A Simple, Sensitive, and Reliable Method for the Simultaneous Determination of Multiple Antibiotics in Vegetables through SPE-HPLC-MS/MS.
Antibiotics, widely used in livestock breeding, enter the environment through animal manure because of incomplete absorption in animals, especially the farmland ecosystem. Therefore, antibiotics may be adsorbed by plants and even become hazardous to human health through the food chain. In this study, a simple, sensitive, and reliable method was developed for the simultaneous determination of eleven antibiotics, including four sulfonamides, two tetracyclines, three fluoroquinolones, tylosin, and chloramphenicol in different vegetable samples using SPE-HPLC-MS/MS. Vegetable samples were extracted by acetonitrile added with hydrochloric acid (125:4, v/v). The extracts were enriched by circumrotating evaporation, and then cleaned through SPE on a hydrophilic-lipophilic balance (HLB) cartridge. All compounds were determined on a C18 reverse phase column through HPLC-MS/MS. The mean recoveries of 11 antibiotics from spiked samples of vegetables ranged from 71.4% to 104.0%. The limits of detection and quantification were 0.06⁻1.88 μg/kg and 0.20⁻6.25 μg/kg, respectively. The applicability of this technique demonstrated its good selectivity, high efficiency, and convenience by the analysis of 35 vegetable samples available from a vegetable greenhouse. Antibiotic residues in vegetables have aroused wide concern from the public. Therefore, standards should be established for antibiotic residues in vegetables to ensure food safety and human health.


Interventions for lowering plasma homocysteine levels in kidney transplant recipients.
Elevated homocysteine levels have been shown to be an independent risk factor for cardiovascular disease. However studies of homocysteine lowering in general and end-stage kidney disease (ESKD) populations have not demonstrated a reduction in cardiovascular event rates. Kidney transplant recipients have high homocysteine levels, high cardiovascular event rates and, unlike the ESKD population, may achieve normalisation of homocysteine levels with homocysteine lowering therapies. Thus may benefit from homocysteine lowering therapy. To evaluate the effects of established homocysteine lowering therapy on cardiovascular mortality in patients with functioning kidney transplants. We searched the Cochrane Renal Group's Specialised Register to 16 March 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Randomised controlled trials of any therapy that has been shown to significantly lower homocysteine levels conducted in people with functioning kidney transplants. Studies were to be included if they compared homocysteine lowering therapy with placebo or usual care, or compare higher versus lower doses of homocysteine lowering therapy. Two authors independently assessed study quality and extracted data. Results were to be expressed as the risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Data was to be pooled using the random effects model. The literature search yielded 359 reports of which only one study was identified that met our inclusion criteria and reported relevant clinical endpoints. This study randomised 4110 adult participants with a functioning kidney transplant and elevated homocysteine levels to folic acid plus high dose B multivitamins or low dose multivitamins who were followed for a mean 4.0 years. Despite effectively lowering homocysteine levels) in homocysteine levels at follow-up (MD -4.40 μmol/L, 95% CI -5.98 to -2.82) there was no evidence the intervention impacted on any of the outcomes reported including cardiovascular mortality (RR 0.91, 95% CI 0.69 to 1.20), all-cause mortality (RR 1.04, 95% CI 0.88 to 1.22), myocardial infarction (RR 1.02, 95% CI 0.77 to 1.35), stroke (RR 1.08, 95% CI 0.69 to 1.71), commencement of renal replacement therapy (RR 1.12, 95% CI 0.91 to 1.37) or all reported adverse events (RR 1.02, 95% CI 0.87 to 1.20). There was no evidence the intervention impacted on the primary endpoint of the study, a cardiovascular event composite (RR 0.99, 95% CI 0.85 to 1.15). The study was of high quality. There is no current evidence to support the use of homocysteine lowering therapy for cardiovascular disease prevention in kidney transplant recipients.


Esophagogastric junction distensibility: a factor contributing to sphincter incompetence.
To quantify the effect of hiatus hernia (HH) on esophagogastric junction (EGJ) distensibility, eight normal subjects and nine gastroesophageal reflux disease (GERD) patients with HH were studied with concurrent manometry, fluoroscopy, and stepwise controlled barostatic distention of the EGJ. The minimal barostatic pressure required to open the EGJ during the interswallow period was determined. Thereafter, barium swallows were imaged in 5-mmHg increments of intrabag pressure. EGJ diameter and length were measured at each pressure during deglutitive relaxation. The EGJ opening diameter was greater in hernia patients compared with normal subjects during deglutitive relaxation at all pressures, and EGJ length was 23% shorter. EGJ opening pressure among hernia patients was lower than normal subjects during the interswallow period. In conclusion, the EGJ of GERD patients with HH was more distensible and shorter than normal subjects. These findings partially explain why HH patients are predisposed to reflux by mechanisms other than transient lower esophageal sphincter relaxations, sustain greater volumes of refluxate, and have a reduced ability to discriminate gas from liquid reflux.


Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully compartmentalized genome-scale metabolic model.
A fully compartmentalized genome-scale metabolic model of Saccharomyces cerevisiae that accounts for 750 genes and their associated transcripts, proteins, and reactions has been reconstructed and validated. All of the 1149 reactions included in this in silico model are both elementally and charge balanced and have been assigned to one of eight cellular locations (extracellular space, cytosol, mitochondrion, peroxisome, nucleus, endoplasmic reticulum, Golgi apparatus, or vacuole). When in silico predictions of 4154 growth phenotypes were compared to two published large-scale gene deletion studies, an 83% agreement was found between iND750's predictions and the experimental studies. Analysis of the failure modes showed that false predictions were primarily caused by iND750's limited inclusion of cellular processes outside of metabolism. This study systematically identified inconsistencies in our knowledge of yeast metabolism that require specific further experimental investigation.


Perceptions of nursing care quality, in acute hospital settings measured by the Karen instruments.
The objectives of this study were to measure the quality of nursing care from the perspectives of patients and personnel and to compare these perspectives. The perception of quality in nursing care is affected by patient needs and it is common that patients and personnel disagree on the nature of the quality. Thus, it is important to measure the quality from both perspectives. A total of 95 patients and 120 personnel from surgical and medical wards at a hospital in Sweden participated. The Karen instruments were used for data collection. A scale index was used for comparison of the perspectives. The patients and personnel were satisfied with the quality of care and there were no obvious differences in the total index. The different subscales indicated areas of lower care quality in need of improvement. The quality of the care seemed to be satisfactory from the perspectives of both the patients and the personal. Further analysis from the subscale or a variable level is needed to define areas of lower care quality. Measurements have to be carried out continuously to guarantee care quality over time, as a result of organisational changes and financial cutbacks.


Using δ13C and δ18O to analyze loblolly pine (Pinus taeda L.) response to experimental drought and fertilization.
Drought frequency and intensity are projected to increase throughout the southeastern USA, the natural range of loblolly pine (Pinus taeda L.), and are expected to have major ecological and economic implications. We analyzed the carbon and oxygen isotopic compositions in tree ring cellulose of loblolly pine in a factorial drought (~30% throughfall reduction) and fertilization experiment, supplemented with trunk sap flow, allometry and microclimate data. We then simulated leaf temperature and applied a multi-dimensional sensitivity analysis to interpret the changes in the oxygen isotope data. This analysis found that the observed changes in tree ring cellulose could only be accounted for by inferring a change in the isotopic composition of the source water, indicating that the drought treatment increased the uptake of stored moisture from earlier precipitation events. The drought treatment also increased intrinsic water-use efficiency, but had no effect on growth, indicating that photosynthesis remained relatively unaffected despite 19% decrease in canopy conductance. In contrast, fertilization increased growth, but had no effect on the isotopic composition of tree ring cellulose, indicating that the fertilizer gains in biomass were attributable to greater leaf area and not to changes in leaf-level gas exchange. The multi-dimensional sensitivity analysis explored model behavior under different scenarios, highlighting the importance of explicit consideration of leaf temperature in the oxygen isotope discrimination (Δ18Oc) simulation and is expected to expand the inference space of the Δ18Oc models for plant ecophysiological studies.


Long-Term Prognosis After Coronary Artery Calcium Scoring Among Low-Intermediate Risk Women and Men.
Cardiovascular screening of women using traditional risk factors has been challenging, with results often classifying a majority of women as lower risk than men. The aim of this report was to determine the long-term prognosis of asymptomatic women and men classified at low-intermediate risk undergoing screening with coronary artery calcium (CAC) scoring. A total of 2363 asymptomatic women and men with traditional risk factors aggregating into a low-intermediate Framingham risk score (6%-9.9%; 10-year predicted risk) underwent CAC scanning. Individuals were followed up for a median of 14.6 years. We estimated all-cause mortality using Cox proportional hazards models; hazard ratios with 95% confidence intervals were calculated. The area under the curve from a receiver operating characteristics curve analysis was calculated. There were 1072 women who were older (55.6 years) when compared with the 1291 men (46.7 years; P<0.0001), resulting in a greater prevalence and extent of CAC; 18.8% of women and 15.1% of men had a CAC score ≥100 (P=0.029). This older group of women had a 1.44-fold higher 15-year adjusted mortality hazard when compared with men (P=0.022). For women, the 15-year mortality ranged from 5.0% for those with a CAC score of 0 to 23.5% for those with a CAC score ≥400 (P<0.001). For men, the 15-year mortality ranged from 3.5% for those with a CAC score of 0 to 18.0% for those with a CAC score ≥400 (P<0.001). Women with CAC scores >10 had a higher mortality risk when compared with men. Our findings extend previous work that CAC effectively identifies high-risk women with a low-intermediate risk factor burden. These data require validation in external cohorts but lend credence to the use of CAC in women to improve risk detection algorithms that are currently based on traditional risk factors.


