNAemia was consistently associated with leukoDNAemia in both groups of patients. However, at least in the transplant patients, plasmaDNAemia was not necessarily associated with clinical symptoms, appearing later and disappearing earlier than leukoDNAemia during the course of infection. Quantitative mean levels of leukoDNAemia were mostly higher than those of plasmaDNAemia in both transplant and AIDS patients. However, in the absence of antiviral treatment, plasmaDNAemia levels were significantly higher in AIDS patients than in transplant recipients, whereas leukoDNAemia levels were not significantly different between the two groups of patients. A significant correlation was found between leukoDNAemia and plasmaDNAemia in AIDS patients, as well as in transplant recipients, although to a lesser degree. However, from a diagnostic standpoint, quantitative determination of plasmaDNAemia appears to represent a much less sensitive parameter than that of leukoDNAemia (or antigenemia) for monitoring HCMV infections and antiviral treatment.


The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A.
Thrombin is a positive mediator of thrombus formation through the proteolytic activation of protease-activated receptors (PARs), fibrinogen, factor XI (fXI), and other substrates, and a negative regulator through activation of protein C, a natural anticoagulant with anti-inflammatory/cytoprotective properties. Protease-engineering studies have established that 2 active-site substitutions, W215A and E217A (fII(WE)), result in dramatically reduced catalytic efficiency with procoagulant substrates while largely preserving thrombomodulin (TM)-dependent protein C activation. To explore the hypothesis that a prothrombin variant favoring antithrombotic pathways would be compatible with development but limit inflammatory processes in vivo, we generated mice carrying the fII(WE) mutations within the endogenous prothrombin gene. Unlike fII-null embryos, fII(WE/WE) mice uniformly developed to term. Nevertheless, these mice ultimately succumbed to spontaneous bleeding events shortly after birth. Heterozygous fII(WT/WE) mice were viable and fertile despite a shift toward an antithrombotic phenotype exemplified by prolonged tail-bleeding times and times-to-occlusion after FeCl₃ vessel injury. More interestingly, prothrombin(WE) expression significantly ameliorated the development of inflammatory joint disease in mice challenged with collagen-induced arthritis (CIA). The administration of active recombinant thrombin(WE) also suppressed the development of CIA in wild-type mice. These studies provide a proof-of-principle that pro/thrombin variants engineered with altered substrate specificity may offer therapeutic opportunities for limiting inflammatory disease processes.


Training for Tuberculosis Elimination in Indonesia: Achievements, Reflections, and Potential for Impact.
Indonesia has the third highest tuberculosis (TB) caseload internationally. A cornerstone for strengthening health systems to respond to TB is a well-trained workforce. In a partnership between Indonesian and Australian institutions, TB training was run during 2018 to strengthen the local capacity to meet End TB strategy targets. This paper aims to report on course design, delivery, training outcomes, and reflections. Seventy-six Indonesian healthcare workers, program staff, researchers, and policy-makers were selected from over 800 applicants. The structure comprised three trainings, each with a pre-course workshop (in Indonesia) to identify learning needs, a two-week block (Australia), and a post-course workshop (Indonesia). The training content delivered was a combination of TB technical knowledge and program/project theory, design, and logic, and the training utilised multiple teaching and learning methods. An innovative element of the training was participant-designed TB workplace projects focusing on context-specific priorities. Evaluation was undertaken using participant surveys and appraisal of the projects. Participants rated the course highly, while success in project implementation varied. Reflections include the importance of involving Indonesian experts in delivery of training, the need to understand participant learning requirements and adapt the training content accordingly, and the challenge of measuring tangible training outputs.


Carcinomas of the Uterine Cervix: Comprehensive Review With An Update on Pathogenesis, Nomenclature of Precursor and Invasive Lesions, and Differential Diagnostic Considerations.
Most cervical carcinomas and their related lesions are attributed to an infection by human papillomavirus (HPV). The infection usually starts in the basal cells at the squamocolumnar junction. It causes cell proliferation and maturation abnormalities along with nuclear abnormalities resulting in low-grade squamous intraepithelial lesions. An overwhelming majority of these lesions spontaneously disappear, and the infection is cleared. In a small subset of high-risk HPV infection cases, the lesions may persist and progress to high-grade squamous intraepithelial lesions. These are associated with the incorporation of the viral genome into the human genome. Some of the high-grade squamous intraepithelial lesions, over several years, progress to invasive carcinoma. Carcinomas of the cervix are usually squamous cell carcinomas (SCCs), but 20% to 25% of the cases may manifest as adenocarcinomas. Similar to SCC, adenocarcinomas may initially manifest as adenocarcinomas in situ and may progress to invasive carcinomas after a variable period of time. In the recently published World Health Organization classification of female genital tumors, SCCs, and adenocarcinomas of the cervix are divided into HPV-associated and HPV-independent tumors. This review draws on the latest terminology and the several morphologic subtypes recognized for each category.


Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity.
Activity-dependent transcription has emerged as a major source of gene products that regulate neuronal excitability, connectivity, and synaptic properties. However, the elongation rate of RNA polymerases imposes a significant temporal constraint for transcript synthesis, in particular for long genes where new synthesis requires hours. Here we reveal a novel, transcription-independent mechanism that releases transcripts within minutes of neuronal stimulation. We found that, in the mouse neocortex, polyadenylated transcripts retain select introns and are stably accumulated in the cell nucleus. A subset of these intron retention transcripts undergoes activity-dependent splicing, cytoplasmic export, and ribosome loading, thus acutely releasing mRNAs in response to stimulation. This process requires NMDA receptor- and calmodulin-dependent kinase pathways, and it is particularly prevalent for long transcripts. We conclude that regulated intron retention in fully transcribed RNAs represents a mechanism to rapidly mobilize a pool of mRNAs in response to neuronal activity.


Nantenine: an antagonist of the behavioral and physiological effects of MDMA in mice.
No selective antagonists for the effects of MDMA have yet been identified. The structurally-similar, naturally-occurring plant alkaloid nantenine (9,10-methylenedioxy-1,2 dimethoxyaporphine) may represent such a compound. To investigate the capacity of nantenine to block and/or reverse MDMA-induced hyperthermia, lethality, locomotor stimulation, and head twitches in mice, and to compare these actions with those of the selective alpha1 antagonist prazosin and the selective 5-HT2A antagonist M100907. Pretreatments of either 10 mg/kg nantenine or 1 mg/kg prazosin were administered 15 min before 32 mg/kg MDMA; core temperature and locomotor stimulation were then monitored via radiotelemetry for at least 3 h. In further hyperthermia studies, 32 mg/kg MDMA was administered first and temperature was allowed to rise for 30 min; 10 mg/kg nantenine, 1 mg/kg prazosin, or 1 mg/kg M100907 was then administered in an attempt to reverse MDMA-induced hyperthermia. In lethality assays, percent lethality was quantified 2 h after MDMA injection in two distinct housing conditions, one or 12 mice per cage, with or without 15 min pretreatments of 10 mg/kg nantenine or 1 mg/kg prazosin. Drug elicited head twitches were quantified for 10 min following administration of either MDMA enantiomer, with and without pretreatments of 1 mg/kg nantenine, 0.1 mg/kg prazosin, or 0.001 mg/kg M100907. Nantenine blocked and rapidly reversed MDMA-induced hyperthermia, attenuated lethality in both housing conditions, and reduced MDMA-induced locomotor stimulation and head twitches in mice. Prazosin blocked, but did not reverse, MDMA-induced hyperthermia, attenuated lethality (more effectively in singly-housed animals), and reduced MDMA-induced locomotor stimulation and head twitches. M100907 did not reverse MDMA-induced hyperthermia, but effectively blocked drug-elicited head twitches. Nantenine functions as an effective antagonist against a wide range of MDMA-induced effects in mice. The antagonist actions of this compound at serotonin and adrenergic receptors may be differentially implicated across endpoints.