Transient elastography for the prediction of oxaliplatin-associated liver injury in colon cancer patients: a preliminary analysis.
The prognosis of advanced colon cancer has improved significantly over the last decade since new chemotherapy regimens including oxaliplatin have been developed. However, oxaliplatin-induced liver injury and characterized hepatic hemostatic status can occur after chemotherapy. The assessment of this type of liver injury is often difficult. Elastography (Fibroscan) was used to evaluate liver injury in five cases before and after 5-FU, leucovorin, and oxaliplatin combination (FOLFOX) treatment. A clear change was observed in the stiffness of liver after chemotherapy within 48 h, and the hepatic stiffness was normalized in most cases after 2 weeks. Among the five patients, one patient showed aberrant elevation after a FOLFOX treatment, and the patient showed liver injury pathologically. Elastography is a good tool for evaluating hepatic injury after FOLFOX treatment.


Preparing medical students for the e-patient.
The emergence of the e-patient has resulted in many medical practitioners' being ill-equipped to deal with the 21st-century medical practice. This Guide is a teaching guide for medical educators so that they can prepare their students for the new environment that has resulted from the emergence of the e-patient. Within the context of theoretical perspectives, the Guide begins by defining the concept, and examining the history of the e-patient, detailing typical e-patient activities and some complexities raised by these activities. Finally, the Guide details the topic areas that should be covered in a course aimed at preparing medical students for e-patients. The result is a theoretical and practical teaching Guide that equips medical teachers and their students with the necessary background information, and also assists teachers in the teaching of that information so that their students may become health practitioners fully equipped to deal with the problems and potential of the e-patient.


Identification and classification of differentially expressed genes in non-small cell lung cancer by expression profiling on a global human 59.620-element oligonucleotide array.
Improvements in detection, treatment and prognosis for patients with non-small cell lung cancer (NSCLC) depend on the molecular understanding of tumor development and progression. Using Affymetrix GeneChips comprising 59,620 elements, we determined the gene expression profiles of 89 NSCLC and 15 normal lung samples. We found 187 (0.3%) genes, which are at least 2-fold overexpressed and 157 (0.3%) genes 2-fold less expressed in NSCLC compared with normal lung. Cell cycle regulation, cell adhesion and nucleotide metabolism were the major biological processes connected to a large proportion of genes up-regulated in NSCLC. Down-regulated genes were frequently involved in metabolic/catabolic processes and signal transduction. The expression of specific genes revealed reliable differentiation of tumor from normal lung tissues, as well as the classification of both NSCLC subtypes squamous cell carcinoma and adenocarcinoma. In this context, collagens (COL7, 17) and cytokeratins (CK6, 15, 17) are preferentially induced in squamous cell carcinoma, whereas several transcription factors (TTF1, DAT1, TF-2) are exclusively elevated in adenocarcinomas. Some gene products involved in the metastatic process [matrixmetalloproteinase 12 (MMP-12) and urokinase plasminogen activator alpha (uPA)] were found as prognostic markers for the recurrence free interval and survival. Particularly, the simultaneous use of the MMP-12 and uPA expression predicted relapse-free and global survival of the patients. Screening of NSCLC with a genome-wide array revealed diagnostic, prognostic and potential therapeutic targets that might be suitable for an individual risk profile by tumor specific arrays.


Age-related changes of elements in the tendons of the peroneus longus muscles in Thai, Japanese, and monkeys.
To elucidate compositional changes of the tendon of the peroneus longus muscle with aging, the authors investigated age-related changes of elements in the insertion of tendons of the peroneus longus muscle (peroneus longus tendons) in Thai, Japanese, and monkeys and the relationships among element contents by direct chemical analysis. After ordinary dissections at Chiang Mai University and Nara Medical University were finished, the peroneus longus tendons were resected from the subjects. The peroneus longus tendons were also resected from rhesus and Japanese monkeys bred in Primate Research Institute, Kyoto University. The wraparound regions of the insertion tendons of the peroneus longus muscle in contact with the cuboid bone were used as the peroneus longus tendon. After ashing with nitric acid and perchloric acid, element contents were determined with an inductively coupled plasma-atomic emission spectrometer. It was found that there were no significant correlations between age and the seven elements, such as Ca, P, S, Mg, Zn, Fe, and Na, in the peroneus longus tendons of Thai and Japanese. The Ca content higher than 10 mg/g was contained in seven cases out of 34 peroneus longus tendons of Thai (incidence = 20.6%) and in one case out of 22 peroneus longus tendons of Japanese (incidence = 4.5%), respectively. All of the peroneus longus tendons with the Ca content higher than 10 mg/g were found in Thai and Japanese men. In the peroneus longus tendons of monkeys, the Ca and P content increased suddenly at 2 years of age and reached to about 40 mg/g at 5 years of age. Thereafter, the Ca and P content did not increase in the peroneus longus tendons of monkeys at old age. Regarding the relationships among element contents, significant direct correlations were found among the contents of Ca, P, Mg, Zn, and Na in Thai and monkeys, whereas significant inverse correlations were found between S and element contents, such as Ca, P, Mg, Zn, and Na, in Thai and monkeys.


Differential cytokine contributions of perivascular haematopoietic stem cell niches.
Arterioles and sinusoids of the bone marrow (BM) are accompanied by stromal cells that express nerve/glial antigen 2 (NG2) and leptin receptor (LepR), and constitute specialized niches that regulate quiescence and proliferation of haematopoietic stem cells (HSCs). However, how niche cells differentially regulate HSC functions remains unknown. Here, we show that the effects of cytokines regulating HSC functions are dependent on the producing cell sources. Deletion of chemokine C-X-C motif ligand 12 (Cxcl12) or stem cell factor (Scf) from all perivascular cells marked by nestin-GFP dramatically depleted BM HSCs. Selective Cxcl12 deletion from arteriolar NG2+ cells, but not from sinusoidal LepR+ cells, caused HSC reductions and altered HSC localization in BM. By contrast, deletion of Scf in LepR+ cells, but not NG2+ cells, led to reductions in BM HSC numbers. These results uncover distinct contributions of cytokines derived from perivascular cells in separate vascular niches to HSC maintenance.


Assessing the quality and reproducibility of a proteomic platform for clinical stroke biomarker discovery.
The aim of this study was to investigate the quality and reproducibility of mass spectra derived from a matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) platform in a patient population undergoing carotid endarterectomy. Plasma samples were either digested with trypsin or left undigested, fractionated with either C18 or weak cation exchange (WCX) columns and analysed by MALDI-TOF MS. Quality of mass spectra for each method was assessed by baseline correction (lower area under the curve ratio indicating higher quality) and signal-to-noise ratio. Mean coefficient of variation (CV%) assessed reproducibility between repeated experiments and methods. Identified mass peak intensity differences were assessed for consistency across repeated experiments. Plasma from six patients was analysed. The quality of mass spectra was significantly better when derived from digested plasma fractionated by either WCX or C18 methods compared to undigested plasma fractionated by WCX (analysis of variance, p < 0.05). Mean CV% for repeated experiments was 18% and 28% for WCX and C18 fractionated digested plasma, respectively. A small number of differences in mass peak intensities were consistently observed in repeated experiments. Repeated experiments are required to confidently identify non-random mass peak intensity differences as putative plasma biomarkers that merit further investigation.


2-Oxoacid dehydrogenase multienzyme complexes in the halophilic Archaea? Gene sequences and protein structural predictions.
All Archaea catalyse the conversion of pyruvate to acetyl-CoA via a simple pyruvate oxidoreductase. This is in contrast to the Eukarya and most aerobic bacteria, which use the pyruvate dehydrogenase multienzyme complex [PDHC], consisting of multiple copies of three component enzymes: E1 (pyruvate decarboxylase), E2 (lipoate acetyl-transferase) and E3 (dihydrolipoamide dehydrogenase, DHLipDH). Until now no PDHC activity has been found in the Archaea, although DHLipDH has been discovered in the extremely halophilic Archaea and its gene sequence has been determined. In this paper, the discovery and sequencing of an operon containing the DHLipDH gene in the halophilic archaeon Haloferax volcanii are reported. Upstream of the DHLipDH gene are 3 ORFs which show highest sequence identities with the E1alpha, E1beta and E2 genes of the PDHC from gram-positive organisms. Structural predictions of the proposed protein product of the E2 gene show a domain structure characteristic of the E2 component in PDHCs, and catalytically important residues, including the lysine to which the lipoic acid cofactor is covalently bound, are conserved. Northern analyses indicate the transcription of the whole operon, but no PDHC enzymic activity could be detected in cell extracts. The presence in the E2 gene of an insertion (equivalent to approximately 100 aa) not found in bacterial or eukaryal E2 proteins, might be predicted to prevent multienzyme complex assembly. This is the first detailed report of the genes for a putative 2-oxoacid dehydrogenase complex in the Archaea, and the evolutionary and metabolic consequences of these findings are discussed.


Neurological outcome after surgical management of adult tethered cord syndrome.
Although postsurgical neurological outcomes in patients with tethered cord syndrome (TCS) are well known, the rate and development of neurological improvement after first-time tethered cord release is incompletely understood. The authors reviewed their institutional experience with the surgical management of adult TCS to assess the time course of symptomatic improvement, and to identify the patient subgroups most likely to experience improvement of motor symptoms. The authors retrospectively reviewed 29 consecutive cases of first-time adult tethered cord release. Clinical symptoms of pain and motor and urinary dysfunction were evaluated at 1 and 3 months after surgery, and then every 6 months thereafter. Rates of improvement in pain and motor or urinary dysfunction over time were identified, and presenting factors associated with improvement of motor symptoms were assessed using a multivariate survival analysis (Cox model). The mean patient age was 38 +/- 13 years. The causes of TCS included lipomyelomeningocele in 3 patients (10%), tight filum in 3 (10%), lumbosacral lipoma in 4 (14%), intradural tumor in 3 (10%), previous lumbosacral surgery in 2 (7%), and previous repair of myelomeningocele in 14 (48%). The mean +/- SD duration of symptoms before presentation was 5 +/- 7 months. Clinical presentation included diffuse pain/parasthesias in both lower extremities in 13 patients (45%), or perineal distribution in 18 (62%), lower extremity weakness in 17 (59%), gait difficulties in 17 (59%), and bladder dysfunction in 14 (48%). Laminectomy was performed in a mean of 2.5 +/- 0.7 levels per patient, and 9 patients (30%) received duraplasty. At 18 months postoperatively, 47% of patients had improved urinary symptoms, 69% had improved lower extremity weakness and gait, and 79% had decreased painful dysesthesias. Median time to symptomatic improvement was least for pain (1 month), then motor (2.3 months), and then urinary symptoms (4.3 months; p = 0.04). In patients demonstrating improvement, 96% improved within 6 months of surgery. Only 4% improved beyond 1-year postoperatively. In a multivariate analysis, the authors found that patients who presented with asymmetrical lower extremity weakness (p = 0.0021, hazard ratio 5.7) or lower extremity hyperreflexia (p = 0.037, hazard ratio = 4.1) were most likely to experience improvement in motor symptoms. In the authors' experience, pain and motor and urinary dysfunction improve postoperatively in the majority of patients. The rate of symptomatic improvement was greatest for pain resolution, followed by motor, and then urinary improvement. Patients who experienced improvement in any symptom had done so by 6 months after tethered cord release. Patients with asymmetrical motor symptoms or lower extremity hyperreflexia at presentation were most likely to experience improvements in motor symptoms. These findings may help guide patient education and surgical decision-making.


Protein folding and conformational stress in microbial cells producing recombinant proteins: a host comparative overview.
Different species of microorganisms including yeasts, filamentous fungi and bacteria have been used in the past 25 years for the controlled production of foreign proteins of scientific, pharmacological or industrial interest. A major obstacle for protein production processes and a limit to overall success has been the abundance of misfolded polypeptides, which fail to reach their native conformation. The presence of misfolded or folding-reluctant protein species causes considerable stress in host cells. The characterization of such adverse conditions and the elicited cell responses have permitted to better understand the physiology and molecular biology of conformational stress. Therefore, microbial cell factories for recombinant protein production are depicted here as a source of knowledge that has considerably helped to picture the extremely rich landscape of in vivo protein folding, and the main cellular players of this complex process are described for the most important cell factories used for biotechnological purposes.


The antimicrobial activity of the essential oil from Achillea fragrantissima.
Essential oil from Achillea fragrantissima exerted a bactericidic effect on several gram positive and gram negative bacterial strains, as well as on Candida albicans. The oil was fractionated on sillica gel columns by a gradient of ether in petrol ether (30 degrees C-40 degrees C). Two fractions which contained less polar compounds were active against C. albicans only. The fractions which contained more polar compounds inhibited the growth of all the microorganisms tested. One of these compounds was identified as terpinen-4-ol. Commercial terpinen-4-ol had a similar antimicrobial activity.


LATENT SPACE MODELS FOR MULTIVIEW NETWORK DATA.
Social relationships consist of interactions along multiple dimensions. In social networks, this means that individuals form multiple types of relationships with the same person (e.g., an individual will not trust all of his/her acquaintances). Statistical models for these data require understanding two related types of dependence structure: (i) structure within each relationship type, or network view, and (ii) the association between views. In this paper, we propose a statistical framework that parsimoniously represents dependence between relationship types while also maintaining enough flexibility to allow individuals to serve different roles in different relationship types. Our approach builds on work on latent space models for networks [see, e.g., J. Amer. Statist. Assoc.97 (2002) 1090-1098]. These models represent the propensity for two individuals to form edges as conditionally independent given the distance between the individuals in an unobserved social space. Our work departs from previous work in this area by representing dependence structure between network views through a multivariate Bernoulli likelihood, providing a representation of between-view association. This approach infers correlations between views not explained by the latent space model. Using our method, we explore 6 multiview network structures across 75 villages in rural southern Karnataka, India [Banerjee et al. (2013)].


Quiet, clean, green, and active: A Navigation Guide systematic review of the impacts of spatially correlated urban exposures on a range of physical health outcomes.
Recent epidemiologic analyses have considered impacts of multiple spatially correlated urban exposures, but this literature has not been systematically evaluated. To characterize the long-term impacts of four distinct spatially correlated urban environmental exposures - traffic-related air pollution (TRAP), noise, natural spaces, and neighborhood walkability - by evaluating studies including measures of at least two such exposures in relationship to mortality, cardiovascular disease, chronic respiratory disease, allergy, type 2 diabetes, or reproductive outcomes. Following the Navigation Guide framework, the literature was searched for studies published since 2003 and meeting predefined inclusion criteria. Identified studies were scored individually for risk of bias and all studies related to an exposure-group set were appraised for overall quality and strength of evidence. A total of 51 individual studies (TRAP and noise: n = 29; TRAP and natural spaces: n = 10; noise and natural spaces: n = 2; TRAP, noise, and natural spaces: n = 7; TRAP, noise, natural spaces, and walkability: n = 3) were included. When TRAP and noise were considered jointly, evidence was sufficient for increased cardiovascular morbidity with higher noise exposures; sufficient for no effect of TRAP on CVD morbidity; sufficient for increased mortality with higher TRAP exposures, but limited for noise; and limited for increased adverse reproductive outcomes with higher TRAP exposures and no effect of noise. Looking at natural spaces and TRAP, there was limited evidence for lower risk of chronic respiratory disease and small increases in birthweight with greater natural space; this relationship with birthweight persisted after adjustment for noise as well. Evidence was inadequate for all other exposure groups and outcomes. Studies that properly account for the complexity of relationships between urban form and physical health are limited but suggest that even highly correlated exposures may have distinct effects. PROSPERO 2018 CRD42018106050.


Improving the provision of services to young people from refugee backgrounds with comorbid mental health and substance use problems: addressing the barriers.
South Australia (SA) has resettled 151,134 refugees in the last ten years (Department of Immigration and Border Protection, Settlement reporting facility, 2014). Northern metropolitan Adelaide, an area which experiences significant social disadvantage, has received a significant number of (predominantly young) refugees. Research indicates that refugee youth are at elevated risk of mental health (MH) and alcohol and other drug (AOD) problems. These factors, along with the low socio-economic status of northern Adelaide, the number of refugee youth residing there, and the added complexity of treating comorbid MH and AOD problems (comorbidity) prompted this research. We investigated the barriers and facilitators to culturally responsive comorbidity care for these youth and whether the MH and AOD services were equipped to provide such support. This mixed-methods study employed semi-structured interviews with refugee youth and service providers and an online survey with managers of services. Thirty participants (15 refugee youth, 15 service providers) took part in the semi-structured interviews and 56 (40 complete, 16 partially-complete) in the survey. Thematic analysis of the interview data revealed the most commonly reported barriers related to four broad areas: (1) organisational and structural, (2) access and engagement, (3) treatment and service delivery, and (4) training and resources. Survey data supported the barriers identified in the qualitative findings. This research highlights significant gaps in the response of MH and AOD services to refugee youth with comorbidity. Based on the findings, ways of overcoming the barriers are discussed, and are of particular relevance to policy makers, organisations and clinicians.


Combinatorial gene regulation using auto-regulation.
As many as 59% of the transcription factors in Escherichia coli regulate the transcription rate of their own genes. This suggests that auto-regulation has one or more important functions. Here, one possible function is studied. Often the transcription rate of an auto-regulator is also controlled by additional transcription factors. In these cases, the way the expression of the auto-regulator responds to changes in the concentrations of the "input" regulators (the response function) is obviously affected by the auto-regulation. We suggest that, conversely, auto-regulation may be used to optimize this response function. To test this hypothesis, we use an evolutionary algorithm and a chemical-physical model of transcription regulation to design model cis-regulatory constructs with predefined response functions. In these simulations, auto-regulation can evolve if this provides a functional benefit. When selecting for a series of elementary response functions-Boolean logic gates and linear responses-the cis-regulatory regions resulting from the simulations indeed often exploit auto-regulation. Surprisingly, the resulting constructs use auto-activation rather than auto-repression. Several design principles show up repeatedly in the simulation results. They demonstrate how auto-activation can be used to generate sharp, switch-like activation and repression circuits and how linearly decreasing response functions can be obtained. Auto-repression, on the other hand, resulted only when a high response speed or a suppression of intrinsic noise was also selected for. The results suggest that, while auto-repression may primarily be valuable to improve the dynamical properties of regulatory circuits, auto-activation is likely to evolve even when selection acts on the shape of response function only.