Cloning and characterization of two human cDNAs encoding the mRNA capping enzyme.
Previous studies demonstrated that the mammalian mRNA capping enzyme is a bifunctional enzyme containing RNA 5'-triphosphatase and mRNA guanylyl-transferase activities in a single polypeptide. In yeast, both the above activities are separated into two different subunits, alpha and beta, the genes for which we have cloned recently. It is thus interesting to compare the structural and functional relationships between the mammalian and yeast capping enzymes. Here we isolated two human cDNAs encoding mRNA capping enzymes termed hCAP1a and hCAP1b which encode 597 and 541 amino acids, respectively. They are different only at the region coding for the C-terminal portion of the enzyme. Comparison of the deduced amino acid sequences with other cellular and viral capping enzymes showed that all the regions conserved among mRNA guanylyltransferases are observed in our clones except one conserved C-terminal region which was absent in the hCAP1b protein. The purified recombinant hCAP1a gene product, hCAP1a, exhibited both RNA 5'-triphosphatase and mRNA guanylyltransferase activities. Deletion mutant analysis of hCAP1a showed that the N-terminal 213 amino acid fragment containing a tyrosine specific protein phosphatase motif catalyzed the RNA 5'-triphosphatase activity and the C-terminal 369 amino acid fragment exhibited the mRNA guanylyltransferase activity. On the other hand, hCAP1b showed RNA 5'-triphosphatase activity, but neither enzyme-GMP covalent complex formation nor cap structure formation was detected.


Is Helicobacter pylori a cause of gastric cancer? An appraisal of the seroepidemiological evidence.
The epidemiological evidence linking Helicobacter pylori infection to stomach cancer is reviewed here in ascending order of epidemiological strength. Only those studies in which exposure to H. pylori was assessed by serology are considered. Ecological studies or geographical correlation studies have revealed inconsistent results when the incidence or mortality rates of stomach cancer have been correlated with the prevalence rates of H. pylori infection. Only those studies with a wide range in gastric cancer rates and in which a large number of populations are compared show weak but significant positive correlations. However, it is well known that these studies are difficult to interpret and do not provide strong evidence for a causal association. In only those case-control studies carried out in low-risk countries for gastric cancer, an increased risk for stomach cancer has been found associated with the presence of H. pylori antibodies. In high-risk countries for gastric cancer the lack of association may be explained by the use of inappropriate serological assays. Three case-control studies nested within cohorts have consistently shown an increased risk among subjects in whom the presence of H. pylori antibodies have been detected many years before the cancer diagnosis. They constitute the strongest evidence for a causal association. The final proof of causality will be provided by intervention studies in which it is demonstrated that long-term eradication of H. pylori is followed by a reduction in the gastric cancer rates. However, our own experience has shown that such studies are not easy to implement.


Nosocomial infections. A college of American pathologists Q-probes study in 512 North American institutions.
We report nosocomial infection surveillance methods and hospital infection rates in 512 institutions obtained from a Q-Probes study of the College of American Pathologists, Northfield, Ill. The results showed that nosocomial infection surveillance procedures were well standardized. Use of microbiology reports was the most common case-finding method (97.3%), followed by review of the patient's medical record (86.1%). The median number of full-time equivalents per 100 occupied beds utilized for infection control services was 0.64, and these full-time equivalents spent 40% of their time on surveillance activities. A computer was used in 81% of institutions to assist in conducting surveillance, although this usage was not associated with decreased surveillance time or personnel required. This study provided data on total and site-specific infection rates for a wide range of small to large hospitals. When stratified into subgroups (based on teaching status and hospital size), infections rates in this study were comparable with those of the National Nosocomial Infection Surveillance program, and showed a trend of increasing rates of nosocomial bloodstream and surgical wound infections.


Two Cases of Cardiac Implantable Electronic Device Placement via Persistent Left Superior Vena Cava.
Persistent left superior vena cava (PLSVC) is the most common variation of anomalous venous return to the heart and present in 0.1-0.5% of the general population. The left anterior cardinal veins typically obliterate during early cardiac development but failure of involution results in PLSVC. It is an asymptomatic congenital anomaly, usually discovered while performing interventions through the left subclavian vein or during cardiovascular imaging. PLSVC can be associated with cardiac arrhythmias and congenital heart disease. We present two cases of PLSVC: first, a 68-year-old male who presented with complete heart block, for which a temporary pacemaker was initially inserted followed by a permanent pacemaker; second, a 53-year-old female with a history of hypertension and ischemic cardiomyopathy with a left ventricular ejection fraction of 25%, and a survivor of sudden cardiac death, who underwent an implantable cardioverter-defibrillator (ICD) for secondary prevention. Both cases of PLSVC were detected incidentally during the transvenous approach to the heart. PLSVC was suspected by the unusually left medial position of the lead, while cineflouroscopy showed the venous trajectory toward the coronary sinus and drainage into the right atrium. It is technically difficult to cross the wire through the tricuspid valve when coming from the PLSVC and coronary sinus without making a loop in the right atrium, which is known as a wide loop technique. PLSVC is an uncommon anomalous anatomical variant and should be recognized appropriately by specialists who frequently carry out procedures through the left subclavian vein, such as implantation of permanent pacemaker, ICD and cardiac resynchronization therapy. It should also be recognized that wide loop formation of the right ventricular lead in the right atrium is helpful to cross the tricuspid valve and to affix the lead in the right ventricle. Persistent left superior vena cava is an anatomical variant that should be recognized by specialists who frequently carry procedures through the left subclavian vein (e.g. implantation of a permanent pacemaker, implantable cardioverter-defibrillator and cardiac resynchronization therapy).Maneuvers like wide loop formation of the right ventricular lead in the right atrium is helpful to cross the tricuspid valve and to affix the lead in the right ventricle.The cardiac imaging specialist should also suspect and rule out PLSVC on encountering a dilated coronary sinus on any imaging modality.


The Role of Anterior Cingulate Cortex in the Affective Evaluation of Conflict.
An influential theory of ACC function argues that this brain region plays a crucial role in the affective evaluation of performance monitoring and control demands. Specifically, control-demanding processes such as response conflict are thought to be registered as aversive signals by ACC, which in turn triggers processing adjustments to support avoidance learning. In support of conflict being treated as an aversive event, recent behavioral studies demonstrated that incongruent (i.e., conflict inducing), relative to congruent, stimuli can speed up subsequent negative, relative to positive, affective picture processing. Here, we used fMRI to investigate directly whether ACC activity in response to negative versus positive pictures is modulated by preceding control demands, consisting of conflict and task-switching conditions. The results show that negative, relative to positive, pictures elicited higher ACC activation after congruent, relative to incongruent, trials, suggesting that ACC's response to negative (positive) pictures was indeed affectively primed by incongruent (congruent) trials. Interestingly, this pattern of results was observed on task repetitions but disappeared on task alternations. This study supports the proposal that conflict induces negative affect and is the first to show that this affective signal is reflected in ACC activation.


Melanoma patients receive more follow-up care than current guideline recommendations: a study of 546 patients from the general Dutch population.
Follow-up of melanoma patients has been a continuing issue for discussion in the past years partly due to ever increasing incidence of this disease, as well as the lack of agreement regarding the reasons for, and the frequency of follow-up. Patients' perspectives are often not included in this continuing discussion on follow-up of melanoma patients. To examine to what extent follow-up was experienced, according to the guideline of 2005, by physicians and melanoma patients in a Dutch population from the south-east area of the Netherlands. The patient's perspective and satisfaction over said follow-up shall also be taken into account. Follow-up among melanoma survivors was investigated and compared with the recommendations of the current Dutch national guideline. All 699 melanoma patients registered at the Eindhoven Cancer Registry (between 1998 and 2008), and treated in 3 regional hospitals, were contacted via postal mail. The survey questioned about treatment, symptoms, impact on daily life and follow-up. Patients with multiple melanomas (n = 16) were excluded. Response rate was 80%, 418 patients were still under surveillance for their melanoma. The average time since diagnoses was 4 years, 71% had stage I melanoma. Almost 80% of patients with a Breslow thickness <1 mm, reported more frequent follow-up visits than the guideline recommends. Only 5% of the patients wanted to reduce their follow-up frequency. Eighty percent of patients were under supervision of a dermatologist: physical examination (25%), lymph node palpation (11%) and/or scar inspection (20%) did not regularly occur. These proportions were significantly higher among other specialism. Follow-up frequency was higher than recommended by the current melanoma guideline in a large group of patients, mainly those with lower Breslow thickness.


Clinical significance of nutritional risk screening tool for hospitalised children with acute burn injuries: a cross-sectional study.
We assessed the nutritional risks among children hospitalised with acute burn injuries and their associated clinical outcomes using three nutritional risk screening (NRS) tools: Screening Tool for Risk of Impaired Nutritional Status and Growth (STRONGKIDS ), Pediatric Yorkhill Malnutrition Score (PYMS) and Screening Tool for the Assessment for Malnutrition in Pediatrics (STAMP). This prospective cross-sectional study was conducted from October 2015 to November 2016, in a regional burn centre. Patients were screened by two independent observers, using the three NRS tools. A total of 100 children aged 3 months to 16.5 years were included. STRONGKIDS identified 16% of patients as having high risk, with being identified 45% by PYMS and 44% by STAMP. After adjustment for confounding factors in multivariate regression analysis, patients in the high-risk group had significantly longer median (SD) lengths of stay [medium versus high risk: STRONGKIDS , 9.5 (6.6) versus 15.0 (24.2) days; PYMS, 8.5 (4.4) versus 13.0 (16.1) days; STAMP, 9.0 (5.7) versus 11.0 (17.4) days] and greater median (SD) weight loss [medium versus high risk: STRONGKIDS, 0.15 (0.8) versus -0.35 (0.8) kg; STAMP, 0.5 (0.7) versus 0 (0.1) kg] than patients in the medium-risk group (P < 0.05). The strengths of agreement in the nutritional risk classification between the two observers were good (κ for STRONGKIDS = 0.61; PYMS = 0.79; STAMP = 0.75) (P < 0.01). The STRONGKIDS , PYMS and STAMP tools could be useful and practical for determining which hospitalised children with acute burn injuries will need additional nutritional intervention.


Risk score based on three mRNA expression predicts the survival of bladder cancer.
Bladder cancer (BLCA) is one of the most malignant cancers worldwide, and its prognosis varies. 1214 BLCA samples in five different datasets and 2 platforms were enrolled in this study. By utilizing the gene expression in The Cancer Genome Atlas (TCGA) dataset, and another two datasets, in GSE13507 and GSE31684, we constructed a risk score staging system with Cox multivariate regression to evaluate predict the outcome of BLCA patients. Three genes consist of RCOR1, ST3GAL5, and COL10A1 were used to predict the survival of BLCA patients. The patients with low risk score have a better survival rate than those with high risk score, significantly. The survival profiles of another two datasets (GSE13507 and GSE31684), which were used for candidate gene selection, were similar as the training dataset (TCGA). Furthermore, survival prediction effect of risk score staging system in another 2 independent datasets, GSE40875 and E-TABM-4321, were also validated. Compared with other clinical observations, and the risk score performs better in evaluating the survival of BLCA patients. Moreover, the correlation between radiation were also evaluated, and we found that patients have a poor survival in high risk group, regardless of radiation. Gene Set Enrichment Analysis was also implemented to find the difference between high-risk and low-risk groups on biological pathways, and focal adhesion and JAK signaling pathway were significantly enriched. In summary, we developed a risk staging model for BLCA patients with three gene expression. The model is independent from and performs better than other clinical information.


The influence of sex on rheumatoid arthritis: a prospective study of onset and outcome after 2 years.
This prospective study analyzed influence of patient's sex on early rheumatoid arthritis (RA) within one year of disease onset and after 2 years' followup. A total of 844 consecutive patients, 538 women, with RA of less than 12 months were studied. Standardized clinical and radiographic assessments were performed at study entry and after 2 years. The association of several variables at study entry with the outcome variables Disease Activity Score (DAS28), functional disability measured by the Health Assessment Questionnaire (HAQ), and, in 390 patients, Larsen score at the 2-year followup were analyzed in men and women separately. At study entry the women were younger compared with the men and the sexes showed different age distributions. The women had higher DAS28 and HAQ scores. However, women below 50 years of age at study entry had milder disease than older women and close to that of men. At 2-year followup the women still had higher DAS28 and HAQ scores compared to men, who had achieved remission in a higher frequency. Larsen score showed no sex difference either at study entry or after 2 years. Presence of rheumatoid factor (RF) was associated with lower age at study entry and higher DAS28 at followup in men only. Higher DAS28 and HAQ scores at entry were more strongly correlated with severe disease at followup in women than in men. Presence of the "shared epitope" was not associated with age or the outcome variables DAS28 and Larsen score in either sex. The disease phenotype in early RA was significantly different between men and women, particularly concerning age, disease activity, and functional capacity. There were differences between the sexes concerning early disease characteristics associated with outcome at 2 years of followup.


Shift of circadian feeding pattern by high-fat diets is coincident with reward deficits in obese mice.
Recent studies provide evidence that high-fat diets (HF) trigger both i) a deficit of reward responses linked to a decrease of mesolimbic dopaminergic activity, and ii) a disorganization of circadian feeding behavior that switch from a structured meal-based schedule to a continuous snacking, even during periods normally devoted to rest. This feeding pattern has been shown to be a cause of HF-induced overweight and obesity. Our hypothesis deals with the eventual link between the rewarding properties of food and the circadian distribution of meals. We have investigated the effect of circadian feeding pattern on reward circuits by means of the conditioned-place preference (CPP) paradigm and we have characterized the rewarding properties of natural (food) and artificial (cocaine) reinforcers both in free-feeding ad libitum HF mice and in HF animals submitted to a re-organized feeding schedule based on the standard feeding behavior displayed by mice feeding normal chow ("forced synchronization"). We demonstrate that i) ad libitum HF diet attenuates cocaine and food reward in the CPP protocol, and ii) forced synchronization of feeding prevents this reward deficit. Our study provides further evidence that the rewarding impact of food with low palatability is diminished in mice exposed to a high-fat diet and strongly suggest that the decreased sensitivity to chow as a positive reinforcer triggers a disorganized feeding pattern which might account for metabolic disorders leading to obesity.


The irony of a rich country: issues of financial access to and availability of healthy food in the Republic of Ireland.
To determine the weekly financial cost of a diet as recommended by national policy in two parents with two children, single parents with one child and single old people with low income, and begin to identify, in a rich country context, variation in food item availability, price and household purchasing capacity. Food baskets were developed based on national dietary recommendations and purchasing patterns of these household groups. National-level prices of each food were identified, as well as pricing across a representative selection of Irish retail outlet types. Basket costs were assessed relative to the financial capacity of household type. The types of retail outlets in which low-income groups tend to shop do not carry many own brand items and is less likely to stock healthy options, but when they do, they are more expensive than in other outlets. Single parents with one child, two adults with two children and single older people would have to spend 80%, 69% and 38%, respectively, of their weekly household income to purchase the food basket based on economy-line products. Financial access to and availability of healthy food options must be considered through a national policy cognisant of basic human needs for healthy living. This research provides evidence on the direct costs of healthy eating for policy and planning to ensure not only financial capacity but also to guarantee that affordable healthy food choices are physically available to all groups in society.


Intergenerational continuity and stability in early family formation.
This study examines intergenerational continuity (mean level similarity) and stability (maintenance of rank ordering of individuals) in age and marital status at the time of becoming a young parent using prospective data from 3 generations of 585 families. G2 participants were recruited at the age of 5 years and followed until the age of 28, by which time 227 had become parents themselves. The findings suggest that despite dramatic intergenerational discontinuities with young adults, on average, now being more likely to be unmarried and older at the time of becoming parents than in previous generations, intergenerational stability in age and marital status at the time of becoming a young parent is still substantial. This intergenerational stability was, for the most part, not moderated by demographic, familial, or behavioral factors, suggesting that a developmental, multigenerational perspective is necessary to understand what has previously been considered a largely demographic issue. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease.
Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient's alloHSCT donor. Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease-negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels. Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.


Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma.
Multiple myeloma is characterized by the malignant proliferating antibody-producing plasma cells in the bone marrow. Despite recent advances in therapy that improve the survival of patients, multiple myeloma remains incurable and therapy resistance is the major factor causing lethality. Clearly, more effective treatments are necessary. In recent years it has become apparent that, as highly secretory antibody-producing cells, multiple myeloma cells require an increased capacity to cope with unfolded proteins and are particularly sensitive to compounds targeting proteostasis such as proteasome inhibitors, which represent one of the most prominent new therapeutic strategies. Because of the increased requirement for dealing with secretory proteins within the endoplasmic reticulum, multiple myeloma cells are heavily reliant for survival on a set of signaling pathways, known as the unfolded protein response (UPR). Thus, directly targeting the UPR emerges as a new promising therapeutic strategy. Here, we provide an overview of the current understanding of the UPR signaling in cancer, and outline its important role in myeloma pathogenesis and treatment. We discuss new therapeutic approaches based on targeting the protein quality control machinery and particularly the IRE1α/XBP1 axis of the UPR.