On the physiological importance of endoproteolysis of CAAX proteins: heart-specific RCE1 knockout mice develop a lethal cardiomyopathy.
Proteins terminating with a CAAX motif, such as the Ras proteins and the nuclear lamins, undergo post-translational modification of a C-terminal cysteine with an isoprenyl lipid via a process called protein prenylation. After prenylation, the last three residues of CAAX proteins are clipped off by Rce1, an integral membrane endoprotease of the endoplasmic reticulum. Prenylation is crucial to the function of many CAAX proteins, but the physiologic significance of endoproteolytic processing has remained obscure. To address this issue, we used Cre/loxP recombination techniques to create mice lacking Rce1 in the heart, an organ where Rce1 is expressed at particularly high levels. The hearts from heart-specific Rce1 knockout mice manifested reduced levels of both the Rce1 mRNA and CAAX endoprotease activity, and the hearts manifested an accumulation of CAAX protein substrates. The heart-specific Rce1 knockout mice initially appeared healthy but died starting at 3-5 months of age. By 10 months of age, approximately 70% of the mice had died. Pathological studies revealed that the heart-specific Rce1 knockout mice had a dilated cardiomyopathy. By contrast, liver-specific Rce1 knockout mice appeared healthy, had normal transaminase levels, and had normal liver histology. These studies indicate that the endoproteolytic processing of CAAX proteins is essential for cardiac function but is less important for the liver.


The Cost-Effectiveness of Professional Doula Care for a Woman's First Two Births: A Decision Analysis Model.
Multiple studies have demonstrated the benefits of intrapartum doula care, including lower risk for cesarean birth and shortened labor time for nulliparous women. However, analyses investigating the cost-effectiveness of doula care are limited. This study evaluated the potential cost-effectiveness of professional doula support during a woman's first birth in a theoretical population of US women, with all women having a second birth without doula care. A cost-effectiveness model was designed to compare outcomes in women with a professional doula versus no doula labor support. A theoretical cohort of 1.6 million women, the approximate number of annual low-risk, nulliparous, term, singleton births in the United States, was used. Outcomes included mode of birth, maternal death, uterine rupture, cesarean hysterectomy, costs, and quality-adjusted life years (QALYs). Probability estimates used in the model were derived from the literature, and a cost-effectiveness threshold was set at $100,000 per QALY. Sensitivity analyses were used to investigate the robustness of the results. In this theoretical model, professional doula care during the first birth resulted in fewer cesarean births and improved QALYs. Additionally, doula support resulted in 202,538 fewer cesarean births, 46 fewer maternal deaths secondary to fewer cesarean births, 99 fewer uterine ruptures, and 26 fewer hysterectomies, with an additional cost of $185 million and 7617 increased QALYs for the first and subsequent births. Sensitivity analyses demonstrated a professional doula was potentially cost-saving up to $884 and cost-effective up to $1360 per doula. Professional doula care during a woman's first birth may lead to improved outcomes and increased QALYs during her first and second births. Given the limitations of this analysis, the cost-effectiveness estimate is likely conservative, further supporting broader integration of professional doulas into the US maternity care system and highlighting the need for higher doula care reimbursement.


Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci.
The human genome contains a group of gene families whose members map within the same regions of chromosomes 1, 6, and 9. The number of gene families involved and their pronounced clustering to the same areas of the genome indicate that their mapping relationship is nonrandom. By combining mapping data and sequence information for the gene families, we have determined that these sequences are part of a large region that spans several megabases. This region is present in three copies: on the long arm of human chromosome 1, the short arm of chromosome 6, and the long arm of chromosome 9. We have characterized the phylogenesis of two of the gene families involved and propose an evolutionary route for the creation of the three regions. Our analysis led us to predict and demonstrate the presence of two loci, a PBX locus on chromosome 6 and a NOTCH locus on chromosome 1. The discovery of this triplicated region increases our understanding of the evolution of the human genome and may have considerable practical implications for gene mapping prediction and novel approaches to isolating new gene family members and uncloned disease loci.


The integration and functional evaluation of rabbit pacing cells transplanted into the left ventricular free wall.
To evaluate the feasibility of cell transplantation to treat bradyarrhythmia, we analyzed the in vivo integration and pacing function after transplantation of mHCN4-modified rabbit bone marrow mesenchymal stem cells (MSCs) into the rabbit left ventricle free wall epicardium. In our investigation, we injected MSCs transduced with or without mHCN4 into the rabbit left ventricle free wall epicardium. Chemical ablation of the sinoatrial node was performed and bilateral vagus nerves were sequentially stimulated to observe premature left ventricular contraction or left ventricular rhythm. We found that the mHCN4-transduced MSC group had a significantly higher ventricular rate and a shorter QRS duration than that of the control and EGFP group. Furthermore, the mHCN4-transduced MSCs, but not the control cells, gradually adapted long-spindle morphology and became indistinguishable from adjacent ventricle myocytes. The modified MSCs showed pacing function approximately 1 week after transplantation and persisted at least 4 weeks after transplantation. In conclusion, a bradyarrhythmia model can be successfully established by chemical ablation of the sinoatrial node and sequential bilateral vagus nerve stimulation. The mHCN4-modified rabbit MSCs displayed evident dynamic morphology changes after being transplanted into rabbit left ventricle free wall epicardium. Our studies may provide a promising strategy of using modified stem cell transplantation to treat bradyarrhythmia.


Solving the chemical master equation using sliding windows.
The chemical master equation (CME) is a system of ordinary differential equations that describes the evolution of a network of chemical reactions as a stochastic process. Its solution yields the probability density vector of the system at each point in time. Solving the CME numerically is in many cases computationally expensive or even infeasible as the number of reachable states can be very large or infinite. We introduce the sliding window method, which computes an approximate solution of the CME by performing a sequence of local analysis steps. In each step, only a manageable subset of states is considered, representing a "window" into the state space. In subsequent steps, the window follows the direction in which the probability mass moves, until the time period of interest has elapsed. We construct the window based on a deterministic approximation of the future behavior of the system by estimating upper and lower bounds on the populations of the chemical species. In order to show the effectiveness of our approach, we apply it to several examples previously described in the literature. The experimental results show that the proposed method speeds up the analysis considerably, compared to a global analysis, while still providing high accuracy. The sliding window method is a novel approach to address the performance problems of numerical algorithms for the solution of the chemical master equation. The method efficiently approximates the probability distributions at the time points of interest for a variety of chemically reacting systems, including systems for which no upper bound on the population sizes of the chemical species is known a priori.


Neuromuscular Fatigue and Recovery after Heavy Resistance, Jump, and Sprint Training.
Training methods that require maximal intensity efforts against light and heavy resistance are commonly used for athletic development. Typically, these sessions are separated by at least 48 h recovery on the assumption that such efforts elicit marked fatigue of the central nervous system (CNS), but this posit has not been well studied. The aim of the study was to assess the etiology and recovery of fatigue after heavy-resistance (strength), jump, and sprint training methods. Ten male athletes completed three training sessions requiring maximal efforts that varied in their loading characteristics: (i) heavy-resistance exercise (10 × 5 back squats at 80% one-repetition maximum [1RM]) (STR), (ii) jumping exercise (10 × 5 jump squats) (JUMP), and (iii) maximal sprinting (15 × 30 m) (SPR). Preparticipants, postparticipants, and 24-, 48-, and 72-h postparticipants completed a battery of tests to measure neuromuscular function using electrical stimulation of the femoral nerve, and single- and paired-pulse magnetic stimulation of the motor cortex, with evoked responses recorded from the knee extensors. Fatigue was self-reported at each time point using a visual analog scale. Each intervention elicited fatigue that resolved by 48 (JUMP) and 72 h (STR and SPR). Decrements in muscle function (reductions in the potentiated quadriceps twitch force) persisted for 48 h after all exercise. Reductions in voluntary activation were present for 24 h after JUMP and SPRINT, and 48 h after STR. No other differences in CNS function were observed as a consequence of training. Strength, jump, and sprint training requiring repeated maximum efforts elicits fatigue that requires up to 72 h to fully resolve, but this fatigue is not primarily underpinned by decrements in CNS function.


Analysis of osteoarthritis in a mouse model of the progeroid human DNA repair syndrome trichothiodystrophy.
The increasing average age in developed societies is paralleled by an increase in the prevalence of many age-related diseases such as osteoarthritis (OA), which is characterized by deformation of the joint due to cartilage damage and increased turnover of subchondral bone. Consequently, deficiency in DNA repair, often associated with premature aging, may lead to increased pathology of these two tissues. To examine this possibility, we analyzed the bone and cartilage phenotype of male and female knee joints derived from 52- to 104-week-old WT C57Bl/6 and trichothiodystrophy (TTD) mice, who carry a defect in the nucleotide excision repair pathway and display many features of premature aging. Using micro-CT, we found bone loss in all groups of 104-week-old compared to 52-week-old mice. Cartilage damage was mild to moderate in all mice. Surprisingly, female TTD mice had less cartilage damage, proteoglycan depletion, and osteophytosis compared to WT controls. OA severity in males did not significantly differ between genotypes, although TTD males had less osteophytosis. These results indicate that in premature aging TTD mice age-related changes in cartilage were not more severe compared to WT mice, in striking contrast with bone and many other tissues. This segmental aging character may be explained by a difference in vasculature and thereby oxygen load in cartilage and bone. Alternatively, a difference in impact of an anti-aging response, previously found to be triggered by accumulation of DNA damage, might help explain why female mice were protected from cartilage damage. These findings underline the exceptional segmental nature of progeroid conditions and provide an explanation for pro- and anti-aging features occurring in the same individual.