Chemical components of the roots of Noni (Morinda citrifolia) and their cytotoxic effects.
Roots of Morinda citrifolia (Noni or Yor in Thai) have been used traditionally for thousands of years to treat chronic diseases such as cancer and heart disease. In this study, three new anthraquinones together with 15 known compounds were isolated from the roots of M. citrifolia (Rubiaceae). Their structures were established by spectroscopic methods, particularly 1D and 2D NMR techniques. Six known compounds, together with two new compounds (2 and 3) showed significant inhibitory effects on the proliferation of human lung and colon cancer cells.


Arterial stiffening provides sufficient explanation for primary hypertension.
Hypertension is one of the most common age-related chronic disorders, and by predisposing individuals for heart failure, stroke, and kidney disease, it is a major source of morbidity and mortality. Its etiology remains enigmatic despite intense research efforts over many decades. By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that arterial stiffening seems sufficient to explain age-related emergence of hypertension. Specifically, the empirically observed chronic changes in pulse pressure with age and the impaired capacity of hypertensive individuals to regulate short-term changes in blood pressure arise as emergent properties of the integrated system. The results are consistent with available experimental data from chemical and surgical manipulation of the cardio-vascular system. In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function.


Blastocysts exhibit sex-specific signalling of IFNT transcription, translation and activity.
Preimplantation bovine blastocyst supernatants exhibit sex-dependent antiviral activity, due to the ruminant pregnancy recognition signal interferon tau (IFNT). Differing potencies of IFNT variants have been supposed as cause, although evidence remains scarce. Here, we aimed at quantifying the sex-dependent IFNT production on transcriptional, translational and biological activity level in bovine blastocysts, to elucidate the origin of differences in antiviral activity between male and female blastocysts. Day 8 bovine blastocysts were co-cultured with endometrial stroma cells for 48 h. The embryonic IFNT mRNA expression was determined by quantitative reverse transcription followed by polymerase chain reaction (RT-qPCR). Additionally, the IFNT protein concentration was determined using a sensitive in-house developed IFNT-specific enzyme-linked immunosorbent assay (ELISA). The biological activity was assessed by quantifying the response of interferon-stimulated gene (ISG) expression in endometrial stroma cells. While the IFNT-specific ELISA displayed a limit of detection of 7.3 pg/mL, the stroma cell culture system showed to react to as little as 0.1 pg/mL IFNT in RT-qPCR analysis. The female blastocysts had a significant, 5.6-fold, 3.6-fold and 5.2-fold higher IFNT production than male blastocysts as determined by transcript abundance, protein concentration and, protein activity, respectively. Additionally, all parameters correlated positively, and therefore, we conclude that female blastocysts most likely have an increased IFNT gene and protein expression rather than expressing more potent IFNT variants.


Subgingival bacteria in Ghanaian adolescents with or without progression of attachment loss.
This study describes subgingival bacterial profiles associated with clinical periodontal status in Ghanaian adolescents with or without progression of attachment loss. Among 500 adolescents included in a cohort study, 397 returned 2 years later for a periodontal re-examination, including full-mouth CAL measurements. At follow-up, a subgroup of 98 adolescents was also subjected to bacterial sampling with paper points at four periodontal sites (mesial aspect of 11, 26, 31, and 46) and analyzed with the checkerboard DNA-DNA hybridization technique against DNA-probes from nine periodontitis-associated bacterial species. The 98 Ghanaian adolescents examined in the present study were similar to the entire group examined at the 2-year follow-up with respect to age, gender, and CAL ≥3 mm. A high detection frequency of Fusobacterium nucleatum and Prevotella intermedia (>99%) using checkerboard analysis was found, while for Aggregatibacter actinomycetemcomitans the detection frequency was <50%. A strong correlation was found at the individual level between the presence of P. intermedia and the total CAL change, and P. intermedia and Porphyromonas gingivalis were strongly correlated with a change in CAL and probing pocket depth (PPD) at the sampled sites. In a linear regression model, a significant discriminating factor for the total CAL change in the dentition during the 2-year follow-up period was obtained for P. intermedia and public school. This study indicates that subgingival bacterial species other than A. actinomycetemcomitans, for example, P. intermedia, have a significant association with periodontal breakdown (change in CAL) in Ghanaian adolescents with progression of periodontal attachment loss.


Resident education in the era of patient safety: a nationwide analysis of outcomes and complications in resident-assisted oncologic surgery.
Complex, oncologic surgery is an important component of resident education. Our objective was to evaluate the impact of resident participation in oncologic procedures on overall 30-day morbidity and mortality. A retrospective cohort analysis was performed using the National Surgical Quality Improvement Program Participant User Files for 2005-2009. Colorectal, hepatopancreaticobiliary, and gastroesophageal oncology procedures were included. Multivariate logistic regression was used to assess the impact of trainee involvement on 30-day morbidity and mortality after adjusting for potential confounders. A total of 77,862 patients were included for analysis, 53,885 (69.2%) involving surgical trainees and 23,977 (30.8%) without trainees. The overall 30-day morbidity was significantly higher in the trainee group [27.2 vs. 21%, adjusted odds ratio (AOR) 1.19, 95% confidence interval (CI) 1.15-1.24, p < 0.0001)]; however, there was significantly lower 30-day postoperative mortality in the trainee group (1.9 vs. 2.1%, AOR 0.87, 95% CI 0.77-0.98, p = 0.02) and significantly lower failure-to-rescue rate (defined as mortality rate among patients suffering one or more postoperative complications) (5.9 vs. 7.6%, AOR 0.79, 95% CI 0.68-0.90, p = 0.001). The overall 30-day morbidity was highest in the PGY 5 level (29%) compared to 24% for PGY 1 or 2 and 23% for PGY 3 (AOR per level increase 1.05, 95% CI 1.03-1.07, p < 0.0001). Trainee participation in complex, oncologic surgery is associated with significantly higher rates of 30-day postoperative complications in NSQIP-participating hospitals; however, this effect is countered by overall lower 30-day mortality and improved rescue rate in preventing death among patients suffering complications.


Resveratrol stimulates mitochondrial bioenergetics to protect retinal pigment epithelial cells from oxidative damage.
Resveratrol (RSV) alleviates oxidative damage in human adult retinal pigment epithelial (ARPE) cells. Mitochondrial bioenergetics is associated with oxidative stress. The purpose of this study was to examine the role of mitochondrial bioenergetics in the cytoprotective effect of RSV. Its role in protection against the adverse effects of cigarette smoke (CS) in experimental choroidal neovascularization (CNV) was also examined. Cultured ARPE-19 cells were treated with acrolein alone or acrolein with added RSV. Temporal changes in cell viability, expression of the antioxidant protein, and mitochondrial bioenergetics were evaluated. In an animal study, CNV lesions were created in Brown Norway rats by laser-induced photocoagulation. Effects of CS alone or with additional RSV treatment on CNV lesions were quantified by fundus fluorescein angiography. In ARPE-19 cells, RSV rescued acrolein-induced cell death, alongside reversal of acrolein-induced superoxide dismutase expression. Resveratrol increased the mitochondrial bioenergetics, including basal respiratory rate, adenosine triphosphate synthesis via oxidative phosphorylation, and maximal mitochondrial capacity. In animal experiments, CS induced a significant increase in CNV following laser injury, and this increase in CNV was appreciably prevented following peripheral infusion of RSV. Our results indicate that RSV, a major polyphenol found in red wine, exerts protection against acrolein-induced cytotoxicity in human ARPE-19 cells via increases in the mitochondrial bioenergetics. In addition, the antioxidant effect of RSV may contribute to protection against laser-induced CNV in animals exposed to CS. Therefore, RSV might be beneficial for treatment of acrolein-induced or CS-evoked RPE degeneration.


Matrix Polysaccharides and SiaD Diguanylate Cyclase Alter Community Structure and Competitiveness of Pseudomonas aeruginosa during Dual-Species Biofilm Development with Staphylococcus aureus.
Mixed-species biofilms display a number of emergent properties, including enhanced antimicrobial tolerance and communal metabolism. These properties may depend on interspecies relationships and the structure of the biofilm. However, the contribution of specific matrix components to emergent properties of mixed-species biofilms remains poorly understood. Using a dual-species biofilm community formed by the opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus, we found that whilst neither Pel nor Psl polysaccharides, produced by P. aeruginosa, affect relative species abundance in mature P. aeruginosa and S. aureus biofilms, Psl production is associated with increased P. aeruginosa abundance and reduced S. aureus aggregation in the early stages of biofilm formation. Our data suggest that the competitive effect of Psl is not associated with its structural role in cross-linking the matrix and adhering to P. aeruginosa cells but is instead mediated through the activation of the diguanylate cyclase SiaD. This regulatory control was also found to be independent of the siderophore pyoverdine and Pseudomonas quinolone signal, which have previously been proposed to reduce S. aureus viability by inducing lactic acid fermentation-based growth. In contrast to the effect mediated by Psl, Pel reduced the effective crosslinking of the biofilm matrix and facilitated superdiffusivity in microcolony regions. These changes in matrix cross-linking enhance biofilm surface spreading and expansion of microcolonies in the later stages of biofilm development, improving overall dual-species biofilm growth and increasing biovolume severalfold. Thus, the biofilm matrix and regulators associated with matrix production play essential roles in mixed-species biofilm interactions.IMPORTANCE Bacteria in natural and engineered environments form biofilms that include many different species. Microorganisms rely on a number of different strategies to manage social interactions with other species and to access resources, build biofilm consortia, and optimize growth. For example, Pseudomonasaeruginosa and Staphylococcus aureus are biofilm-forming bacteria that coinfect the lungs of cystic fibrosis patients and diabetic and chronic wounds. P. aeruginosa is known to antagonize S. aureus growth. However, many of the factors responsible for mixed-species interactions and outcomes such as infections are poorly understood. Biofilm bacteria are encased in a self-produced extracellular matrix that facilitates interspecies behavior and biofilm development. In this study, we examined the poorly understood roles of the major matrix biopolymers and their regulators in mixed-species biofilm interactions and development.


6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signalling.
Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.


Evidence-based practice: SLTs under siege or opportunity for growth? The use and nature of research evidence in the profession.
Speech and language therapists are encouraged to be evidence-based practitioners in contemporary clinical practice. This apparently signifies their commitment to 'good' practice. An examination of evidence-based practice (EBP) and its adoption in clinical practice is therefore warranted. This paper aims to explore EBP, specifically research evidence, as related to the field of speech and language therapy (SLT), using profession specific and cross-disciplinary examples. It asks the reader to consider whether research evidence contributes positively to SLT practice, or adds to the demands placed on clinicians? A review of the literature on the nature and use of research evidence in the field of speech and language therapy and related health professions was undertaken using multiple databases (Cochrane, Medline, Cinahal, BioMed, Trip, Dare) and the following up of references provided within texts and articles. This paper asks the reader to consider the topic from the perspective of the nature of research produced, the barriers perceived, and the use of research evidence by SLTs and the allied health professions. The uptake of research evidence in the profession is similar to other health professions and continues to be problematic. There are multiple reasons why this is so, originating from both the nature and use of research. Research evidence is one of the pillars of EBP. Despite problems with the nature and use of such evidence, it has a positive contribution to make to clinical practice as it provides for a scientific touchstone. However, it may be that the speech and language therapist and not the research evidence is the primary pivot upon which scientific practice is based.


Bovine colostrum supports the serum-free proliferation of epithelial cells but not of fibroblasts in long-term culture.
Medium lacking serum but supplemented with milk will support the growth of sparse cells in culture. Milk obtained within 8 h after the birth of a calf (day 1 colostrum) is the most effective in supporting proliferation. In mixed cultures of early-passage bovine embryonic kidney (BEK) or early-passage calf kidney (CK) cells, both epithelial cells and fibroblasts grow in Dulbecco's modified eagle's medium (DMEM) supplemented with serum. However, only cells that appear to be epithelial-like grow in DMEM supplemented with colostrum. Sparse cultures of early-passage human and rat fibroblasts that grow readily in DMEM supplemented with serum do not grow in DMEM supplemented with colostrum. Canine kidney epithelial cells (MDCK), when plated sparsely, grow exponentially in DMEM supplemented with day 1 bovine colostrum. The generation time is 26 h, the same growth rate as in DMEM supplemented with calf serum. The MDCK cells can be subcultured and regrown to confluence repeatedly in colostrum-supplemented DMEM. Growth in DMEM supplemented with colostrum does not alter the morphological characteristics of the MDCK cells, which are polygonal, contain microvilli at the apical surface, and are connected by tight junctions and desmosomes. MDCK cells do not proliferate in DMEM supplemented with milk obtained 1 wk after the birth of a calf.


Ultra-high quality factor optical resonators based on semiconductor nanowires.
We propose a platform to achieve ultra-high Quality factor (Q) optical resonators based on semiconductor nanowires. By defining onedimensional photonic crystal at nanowire ends and engineering the microcavity pattern, cavities with Q of 3 x 10(5) and mode volume smaller than 0.2(lambda/n)(3) have been designed. This represents an increase of almost three orders of magnitude over the Quality factor of an as-grown nanowire. Our cavities are well-suited for the realization of nanowire-based low-threshold lasers, single-photon sources and quantum optical devices that operate in the strong-coupling limit.


Early visual responses predict conscious face perception within and between subjects during binocular rivalry.
Previous studies indicate that conscious face perception may be related to neural activity in a large time window around 170-800 msec after stimulus presentation, yet in the majority of these studies changes in conscious experience are confounded with changes in physical stimulation. Using multivariate classification on MEG data recorded when participants reported changes in conscious perception evoked by binocular rivalry between a face and a grating, we showed that only MEG signals in the 120-320 msec time range, peaking at the M170 around 180 msec and the P2m at around 260 msec, reliably predicted conscious experience. Conscious perception could not only be decoded significantly better than chance from the sensors that showed the largest average difference, as previous studies suggest, but also from patterns of activity across groups of occipital sensors that individually were unable to predict perception better than chance. In addition, source space analyses showed that sources in the early and late visual system predicted conscious perception more accurately than frontal and parietal sites, although conscious perception could also be decoded there. Finally, the patterns of neural activity associated with conscious face perception generalized from one participant to another around the times of maximum prediction accuracy. Our work thus demonstrates that the neural correlates of particular conscious contents (here, faces) are highly consistent in time and space within individuals and that these correlates are shared to some extent between individuals.


Efficacy of habit-based weight loss interventions: a systematic review and meta-analysis.
Habit-based interventions are a novel and emerging strategy to help reduce excess weight in individuals with overweight or obesity. This systematic review and meta-analysis aims to determine the efficacy of habit-based interventions on weight loss. We identified potential studies through electronic searches in February 2019. Included studies were randomized/quasi randomized controlled trials comparing weight loss interventions founded on habit-theory with a control (active or non-active) and enrolled adults with overweight or obesity (body mass index ≥ 25 kg/m2). Five trials (630 participants) met our inclusion criteria. After the intervention period (range 8-14 weeks), weight loss was modest but statistically different between groups (1.4 kg [95% confidence interval 0.5, 2.3; P = 0.004]) favoring habit-based interventions. Intervention groups averaged 2.5 kg weight loss (range 1.7 to 6.7 kg) compared with control 1.5 kg (range 0.4 to 5.8 kg) and were 2.4 times more likely to achieve clinically beneficial weight loss (≥ 5% weight reduction). Average weight losses in adults with overweight and obesity using habit-based interventions appear to be of clinical benefit. There were statistically significant differences in weight loss between habit-based interventions and controls, post-intervention. Longer studies powered to examine at least 12-month follow-up are required to more accurately determine the role of habit-based interventions on long-term weight loss maintenance.Trial registration Prospero ID: CRD42017065589. Available from https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017065589 .