Response shift in quality of life after endoscopic sinus surgery for chronic rhinosinusitis.
Patient-reported measures are designed to detect a true change in outcome, but they are also subject to change from biases inherent to self-reporting: changing internal standards, changing priorities, and changing interpretations of a given instrument. These biases are collectively known as "response shifts" and can obscure true change after medical interventions. To determine the presence of response shifts in patients with chronic rhinosinusitis (CRS) after endoscopic sinus surgery. Multisite, prospective, observational cohort study conducted at academic tertiary care centers between February 2011 and May 2013. Study participants comprised a population-based sample of 514 adults (age ≥18 years) with CRS, who elected surgical intervention for continuing medically refractory symptoms. Endoscopic sinus surgery. Preoperative and postoperative data from the 22-item Sinonasal Outcome Test (SNOT-22) survey instrument was characterized using exploratory factor analysis. Subsequent longitudinal structural equation models were estimated to test structure, potential response shifts, and true change in the SNOT-22 scores. A total of 339 participants (66.0%) provided survey evaluations at baseline and 6-month follow-up. Factor analysis of the SNOT-22 revealed 5 correlated, yet distinguishable, underlying factors. Endoscopic sinus surgery had a differential impact across these factors, with the largest effect size in rhinologic symptoms (mean [SD] SNOT-22 scores before and after surgery, 13.18 [5.11] and 7.37 [5.48], respectively; d = -1.13 [P < .001]) and extranasal rhinologic symptoms (8.31 [3.46] and 4.83 [3.68], respectively; d = -1.00 [P < .05]) (d is an effect size measure defined as the difference in means divided by the presurgery SD). Endoscopic sinus surgery had a smaller, yet significant, effect size on the remaining 3 factors: ear/facial symptoms (7.32 [4.6]) and 3.90 [4.07], respectively; d = -0.74 [P < .001]), psychological dysfunction (11.90 [7.21] and 6.50 [6.69], respectively; d = -0.75 [P < .05]), and sleep dysfunction (10.12 [5.59] and 5.88 [5.37], respectively; d = -0.76 [P < .001]). Participants were found to undergo recalibration, reprioritization, and reconceptualization of symptoms after intervention; however, the magnitude of these response shifts was small and not clinically significant. The SNOT-22 measures 5 distinct factors, not a single construct. Reporting of individual subscale scores may improve sensitivity of this instrument in future studies. Participants undergoing endoscopic sinus surgery experience only clinically insignificant response shifts, validating assessment of change through use of presurgery and postsurgery SNOT-22 responses. clinicaltrials.gov Identifier: NCT01332136.


A metadata approach to evaluate the state of ocean knowledge: Strengths, limitations, and application to Mexico.
Climate change, mismanaged resource extraction, and pollution are reshaping global marine ecosystems with direct consequences on human societies. Sustainable ocean development requires knowledge and data across disciplines, scales and knowledge types. Although several disciplines are generating large amounts of data on marine socio-ecological systems, such information is often underutilized due to fragmentation across institutions or stakeholders, limited standardization across scale, time or disciplines, and the fact that information is often not searchable within existing databases. Compiling metadata, the information which describes existing sets of data, is an effective tool that can address these challenges, particularly when metadata corresponding to multiple datasets can be combined to integrate, organize and classify multidisciplinary data. Here, using Mexico as a case study, we describe the compilation and analysis of a metadatabase of ocean knowledge that aims to improve access to information, facilitate multidisciplinary data sharing and integration, and foster collaboration among stakeholders. We also evaluate the knowledge trends and gaps for informing ocean management. Analysis of the metadatabase highlights that past and current research in Mexico focuses strongly on ecology and fisheries, with biological data more consistent over time and space compared to data on human dimensions. Regional imbalances in available information were also evident, with most available information corresponding to the Gulf of California, Campeche Bank and Caribbean and less available for the central and south Pacific and the western Gulf of Mexico. Despite existing knowledge gaps in Mexico and elsewhere, we argue that systematic efforts such as this can often reveal an abundance of information for decision-makers to develop policies that meet key commitments on ocean sustainability. Surmounting current cross-scale social and ecological challenges for sustainability requires transdisciplinary approaches. Metadatabases are critical tools to make efficient use of existing data, highlight and address strengths and deficiencies, and develop scenarios to inform policies for managing complex marine social-ecological systems.


Psychosocial determinants of socioeconomic inequalities in cancer screening participation: a conceptual framework.
Cancer screening participation shows a strong, graded association with socioeconomic status (SES) not only in countries such as the United States, where insurance status can be a barrier for lower income groups, but also in the United Kingdom, where the National Health Service provides all health care to residents, including screening, for free. Traditionally, the literature on socioeconomic inequalities has focused on upstream factors, but more proximal (downstream) influences on screening participation also need to be examined, particularly those that address the graded nature of the association rather than focusing specifically on underserved groups. This review offers a framework that links some of the components and corollaries of SES (life stress, educational opportunities, illness experience) to known psychosocial determinants of screening uptake (beliefs about the value of early detection, fatalistic beliefs about cancer, self-efficacy). The aim is to explain why individuals from lower SES backgrounds perceive cancer screening tests as more threatening, more difficult to accomplish, and less beneficial. A better understanding of the mechanisms through which lower SES causes negative attitudes toward screening could facilitate the development of intervention strategies to reduce screening inequalities.


CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes.
All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation-induced signaling in lymphocytes; however, little is known of its role in non-lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine-induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11-induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacity to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases.


Benign and malignant colorectal strictures in ulcerative colitis.
Colorectal strictures, either benign or malignant, are not uncommon in ulcerative colitis. Fifty nine of 1156 ulcerative colitis patients (5%) admitted to this hospital between 1959 and 1983 developed 70 separate colorectal strictures. Seventeen of the 70 strictures (24%) proved to be malignant and the other 53 benign. Nine patients developed more than one stricture. Three principal features distinguished the 17 malignant from the 53 benign strictures in this series: (1) appearance late in the course of ulcerative colitis (61% probability of malignancy in strictures that develop after 20 years of disease v 0% probability in those occurring before 10 years); (2) location proximal to the splenic flexure (86% probability of malignancy v 47% in sigmoid, 10% in rectum, and 0% in splenic flexure and descending colon); and (3) symptomatic large bowel obstruction (100% probability of malignancy v only 14% in the absence of obstruction or constipation). Moreover, cancer associated with strictures tends to be more advanced (76% stage D, 24% A and B) than that which does not produce strictures (18% stage D, 59% A and B).


Survival and functional outcome of childhood spinal cord low-grade gliomas. Clinical article.
Intramedullary spinal cord low-grade gliomas (LGGs) are rare CNS neoplasms in pediatric patients, and there is little information on therapy for and outcome of these tumors in this population. Furthermore, most patient series combine adult and pediatric patients or high- and low-grade tumors, resulting in controversial data regarding optimal treatment of these children. To clarify these issues, the authors performed a regional population-based study of spinal cord LGGs in pediatric patients. All pediatric patients with LGGs treated during the MR imaging era (1985-2007) were identified in the comprehensive database of the Hospital for Sick Children in Toronto. Data on demographics, pathology, treatment details, and outcomes were collected. Spinal cord LGGs in pediatric patients constituted 29 (4.6%) of 635 LGGs. Epidemiological and clinical data in this cohort were different than in patients with other spinal tumors and strikingly similar to data from pediatric patients with intracranial LGGs. The authors observed an age peak at 2 years and a male predominance in patients with these tumors. Histological testing revealed a Grade I astrocytoma in 86% of tumors. Although 5-year progression-free survival for the entire group was 48 +/- 9%, all patients were alive at a median follow-up of 8.2 years. Five-year progression-free survival was 88 +/- 13% for patients undergoing gross-total resection and 34 +/- 11% for those undergoing all other therapies, respectively (p = 0.02). Chemotherapy and radiation therapy showed similar efficacy, achieving sustained tumor control in most patients. However, this excellent survival rate was associated with an 83% rate of significant neurological and orthopedic sequelae. This study provides basic data on the incidence, clinical course, and outcome of spinal cord LGGs in pediatric patients. The similarities between spinal and intracranial LGGs in pediatric patients showing excellent survival but high morbidity suggest that a less aggressive approach may be the preferable treatment option for these patients.


Current Mathematical Models for Analyzing Anti-Malarial Antibody Data with an Eye to Malaria Elimination and Eradication.
The last decade has witnessed a steady reduction of the malaria burden worldwide. With various countries targeting disease elimination in the near future, the popular parasite infection or entomological inoculation rates are becoming less and less informative of the underlying malaria burden due to a reduced number of infected individuals or mosquitoes at the time of sampling. To overcome such problem, alternative measures based on antibodies against specific malaria antigens have gained recent interest in malaria epidemiology due to the possibility of estimating past disease exposure in absence of infected individuals. This paper aims then to review current mathematical models and corresponding statistical approaches used in antibody data analysis. The application of these models is illustrated with three data sets from Equatorial Guinea, Brazilian Amazonia region, and western Kenyan highlands. A brief discussion is also carried out on the future challenges of using these models in the context of malaria elimination.