Limb Volume Changes and Activities of Daily Living: A Prospective Study.
Background: Breast cancer-related lymphedema (BCRL) limits the movements of patients' limbs, which leads to a diminished ability to achieve essential activities of daily living (ADLs). The purpose of this study was to examine the associations between limb volume changes from the baseline before breast cancer surgery and self-reported difficulty in performing ADLs at 12 months following cancer surgery. We hypothesized that a positive association existed between limb volume changes from the baseline and self-reported difficulty in performing ADLs at 12 months following breast cancer surgery. Methods and Results: The data of the present study were part of a larger study with 140 breast cancer patients recruited before breast cancer surgery and followed up during their first year of treatment. Patients with more than 10% limb volume increase reported more frequent distress in performing 13 ADL items, compared with patients whose limb volume increased by 5%-10%. Regression analysis showed a significant increase in the odds ratio of reporting difficulty in ADLs compared with the group with less than 5% limb volume increase. Conclusion: Overall, patients with a greater limb volume increase underwent more difficulty performing ADLs. Patients reported more difficulty in performing ADLs even with 5%-10% limb volume increase. Currently, there is no standardized guideline to diagnose BCRL, although previous evidence suggests a limb volume increase greater than 10% as a criterion for BCRL. The findings from the present study suggest a more precise and clinically meaningful criteria for diagnosing BCRL to accommodate those with 5%-10% increase in limb volume.


Working memory for cross-domain sequences.
How is information from different content domains bound together into a representation of the whole sequence? Several theories predict that mixing information from different domains specifically impairs the ordering of information from different domains, whereas ordering within domains might be enhanced. In contrast, domain-general models--in which items from different domains are simply assumed to be less confusable--predict that mixing items from different domains enhances ordering, as the list items will on average be less confusable. The results of an experiment showed an overall advantage for mixed over pure lists in ordering information, supporting the domain-general viewpoint. Simulations with a representative domain-general model--the start-end model of Henson [(1998). Short-term memory for serial order: The start-end model. Cognitive Psychology, 36, 73-137]--showed that the model gave a satisfactory account of the data. Together, the data and simulations lend evidence to the idea that a domain-general mechanism is responsible for ordering stimuli from different domains, and that domain-specific effects are attributable to the relative similarity of item representations.


Microbial manipulation of immune function for asthma prevention: inferences from clinical trials.
The "hygiene hypothesis" proposes that the increase in allergic diseases in developing countries reflects a decrease in infections during childhood. Cohort studies suggest, however, that the risks of asthma are increased in children who suffer severe illness from a viral respiratory infection in infancy. This apparent inconsistency can be reconciled through consideration of epidemiologic, clinical, and animal studies. The elements of this line of reasoning are that viral infections can predispose to organ-specific expression of allergic sensitization, and that the severity of illness is shaped by the maturity of immune function, which in turn is influenced by previous contact with bacteria and viruses, whether pathogenic or not. Clinical studies of children and interventional studies of animals indeed suggest that the exposure to microbes through the gastrointestinal tract powerfully shapes immune function. Intestinal microbiota differ in infants who later develop allergic diseases, and feeding Lactobacillus casei to infants at risk has been shown to reduce their rate of developing eczema. This has prompted studies of feeding probiotics as a primary prevention strategy for asthma. We propose that the efficacy of this approach depends on its success in inducing maturation of immune function important in defense against viral infection, rather than on its effectiveness in preventing allergic sensitization. It follows that the endpoints of studies of feeding probiotics to infants at risk for asthma should include not simply tests of responsiveness to allergens, but also assessment of intestinal flora, immune function, and the clinical response to respiratory viral infection.


The long postwar and the politics of penicillin: early circulation and smuggling in Spain, 1944-1954.
In this paper I explore the early circulation of penicillin. I review the early distribution in Spain of a scarce product, reflect on the available sources about the illegal penicillin trade and discuss some cases of smuggling. I argue the early distribution of penicillin involved time and geography, a particular chronology of post Second World War geopolitics. Penicillin practices and experiences belong to this period, in a dictatorship that tolerated smuggling and illegal trade of other products, some, like penicillin, produced in neighbouring countries. As a commodity that crossed borders, penicillin, transiting between the law and hidden trade, between countries and social domains--between war fronts and from a war front to an urban site to be sold--reveals practices of the early years of prosperity in the 1950s. These transits were permanent tests of a society based on taxes and exchanges, law and bureaucracy, control, discipline and the creation of standards.


SIRT6 is required for maintenance of telomere position effect in human cells.
In Saccharomyces cerevisiae, the repressive chromatin environment at telomeres gives rise to telomere position effect (TPE), the epigenetic silencing of telomere-proximal genes. Chromatin-modifying factors that control TPE in yeast have been extensively studied, and, among these, the lifespan regulator and silencing protein Sir2 has a pivotal role. In contrast, the factors that generate and maintain silent telomeric chromatin in human cells remain largely unknown. Here we show that the Sir2 family member SIRT6 is required for maintenance of TPE in human cells. RNAi-mediated depletion of SIRT6 abrogates silencing of both an integrated telomeric transgene and an endogenous telomere-proximal gene. Moreover, enhanced telomeric silencing in response to telomere elongation is associated with increased repressive chromatin marks, and this heterochromatic milieu is lost in SIRT6-deficient cells. Together, these findings establish a new role for SIRT6 in regulating an ageing-associated epigenetic silencing process and provide new mechanistic insight into chromatin silencing at telomeres.


Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.
Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.


Comparison between biochemical responses of the teleost pacu and its hybrid tambacu (Piaractus mesopotamicus x Colossoma macropomum) to short-term nitrite exposure.
Aquatic environmental factors are very changeable in short periods. Among these factors are pH, temperature, dissolved oxygen, ammonia and ions. Nitrite, as one ion naturally present in aquatic systems, deserves particular consideration as it is highly toxic for many species. Among fish, nitrite may have harmful effects, such as methemoglobin (MtHb) formation, disruption to the gill and hepatic structure, which could result in hemolytic anemia and cell hypoxia by reducing the functional hemoglobin content. In this work, we compared hematological and metabolical responses of pacu and its hybrid tambacu exposed to 20 ppm of environmental nitrite. It was observed that the MtHb content was less than 18% in tambacu while pacu reached nearly 8%. These data reflect specific differences in nitrite uptake by the gill. The hematocrit of both fish was distinct; pacu did not have a typical response of poisoning by nitrite. This fact shows less skill of the hybrid to cope with environmental nitrite. Incipient hemolytic anemia was observed in pacu and both species presented a neoglycogenic profile. The glucose-provider character of the liver was more evident in tambacu. The white muscle of both species presented distinct metabolic behavior. While in pacu the white muscle was predominantly oxidative, in tambaqui the lactic fermentation was the most important metabolic profile. Metabolic and hematological observations in both species show that they present distinct metabolical strategies to cope with toxic effects of nitrite and there is no evidence that the hybrid is more resistant to nitrite.


Differential expression of thymic DNA repair genes in low-dose-rate irradiated AKR/J mice.
We previously determined that AKR/J mice housed in a low-dose-rate (LDR) ((137)Cs, 0.7 mGy/h, 2.1 Gy) γ-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) ((137)Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice.


The effect of brushing time and dentifrice on dental plaque removal in vivo.
Routine toothbrushing is the principal method by which individuals remove plaque and control plaque-related diseases, such as periodontitis and caries. Oral health care professionals generally recommend at least 2 minutes brushing with an appropriate technique, and yet the average brushing time in the general population is closer to 45 seconds. Our understanding of the relationship between brushing time and plaque removal, in an untutored general population using a conventional manual toothbrush and dentifrice, is limited. The role of dentifrice in plaque removal is also unclear. This study was undertaken to measure plaque removal during untutored brushing over timed periods between 30 and 180 seconds with 1.5 g dentifrice, using an Aquafresh Flex brush and Aquafresh Advanced dentifrice. Plaque removal after brushing without dentifrice was also determined (at the 60 second time point only). Forty-seven subjects participated in the study, in which plaque level was assessed using the Quigley-Hein (Turesky-modification) Index. Plaque removal increased with brushing time across the range studied, tending towards a maximum at longer brushing times. At the extremes, brushing for 180 seconds removed 55% more plaque than brushing for 30 seconds. Brushing for 120 seconds removed 26% more plaque than brushing for 45 seconds. The use of dentifrice did not increase plaque removal during 60 seconds of brushing. Oral health care professionals should reinforce efforts to persuade patients to brush for longer periods of time, as increasing brushing time to the consensus minimum of 2 minutes from a more typical 45 seconds increases plaque removal to an extent likely to provide clinically significant oral health benefits.