Weight Loss in Patients with Dementia: Considering the Potential Impact of Pharmacotherapy.
Unintentional body weight loss is common in patients with dementia and is linked to cognitive impairment and poorer disease outcomes. It is proposed that some dementia medications with market approval, while aiming to improve cognitive and functional outcomes of a patient with dementia, are associated with reported body weight or body mass index loss. This review presents evidence in the published literature on body weight loss in dementia, describes selected theories behind body weight loss, evaluates the potential impact of approved dementia pharmacotherapies on body weight, considers the potential role for medical foods, understands the potential influence of treatments for neuropsychiatric symptoms and signs, and finally, summarizes this important area.


Antigen recognition. IV. Discrimination by antigen-binding immunocompetent B cells between immunity and tolerance is determined by adherent cells.
Mouse spleen cells capable of specifically binding intrinsically tritium-labeled polymerized flagellin (POL) (labeling by biosynthesis of flagellar protein) via IgM receptors were found to comprise a distinct population of about 20-50 cells per 10(6) lymphocytes. Evidence is presented that the majority of mouse spleen cells binding tritium-labeled POL undergoes blastogenesis after antigen capping, antigen shedding, and receptor reformation. Under conditions of tolerance induction in vitro, however, loss of antigen from the cell surface was inhibited. Such inhibition of antigen redistribution and shedding was reversed by a short pulse of colchicine and new antigen receptors were formed. In spite of this, colchicine had no effect on the tolerant state. However, tolerance could be broken, regardless of presence or absence of the alkaloid, with radioresistant theta-negative accessory (A) cells (adherent cells) from normal but not from tolerant spleen cell populations. "Tolerant" A cells, although they were incapable of cooperating in a response to POL, were capable of participating in a response to a second unrelated antigen. It is concluded that tolerance to POL in vitro is induced by mechanisms other than the physical blocking of bone marrow-derived (B) cell receptors by antigen. Most likely, the discrimination by the B cell between a tolerogenic and immunogenic signal is mediated by A cells.


Differences in Active and Passive Smoking Exposures and Lung Cancer Incidence Between Veterans and Non-Veterans in the Women's Health Initiative.
Women Veterans may have higher rates of both active and passive tobacco exposure than their civilian counterparts, thereby increasing their risk for lung cancer. To compare differences in active and passive smoking exposure and lung cancer incidence among women Veterans and non-Veterans using prospective data from the Women's Health Initiative (WHI). We used data from the WHI, which collected longitudinal demographic, clinical, and laboratory data on 161,808 postmenopausal women. We employed linear and multinomial regression and generalized linear models to compare active and passive smoking exposure between Veterans and non-Veterans and Cox proportional hazards models to estimate differences in lung cancer incidence rates. After adjustment, Veterans had 2.54 additional pack years of smoking compared with non-Veterans (95% confidence interval [CI] 1.68, 3.40). Veterans also had a 1% increase in risk of any passive smoking exposure (95% CI 1.00, 1.02) and a 9% increase in risk of any workplace exposure (95% CI 1.07, 1.11) compared with non-Veterans. After adjustment for age and smoking exposures, Veterans did not have a higher risk of lung cancer compared with non-Veterans (relative risk = 1.06 95% CI 0.86, 1.30). Women Veterans had higher rates of tobacco use and exposure to passive smoking, which were associated with a higher risk for lung cancer compared with non-Veterans. Clinicians who care for Veterans need to be aware that older women Veterans have more exposures to risk factors for lung cancer.


A comparison of effects of broad-spectrum antibiotics and biosurfactants on established bacterial biofilms.
Current antibiofilm solutions based on planktonic bacterial physiology have limited efficacy in clinical and occasionally environmental settings. This has prompted a search for suitable alternatives to conventional therapies. This study compares the inhibitory properties of two biological surfactants (rhamnolipids and a plant-derived surfactant) against a selection of broad-spectrum antibiotics (ampicillin, chloramphenicol and kanamycin). Testing was carried out on a range of bacterial physiologies from planktonic and mixed bacterial biofilms. Rhamnolipids (Rhs) have been extensively characterised for their role in the development of biofilms and inhibition of planktonic bacteria. However, there are limited direct comparisons with antimicrobial substances on established biofilms comprising single or mixed bacterial strains. Baseline measurements of inhibitory activity using planktonic bacterial assays established that broad-spectrum antibiotics were 500 times more effective at inhibiting bacterial growth than either Rhs or plant surfactants. Conversely, Rhs and plant biosurfactants reduced biofilm biomass of established single bacterial biofilms by 74-88 and 74-98 %, respectively. Only kanamycin showed activity against biofilms of Bacillus subtilis and Staphylococcus aureus. Broad-spectrum antibiotics were also ineffective against a complex biofilm of marine bacteria; however, Rhs and plant biosurfactants reduced biofilm biomass by 69 and 42 %, respectively. These data suggest that Rhs and plant-derived surfactants may have an important role in the inhibition of complex biofilms.


Ethnomedicinal studies on plants used by Yanadi tribe of Chandragiri reserve forest area, Chittoor District, Andhra Pradesh, India.
Ethnomedicinal studies on medicinal plants used by Yanadi tribe of Chandragiri reserve forest area are documented during the period of 2014-2015. The study is mainly focused on medicinal importance of plants used by Yanadi tribe to treat various ailments. The information collected on treated ailments, part used, preparation, combination, and addition of ingredients to prepare herbal medicines with the help of standard questionnaire. During the study, 53 types of ailments were treated using 48 medicinal plants belongs to 26 families were documented. Among the medicinal plants, shrubs (15) were most using life form of plants for the preparation of herbal medicines. Leaf part (40%), paste form (33%), and oral administration (63%) of herbal medicines were most preferable. The documented ethnomedicinal importance of this tribe was cross-checked with Dr. Duke's Phytochemical and Ethnobotanical database shows most of the plants were correlated with this database. There is no record of traditional medicinal knowledge of these villages so far, hence the present study is aimed to document the information on medicinal plants used by Yanadi tribe in Chandragiri reserve forest area. The correlation of ethnomedicinal uses with Dr. Duke's Phytochemical and Ethnobotanical database clearly indicates the high medicinal significance of claimed data of this Yanadi tribe.


How Do My Friends Matter? Examining Latino Adolescents' Friendships, School Belonging, and Academic Achievement.
Are Latino adolescents' friendships an untapped resource for academic achievement or perhaps one of the reasons why these youth struggle academically? Using data from the National Longitudinal Study of Adolescent Health (N = 6782; 7th through 12th graders; 52.9 % female), we examined whether the process of Latino students' school belonging mediated the relationships between the context of friendships (i.e., friendship network indicators) and their academic outcomes (i.e., a context-process-outcomes model), and tested whether the process-context link varied by friends' characteristics (i.e., GPA and problem behavior; social capital). Moreover, we tested whether all relationships varied across the four largest Latino subgroups in the U.S. (i.e., Mexican, Central/South American, Puerto Rican, and Cuban). Our findings indicate that being nominated as a friend by peers and perceiving to have friends exerted both direct effects on school belonging in all but one of the Latino ethnic samples (i.e., Puerto Rican samples) and indirect effects on academic achievement in the full Latino, Mexican, and Central/South American samples. As such, school belonging was more likely to explain the links between academic achievement with nominations by peers as a friend and perceived friends than with having close-knit friendship groups. However, having a close-knit group of average or low-achieving friends predicted more school belonging for Mexican youth, but less school belonging for Cubans. Our findings suggest that friendships may be particularly beneficial for the school belonging process of highly marginalized groups in the U.S. (i.e., Mexican-origin).


Basal Ganglia and Thalamic Contributions to Language Function: Insights from A Parallel Distributed Processing Perspective.
Cerebral representations are encoded as patterns of activity involving billions of neurons. Parallel distributed processing (PDP) across these neuronal populations provides the basis for a number of emergent properties: 1) processing occurs and knowledge (long term memories) is stored (as synaptic connection strengths) in exactly the same networks; 2) networks have the capacity for setting into stable attractor states corresponding to concepts, symbols, implicit rules, or data transformations; 3) networks provide the scaffold for the acquisition of knowledge but knowledge is acquired through experience; 4) PDP networks are adept at incorporating the statistical regularities of experience as well as frequency and age of acquisition effects; 5) networks enable content-addressable memory; 6) because knowledge is distributed throughout networks, they exhibit the property of graceful degradation; 7) networks intrinsically provide the capacity for inference. This paper details the features of the basal ganglia and thalamic systems (recurrent and distributed connectivity) that support PDP. The PDP lens and an understanding of the attractor trench dynamics of the basal ganglia provide a natural explanation for the peculiar dysfunctions of Parkinson's disease and the mechanisms by which dopamine deficiency is causal. The PDP lens, coupled with the fact that the basal ganglia of humans bears strong homology to the basal ganglia of lampreys and the central complex of arthropods, reveals that the fundamental function of the basal ganglia is computational and involves the reduction of the vast dimensionality of a complex multi-dimensional array of sensorimotor input into the optimal choice from a small repertoire of behavioral options - the essence of reactive intention (automatic responses to sensory input). There is strong evidence that the sensorimotor basal ganglia make no contributions to cognitive or motor function in humans but can cause serious dysfunction when pathological. It appears that humans, through the course of evolution, have developed cortical capacities (working memory and volitional and reactive attention) for managing sensory input, however complex, that obviate the need for the basal ganglia. The functions of the dorsal tier thalamus, however, even viewed with an understanding of the properties of population encoded representations, remain somewhat more obscure. Possibilities include the enabling of attractor state constellations that optimize function by taking advantage of simultaneous input from multiple cortical areas; selective engagement of cortical representations; and support of the gamma frequency synchrony that enables binding of the multiple network representations that comprise a full concept representation.


Rigorous electromagnetic analysis of volumetrically complex media using the slice absorption method.
There is tremendous demand for numerical methods to perform rigorous analysis of devices that are both large scale and complex throughout their volume. This can arise when devices must be considered with realistic geometry or when they contain artificial materials such as photonic crystals, left-handed materials, nanoparticles, or other metamaterials. The slice absorption method (SAM) was developed to address this need. The method is fully numerical and able to break large problems down into small pieces, or slices, using matrix division or Gaussian elimination instead of eigensystem computations and scattering matrix manipulations. In these regards, the SAM is an attractive alternative to popular techniques like the finite-difference time domain method, rigorous coupled-wave analysis, and the transfer matrix method. To demonstrate the utility of the SAM and benchmark its accuracy, reflection was simulated for a photonic crystal fabricated in SU-8 by multiphoton direct laser writing. Realistic geometry was incorporated into the model by simulating the microfabrication process, which yielded simulation results that matched experimental measurements remarkably well.


Propolis extract protects against radiation-induced intestinal mucositis through anti-apoptotic mechanisms.
Intestinal mucositis is a common side effect during radiotherapy that could be largely prevented by compounds possessing anti-inflammatory or anti-oxidant properties, including extracts of propolis containing a high proportion of flavonoids. A specially formulated aqueous extract of propolis (PWE) has been prepared in such a way to preclude the inclusion of flavonoids but contain mostly organic aromatic acids to study whether it would still protect against radiation-induced intestinal mucositis and to study the possible involvement of apoptotic pathways. Rats were exposed to a gamma radiation dose of 8 Gy from a Cesium-137 source in order to inflict intestinal mucositis. Three days before exposure, rats were given PWE orally and treatment continued for 2 more days. Twenty-four hours later, rats were sacrificed, the small intestine was excised, and sections were examined histologically. Different parameters for apoptosis, inflammation, and oxidative stress were determined in the serum and in intestinal homogenates. Radiation exposure led to histological and biochemical signs of intestinal damage. This was associated with an increase in apoptotic indicators and derangement in oxidative stress parameters. All deranged parameters were largely prevented by PWE. The findings provide evidence that the protective effect of PWE against intestinal radiation damage involves not only its anti-inflammatory and anti-oxidant effects but also its anti-apoptotic properties as well.


Melt-Quenched Glasses of Metal-Organic Frameworks.
Crystalline solids dominate the field of metal-organic frameworks (MOFs), with access to the liquid and glass states of matter usually prohibited by relatively low temperatures of thermal decomposition. In this work, we give due consideration to framework chemistry and topology to expand the phenomenon of the melting of 3D MOFs, linking crystal chemistry to framework melting temperature and kinetic fragility of the glass-forming liquids. Here we show that melting temperatures can be lowered by altering the chemistry of the crystalline MOF state, which provides a route to facilitate the melting of other MOFs. The glasses formed upon vitrification are chemically and structurally distinct from the three other existing categories of melt-quenched glasses (inorganic nonmetallic, organic, and metallic), and retain the basic metal-ligand connectivity of crystalline MOFs, which connects their mechanical properties to their starting chemical composition. The transfer of functionality from crystal to glass points toward new routes to tunable, functional hybrid glasses.


Healthcare utilisation of pregnant women who experience sciatica, leg cramps and/or varicose veins: A cross-sectional survey of 1835 pregnant women.
Common discomforts of pregnancy experienced in the lower extremity include sciatica, leg cramps and varicose veins. Whilst research attention has focused on aetiology and outcomes, the health service utilisation of pregnant women suffering from these complaints has been largely overlooked. To examine the health status and health service utilisation profile of pregnant women experiencing sciatica, leg cramps or varicose veins. Linear and logistic regression was applied to a cross-sectional survey of a pregnant women drawn from the 1973 to 1978 cohort (aged 31-36 years in 2009), of the Australian Longitudinal Study on Women's Health (n=1835). Participant's demographics, health status and health service utilisation were compared for all three complaints based upon three subgroups (yes, sought help; yes, did not seek help; no). A number of women experienced sciatica (22.1%), leg cramps (18.2%) or varicose veins (9.4%). Of these, a greater proportion of women with sciatica (79.3%) or varicose veins (71.5%) sought help for their condition compared with women with leg cramps (46.7%). Comparisons between women with the conditions of interest who did seek help and those who did not only found that women with a university degree were 0.29 (95% CI: 0.10, 0.85) times less likely to seek help for their condition compared to women with a school only education. Further research examining all health seeking behaviour and treatment use of pregnant women who experience lower extremity problems is required in order to facilitate safe, effective and coordinated maternity care to further support these women during pregnancy.


Protective effects of monomethyl fumarate at the inflamed blood-brain barrier.
Reactive oxygen species play a key role in the pathogenesis of multiple sclerosis as they induce blood-brain barrier disruption and enhance transendothelial leukocyte migration. Thus, therapeutic compounds with antioxidant and anti-inflammatory potential could have clinical value in multiple sclerosis. The aim of the current study was to elucidate the therapeutic effects of monomethyl fumarate on inflammatory-mediated changes in blood-brain barrier function and gain insight into the underlying mechanism. The effects of monomethyl fumarate on monocyte transendothelial migration across and adhesion to inflamed human brain endothelial cells (hCMEC/D3) were quantified using standardized in vitro migration and adhesion assays. Flow cytometry analysis and qPCR were used to measure the concomitant effects of monomethyl fumarate treatment on protein expression of cell adhesion molecules. Furthermore, the effects of monomethyl fumarate on the expression and nuclear localization of proteins involved in the activation of antioxidant and inflammatory pathways in human brain endothelial cells were elucidated using nuclear fractionation and Western blotting. Statistical analysis was performed using one-way ANOVA followed by the Bonferroni post-hoc test. Our results show that monomethyl fumarate induced nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and concomitant production of the antioxidant enzymes heme oxygenase-1 and NADPH:quinone oxidoreductase-1 in brain endothelial cells. Importantly, monomethyl fumarate treatment markedly decreased monocyte transendothelial migration across and adhesion to inflamed human brain endothelial cells. Treatment of brain endothelial cells with monomethyl fumarate resulted in a striking reduction of vascular cell adhesion molecule expression. Surprisingly, monomethyl fumarate did not affect nuclear translocation of nuclear factor-кB suggesting that monomethyl fumarate potentially affects activity of nuclear factor-ĸB downstream of nuclear translocation. Taken together, we show that monomethyl fumarate, the primary metabolite of dimethyl fumarate, which is currently used in the clinics for the treatment of relapsing-remitting multiple sclerosis, demonstrates beneficial therapeutic effects at the inflamed blood-brain barrier.


Retinal vessel oxygen saturation is affected in uveitis associated with Vogt-Koyanagi-Harada disease.
To discover whether retinal vessel oxygen metabolism is affected in uveitis associated with Vogt-Koyanagi-Harada (VKH) disease. 41 patients with VKH disease (82 eyes) and 12 healthy subjects (24 eyes) matched in age and gender were prospectively evaluated. Retinal oxygen saturation and vessel calibre were measured with a non-invasive spectrophotometric retinal oximeter (Oxymap T1). In healthy controls, mean arteriolar oxygen saturation (%) was 93.8±5.9 and venular saturation was 60.1±5.8. In acute VKH uveitic phase associated with exudative retinal detachment (n=12), arteriolar and venular oxygen saturation values were 104.7±7.8 and 67.9±7.7, respectively, and both are significantly higher than the healthy group (p<0.001; p=0.001, respectively). In patients with VKH disease who recovered after immunosuppressive therapy and restored normal anatomy without 'sunset glow fundus' (n=13), oximetry values were 96.4±9.6 and 61.6±7.5, respectively, similar to healthy controls. In patients with 'sunset glow fundus' and chorioretinal atrophy (n=16), saturation levels were 88.6±7.8 and 50.0±13.1, respectively, significantly lower than healthy controls (p=0.02; p=0.003, respectively). These patients also had significantly smaller diameter of retinal arterioles and venules compared with controls (p=0.035; p=0.001, respectively). Retinal oxygen metabolism is altered in uveitis associated with VKH disease. Oxygen saturation profile is abnormal in acute uveitic phase of the disease and returns to normal in those who recover with normal fundus appearance, but not in eyes that suffer permanent anatomical damage with 'sunset glow fundus' and chorioretinal atrophy. Retinal oximetry may be of value in evaluating vascular and metabolic aspects of posterior uveitis.