Antimicrobial prescribing behaviour in dogs and cats by Belgian veterinarians.
The objective of this study is to survey general prescribing behaviour by Belgian companion animal veterinarians and to assess agreement of these practices with current treatment guidelines. Therefore an online survey was administered with five realistic and frequently occurring first-line cases to primary-care veterinary practitioners. For each case a predefined pattern of questions were asked about whether or not they would prescribe antimicrobials, if they would prescribe a non-antimicrobial treatment and if they would perform additional diagnostic steps. The responses were compared with recommendations in national guidelines and recent literature. The overall most prescribed antimicrobials were potentiated amoxicillin (43.0 per cent), fluoroquinolones (14.7 per cent), third-generation and fourth-generation cephalosporins (10.9 per cent) and tetracyclines (10.9 per cent). Only 48.3 per cent of the veterinarians complied with the guidelines in nearly all of the clinical scenarios (ie, prescribing antimicrobials when indicated, not prescribing antimicrobials when it is not indicated). Moreover, when prescribing highest priority critically important antimicrobials, susceptibility testing on bacterial cultures was performed in only 12.4 per cent of the prescriptions. The results showed that the prescribing behaviour of antimicrobial compounds by primary-care veterinary practitioners in dogs and cats is often not in agreement with national guidelines. Focus in improvement of this prescribing behaviour should be on performing the appropriate diagnostic steps and decreasing the use of highest priority critically important antimicrobials.


Influence of Solvent Composition on the Performance of Spray-Dried Co-Amorphous Formulations.
Ball-milling is usually used to prepare co-amorphous drug-amino acid (AA) mixtures. In this study, co-amorphous drug-AA mixtures were produced using spray-drying, a scalable industrially preferred preparation method. The influence of the solvent type and solvent composition was investigated. Mixtures of indomethacin (IND) and each of the three AAs arginine, histidine, and lysine were ball-milled and spray-dried at a 1:1 molar ratio, respectively. Spray-drying was performed at different solvent ratios in (a) ethanol and water mixtures and (b) acetone and water mixtures. Different ratios of these solvents were chosen to study the effect of solvent mixtures on co-amorphous formulation. Residual crystallinity, thermal properties, salt/partial salt formation, and powder dissolution profiles of the IND-AA mixtures were investigated and compared to pure crystalline and amorphous IND. It was found that using spray-drying as a preparation method, all IND-AA mixtures could be successfully converted into the respective co-amorphous forms, irrespective of the type of solvent used, but depending on the solvent mixture ratios. Both ball-milled and spray-dried co-amorphous samples showed an enhanced dissolution rate and maintained supersaturation compared to the crystalline and amorphous IND itself. The spray-dried samples resulting in co-amorphous samples were stable for at least seven months of storage.


The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma.
Monoclonal gammopathy of undetermined significance is a pre-malignant precursor of multiple myeloma with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS gene mutations, little is known about the molecular mechanism of malignant transformation. We performed whole exome sequencing together with comparative genomic hybridization plus single nucleotide polymorphism array analysis in 33 flow-cytometry-separated abnormal plasma cell samples from patients with monoclonal gammopathy of undetermined significance to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations and copy-number alterations were present in 97.0% and in 60.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in monoclonal gammopathy of undetermined significance than in myeloma (P<10-4) and we identified six genes that were significantly mutated in myeloma (KRAS, NRAS, DIS3, HIST1H1E, EGR1 and LTB) within the monoclonal gammopathy of undetermined significance dataset. We also found a positive correlation with increasing chromosome changes and somatic gene mutations. IGH translocations, comprising t(4;14), t(11;14), t(14;16) and t(14;20), were present in 27.3% of cases and in a similar frequency to myeloma, consistent with the primary lesion hypothesis. MYC translocations and TP53 deletions or mutations were not detected in samples from patients with monoclonal gammopathy of undetermined significance, indicating that they may be drivers of progression to myeloma. Data from this study show that monoclonal gammopathy of undetermined significance is genetically similar to myeloma, however overall genetic abnormalities are present at significantly lower levels in monoclonal gammopathy of undetermined significant than in myeloma.


Protein-losing enteropathy with an endoscopic feature of 'the watermelon colon'.
A watermelon lesion involving the gastrointestinal tract other than the stomach has not been reported previously except for two cases with rectal involvement and another case with caecal involvement. This report describes a case of protein-losing enteropathy with endoscopic features of 'the watermelon lesion' involving nearly the entire colon. A 57-year-old man presented with a six-month history of generalized oedema and diarrhoea. Laboratory findings included elevated erythrocyte sedimentation rate and decreased serum total protein and albumin. Serum fluorescent anti-nuclear antibody, anti-dsDNA antibody and anti-La antibody were positive. Upper gastrointestinal endoscopy was unremarkable. Colonoscopy showed seven or eight longitudinal reddish stripes along the entire length of the colon and rectum sparing the caecum. Biopsies from the duodenum and colon revealed mildly ectatic lymphatics in the submucosa. Colonic biopsy also exhibited some haemosiderin-laden macrophages in the muscularis mucosae and submucosa. 99mTc-human serum albumin scintigraphy demonstrated a leak into the intestinal lumen. Oral prednisolone therapy was started and his symptoms and signs gradually improved over months. Steroid could be withdrawn after 7 months of therapy, and the patient has remained free of symptoms for 1 year of follow-up after withdrawal of the steroid.


Measures to Assure that Ebola Guidelines Are Correctly Applied.
The purpose of this study was to assure the application, in our primary care health district, of the World Health Organisation and Spanish Ebola virus disease (EVD) guidelines, and to identify and resolve gaps, in order to protect professionals from the risks associated with attending to patients with Ebola. A checklist was drawn up and an audit procedure of the structural, functional and operational conditions was designed for managing a self-presenting patient suspected with EVD in general practice. This audit was applied twice (before and after assessment) in 9 health centres of a health district in Spain. The checklist was structured according to 9 categories (51 elements in total). This tool was designed to avoid errors in the management of EVD patients that are considered very serious in view of their potential consequences. Of the 51 elements on the checklist, 7-26 (14-51%) required direct intervention to rectify deficits in the first audit. The following elements requiring improvement were identified: the incorporation of memory aids to ensure the correct application of the EVD protocol, defining what information should be provided to the patient and (where applicable) anyone accompanying them as well as incorporating advice on how to deal with any individuals with whom they might have come into contact. A second audit assured the adequacy of the proposed solutions. In this study, the tool achieved the successful application of EVD protocol, assuring that primary care centres were able to handle an Ebola suspect patient safely.


Parental control and monitoring of young people's sexual behaviour in rural North-Western Tanzania: implications for sexual and reproductive health interventions.
Parenting through control and monitoring has been found to have an effect on young people's sexual behaviour. There is a dearth of literature from sub-Saharan Africa on this subject. This paper examines parental control and monitoring and the implications of this on young people's sexual decision making in a rural setting in North-Western Tanzania. This study employed an ethnographic research design. Data collection involved 17 focus group discussions and 46 in-depth interviews conducted with young people aged 14-24 years and parents/carers of young people within this age-group. Thematic analysis was conducted with the aid of NVIVO 7 software. Parents were motivated to control and monitor their children's behaviour for reasons such as social respectability and protecting them from undesirable sexual and reproductive health (SRH) outcomes. Parental control and monitoring varied by family structure, gender, schooling status, a young person's contribution to the economic running of the family and previous experience of a SRH outcome such as unplanned pregnancy. Children from single parent families reported that they received less control compared to those from both parent families. While a father's presence in the family seemed important in controlling the activities of young people, a mother's did not have a similar effect. Girls especially those still schooling received more supervision compared to boys. Young women who had already had unplanned pregnancy were not supervised as closely as those who hadn't. Parents employed various techniques to control and monitor their children's sexual activities. Despite parents making efforts to control and monitor their young people's sexual behaviour, they are faced with several challenges (e.g. little time spent with their children) which make it difficult for them to effectively monitor them. There is a need for interventions such as parenting skills building that might enable parents to improve their relationships with children. This would equip parents with the appropriate skills for positive guidance and monitoring of their children and avoid inappropriate parenting behaviour. As much as parents focus their attention on their school going daughters, there is a need to also remember the out-of-school young people as they are also vulnerable to adverse SRH outcomes.


Ionization of doped helium nanodroplets: complexes of C60 with water clusters.
Water clusters are known to undergo an autoprotonation reaction upon ionization by photons or electron impact, resulting in the formation of (H(2)O)(n)H(3)O(+). Ejection of OH cannot be quenched by near-threshold ionization; it is only partly quenched when clusters are complexed with inert gas atoms. Mass spectra recorded by electron ionization of water-doped helium droplets show that the helium matrix also fails to quench OH loss. The situation changes drastically when helium droplets are codoped with C(60). Charged C(60)-water complexes are predominantly unprotonated; C(60)(H(2)O)(4)(+) and (C(60))(2)(H(2)O)(4)(+) appear with enhanced abundance. Another intense ion series is due to C(60)(H(2)O)(n)OH(+); dehydrogenation is proposed to be initiated by charge transfer between the primary He(+) ion and C(60). The resulting electronically excited C(60)(+*) leads to the formation of a doubly charged C(60)-water complex either via emission of an Auger electron from C(60)(+*), or internal Penning ionization of the attached water complex, followed by charge separation within {C(60)(H(2)O)(n)}(2+). This mechanism would also explain previous observations of dehydrogenation reactions in doped helium droplets. Mass-analyzed ion kinetic energy scans reveal spontaneous (unimolecular) dissociation of C(60)(H(2)O)(n)(+). In addition to the loss of single water molecules, a prominent reaction channel yields bare C(60)(+) for sizes n=3, 4, or 6. Ab initio Hartree-Fock calculations for C(60)-water complexes reveal negligible charge transfer within neutral complexes. Cationic complexes are well described as water clusters weakly bound to C(60)(+). For n=3, 4, or 6, fissionlike desorption of the entire water complex from C(60)(H(2)O)(n)(+) energetically competes with the evaporation of a single water molecule.


Risk Factors for Upper and Lower Urinary Tract Cancer Death in a Japanese Population: Findings from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study).
The incidence of bladder cancer is lower in Asian than in Western countries. However, the crude incidence and mortality of bladder cancer have recently increased in Japan because of the increased number of senior citizens. We have already reported risk factors for urothelial cancer in a large populationbased cohort study in Japan (JACC study). However, we did not evaluate the cancer risk in the upper and lower urinary tract separately in our previous study. Here we evaluated the risk of cancer death in the upper and lower urinary tracts, separately, using the database of the JACC study. The analytic cohort included 46,395 males and 64,190 females aged 40 to 79 years old. The Cox proportional hazard model was used to determine hazard ratios and their 95% confidence intervals. Current smoking increased the risk of both upper and lower urinary tract cancer deaths. A history of kidney disease was associated with an increased risk of bladder cancer death, even after controlling for age, sex and smoking status. The present study confirmed that current smoking increases the risk of both upper and lower urinary tract cancer deaths and indicated the possibility that a history of kidney disease may be a risk factor for bladder cancer death in the Japanese population.


Polymer Chain Behavior in Polymer Nanocomposites with Attractive Interactions.
Chain behavior has been determined in polymer nanocomposites (PNCs) comprised of well-dispersed 12 nm diameter silica nanoparticles (NPs) in poly(methyl methacrylate) (PMMA) matrices by Small-Angle Neutron Scattering (SANS) measurements under the Zero Average Contrast (ZAC) condition. In particular, we directly characterize the bound polymer layer surrounding the NPs, revealing the bound layer profile. The SANS spectra in the high-q region also show no significant change in the bulk polymer radius of gyration on the addition of the NPs. We thus suggest that the bulk polymer conformation in PNCs should generally be determined using the high q region of SANS data.


Cholecystokinin tunes firing of an electrically distinct subset of arcuate nucleus neurons by activating A-Type potassium channels.
The physiological activity of hypothalamic arcuate nucleus (ARC) neurons is critical for dynamic maintenance of body energy homeostasis, and its malfunction can result in common metabolic disorders, such as obesity. It is therefore of interest to determine which set of ion channels shapes electrical activity in the ARC. Whole-cell patch clamp of ARC neurons in mouse brain slices identified three electrophysiologically distinct types of neurons. These were distinguished by their rebound "signatures" after hyperpolarizing current injection in current clamp and by the presence of transient inward (Type-B neurons) or outward (Type-A and Type-C neurons) subthreshold voltage-gated currents in voltage-clamp recordings. In turn, the transient outward current (A-current) of Type-C neurons had a lower activation threshold and different time and voltage dependence of inactivation than that of Type-A neurons. The brain-gut peptide cholecystokinin (CCK) has long been recognized to control food intake, but how endogenous CCK modulates the activity of central appetite-regulating networks remains unresolved. Here, we show that low (picomolar) concentrations of CCK rapidly and reversibly slow the firing of ARC Type-C neurons. This effect is mediated by postsynaptic CCK-B receptors and is attributable to potentiation of the A-current. Our study thus identifies several fundamental biophysical mechanisms underlying the physiological activity of ARC neurons and suggests a novel mechanism by which endogenous CCK may control appetite.


Outcome-adaptive lasso: Variable selection for causal inference.
Methodological advancements, including propensity score methods, have resulted in improved unbiased estimation of treatment effects from observational data. Traditionally, a "throw in the kitchen sink" approach has been used to select covariates for inclusion into the propensity score, but recent work shows including unnecessary covariates can impact both the bias and statistical efficiency of propensity score estimators. In particular, the inclusion of covariates that impact exposure but not the outcome, can inflate standard errors without improving bias, while the inclusion of covariates associated with the outcome but unrelated to exposure can improve precision. We propose the outcome-adaptive lasso for selecting appropriate covariates for inclusion in propensity score models to account for confounding bias and maintaining statistical efficiency. This proposed approach can perform variable selection in the presence of a large number of spurious covariates, that is, covariates unrelated to outcome or exposure. We present theoretical and simulation results indicating that the outcome-adaptive lasso selects the propensity score model that includes all true confounders and predictors of outcome, while excluding other covariates. We illustrate covariate selection using the outcome-adaptive lasso, including comparison to alternative approaches, using simulated data and in a survey of patients using opioid therapy to manage chronic pain.


Rhodovulum visakhapatnamense sp. nov.
A Gram-negative, rod-shaped, phototrophic bacterium (JA181(T)) was isolated from a tidal water sample. On the basis of 16S rRNA gene sequence similarity, strain JA181(T) was shown to belong to the class Alphaproteobacteria, most closely related to Rhodovulum sulfidophilum (97.8 % similarity to the type strain), Rhodovulum adriaticum (93 %), Rhodovulum robiginosum (93 %), Rhodovulum iodosum (94 %), Rhodovulum imhoffii (94 %), Rhodovulum strictum (95 %), Rhodovulum euryhalinum (94.6 %) and Rhodovulum marinum (94.6 %). DNA-DNA hybridization with Rdv. sulfidophilum DSM 1374(T) (relatedness of 39 % with strain JA181(T)) and physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain JA181(T) from the eight Rhodovulum species with validly published names. Strain JA181(T) therefore represents a novel species, for which the name Rhodovulum visakhapatnamense sp. nov. is proposed (type strain JA181(T) =JCM 13531(T) =ATCC BAA-1274(T) =DSM 17937(T)).


Transdiagnostic Extension of Delusions: Schizophrenia and Beyond.
Delusion is central to the conceptualization, definition, and identification of schizophrenia. However, in current classifications, the presence of delusions is neither necessary nor sufficient for the diagnosis of schizophrenia, nor is it sufficient to exclude the diagnosis of some other psychiatric conditions. Partly as a consequence of these classification rules, it is possible for delusions to exist transdiagnostically. In this article, we evaluate the extent to which this happens, and in what ways the characteristics of delusions vary according to diagnostic context. We were able to examine their presence and form in delusional disorder, affective disorder, obsessive-compulsive disorder, borderline personality disorder, and dementia, in all of which they have an appreciable presence. There is some evidence that the mechanisms of delusion formation are, at least to an extent, shared across these disorders. This transdiagnostic extension of delusions is an argument for targeting them therapeutically in their own right. However there is a dearth of research to enable the rational transdiagnostic deployment of either pharmacological or psychological treatments.