Investigation of Prescription Status and Exploration of Risk Factors Related to Denosumab-Induced Hypocalcemia in Combination Therapy with 1α,25-Dihydroxy-vitamin D3.
To prevent denosumab-induced hypocalcemia in patients with renal dysfunction, combination therapy with 1α,25-dihydroxy-vitamin D3 (active vitamin D) is recommended. We previously developed a risk prediction model for hypocalcemia in patients with cholecalciferol/calcium (natural vitamin D). However, the prescription status and the risk factors of patients with active vitamin D have not been identified, so we designed this retrospective observational study using a large practice database covering June 2013 to May 2020 to analyze prescription status and risk factors. Patients were classified according to vitamin D type. After that, factors associated with development of hypocalcemia in patients with active vitamin D were explored. Univariate analysis was conducted to compare patient backgrounds between the hypocalcemia and non-hypocalcemia groups. Receiver operating characteristic analysis was conducted to evaluate the predictive potential of the extracted factors. Of the 33442 patients who received denosumab, 22347 and 3560 patients were co-administered natural and active vitamin D, respectively. Patients with active vitamin D had significantly lower renal function (estimated glomerular filtration rate (eGFR) median: 74.0 vs. 69.7 mL/min/1.73 m2), but some patients (23.6%) with sufficient renal function (eGFR ≥90) were also receiving active vitamin D. Of the 3560 patients with active vitamin D, non-hypocalcemia (n = 166) and hypocalcemia (n = 17) groups who met the study criteria were analyzed. Renal function was lower in the hypocalcemia group, and alkaline phosphatase gave the best discrimination. High aspartate aminotransferase (AST), renal dysfunction, high alkaline phosphatase (ALP), and low hemoglobin may be significant factors in risk prediction for hypocalcemia in patients with active vitamin D.


Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers.
Human mitochondrial pyrroline-5-carboxylate reductase (PYCR) is a house-keeping enzyme that catalyzes the reduction of Δ1-pyrroline-5-carboxylate to proline. This enzymatic cycle plays pivotal roles in amino acid metabolism, intracellular redox potential and mitochondrial integrity. Here, we hypothesize that PYCR1 might be a novel prognostic biomarker and therapeutic target for breast cancer. In this study, breast cancer tissue samples were obtained from Zhejiang University (ZJU set). Immunohistochemistry analysis was performed to detect the protein level of PYCR1, and Kaplan-Meier and Cox proportional analyses were employed in this outcome study. The prognostic significance and performance of PYCR1 mRNA were validated on 13 worldwide independent microarray data sets, composed of 2500 assessable breast cancer cases. Our findings revealed that both PYCR1 mRNA and protein expression were significantly associated with tumor size, grade and invasive molecular subtypes of breast cancers. Independent and pooled analyses verified that higher PYCR1 mRNA levels were significantly associated with poor survival of breast cancer patients, regardless of estrogen receptor (ER) status. For in vitro studies, inhibition of PYCR1 by small-hairpin RNA significantly reduced the growth and invasion capabilities of the cells, while enhancing the cytotoxicity of doxorubicin in breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative). Further population study also validated that chemotherapy significantly improved survival in early-stage breast cancer patients with low PYCR1 expression levels. Therefore, PYCR1 might serve as a prognostic biomaker for either ER-positive or ER-negative breast cancer subtypes and can also be a potential target for breast cancer therapy.


A brain mechanism for facilitation of insight by positive affect.
Previous research has shown that people solve insight or creative problems better when in a positive mood (assessed or induced), although the precise mechanisms and neural substrates of this facilitation remain unclear. We assessed mood and personality variables in 79 participants before they attempted to solve problems that can be solved by either an insight or an analytic strategy. Participants higher in positive mood solved more problems, and specifically more with insight, compared with participants lower in positive mood. fMRI was performed on 27 of the participants while they solved problems. Positive mood (and to a lesser extent and in the opposite direction, anxiety) was associated with changes in brain activity during a preparatory interval preceding each solved problem; modulation of preparatory activity in several areas biased people to solve either with insight or analytically. Analyses examined whether (a) positive mood modulated activity in brain areas showing responsivity during preparation; (b) positive mood modulated activity in areas showing stronger activity for insight than noninsight trials either during preparation or solution; and (c) insight effects occurred in areas that showed mood-related effects during preparation. Across three analyses, the ACC showed sensitivity to both mood and insight, demonstrating that positive mood alters preparatory activity in ACC, biasing participants to engage in processing conducive to insight solving. This result suggests that positive mood enhances insight, at least in part, by modulating attention and cognitive control mechanisms via ACC, perhaps enhancing sensitivity to detect non-prepotent solution candidates.


Establishing criteria for human mesenchymal stem cell potency.
This study sought to identify critical determinants of mesenchymal stem cell (MSC) potency using in vitro and in vivo attributes of cells isolated from the bone marrow of age- and sex-matched donors. Adherence to plastic was not indicative of potency, yet capacity for long-term expansion in vitro varied considerably between donors, allowing the grouping of MSCs from the donors into either those with high-growth capacity or low-growth capacity. Using this grouping strategy, high-growth capacity MSCs were smaller in size, had greater colony-forming efficiency, and had longer telomeres. Cell-surface biomarker analysis revealed that the International Society for Cellular Therapy (ISCT) criteria did not distinguish between high-growth capacity and low-growth capacity MSCs, whereas STRO-1 and platelet-derived growth factor receptor alpha were preferentially expressed on high-growth capacity MSCs. These cells also had the highest mean expression of the mRNA transcripts TWIST-1 and DERMO-1. Irrespective of these differences, both groups of donor MSCs produced similar levels of key growth factors and cytokines involved in tissue regeneration and were capable of multilineage differentiation. However, high-growth capacity MSCs produced approximately double the volume of mineralized tissue compared to low-growth capacity MSCs when assessed for ectopic bone-forming ability. The additional phenotypic criteria presented in this study when combined with the existing ISCT minimum criteria and working proposal will permit an improved assessment of MSC potency and provide a basis for establishing the quality of MSCs prior to their therapeutic application.


A questionnaire to assess social stigma.
Psychiatric patients often suffer for two reasons: due to the illness and due to the social stigma of mental illness, that increases the uneasiness and psychic pain of the person suffering from serious psychiatric disorder. This unwell person is often the object of stigma because he is "different" from others, and he also can be margenalised by society. In this study we intend to assess whether these margenalising attitudes might be also present among mental health professionals who have presented psychic problems in a previous period of their life, against sick persons suffering of the same illness even if he is a mental health professional. Two questionnaires have been developed, one for professionals and another for the patients, with the aim of identifying these marginalising attitudes. We intend that this study shall be a multicenter, observational and international study, promoted by the Mental Health Dept. of Naples (ASL Naples 3 South, Italy).


A high-bias, low-variance introduction to Machine Learning for physicists.
Machine Learning (ML) is one of the most exciting and dynamic areas of modern research and application. The purpose of this review is to provide an introduction to the core concepts and tools of machine learning in a manner easily understood and intuitive to physicists. The review begins by covering fundamental concepts in ML and modern statistics such as the bias-variance tradeoff, overfitting, regularization, generalization, and gradient descent before moving on to more advanced topics in both supervised and unsupervised learning. Topics covered in the review include ensemble models, deep learning and neural networks, clustering and data visualization, energy-based models (including MaxEnt models and Restricted Boltzmann Machines), and variational methods. Throughout, we emphasize the many natural connections between ML and statistical physics. A notable aspect of the review is the use of Python Jupyter notebooks to introduce modern ML/statistical packages to readers using physics-inspired datasets (the Ising Model and Monte-Carlo simulations of supersymmetric decays of proton-proton collisions). We conclude with an extended outlook discussing possible uses of machine learning for furthering our understanding of the physical world as well as open problems in ML where physicists may be able to contribute.


Precursor transformation during molecular oxidation catalysis with organometallic iridium complexes.
We present evidence for Cp* being a sacrificial placeholder ligand in the [Cp*Ir(III)(chelate)X] series of homogeneous oxidation catalysts. UV-vis and (1)H NMR profiles as well as MALDI-MS data show a rapid and irreversible loss of the Cp* ligand under reaction conditions, which likely proceeds through an intramolecular inner-sphere oxidation pathway reminiscent of the reductive in situ elimination of diolefin placeholder ligands in hydrogenation catalysis by [(diene)M(I)(L,L')](+) (M = Rh and Ir) precursors. When oxidatively stable chelate ligands are bound to the iridium in addition to the Cp*, the oxidized precursors yield homogeneous solutions with a characteristic blue color that remain active in both water- and CH-oxidation catalysis without further induction period. Electrophoresis suggests the presence of well-defined Ir-cations, and TEM-EDX, XPS, (17)O NMR, and resonance-Raman spectroscopy data are most consistent with the molecular identity of the blue species to be a bis-μ-oxo di-iridium(IV) coordination compound with two waters and one chelate ligand bound to each metal. DFT calculations give insight into the electronic structure of this catalyst resting state, and time-dependent simulations agree with the assignments of the experimental spectroscopic data. [(cod)Ir(I)(chelate)] precursors bearing the same chelate ligands are shown to be equally effective precatalysts for both water- and CH-oxidations using NaIO4 as chemical oxidant.


Distinct causal mechanisms of attentional guidance by working memory and repetition priming in early visual cortex.
Human attention may be guided by representations held in working memory (WM) and also by priming from implicit memory. Neurophysiological data suggest that WM and priming may be associated with distinct neural mechanisms, but this prior evidence is only correlative. Furthermore, the role of the visual cortex in attention biases from memory remains unclear, because most previous studies conflated memory and selection processes. Here, we manipulated memory and attention in an orthogonal fashion and used an interventional approach to demonstrate the functional significance of WM and priming states in visual cortex for attentional biasing. Observers searched for a Landolt target that was preceded by a nonpredictive color cue that either had to be held in WM for a later recognition test or merely attended (priming counterpart). The application of transcranial magnetic stimulation (TMS) over the occipital cortex modulated the impact of memory on search. Critically, the direction of this modulation depended on the memory state. In the WM condition, the application of TMS on validly cued trials (when the cue surrounded the sought target) enhanced search accuracy relative to the invalid trials (when the cue surrounded a distracter); the opposite pattern was observed in the priming condition. That the effects of occipital TMS on selection were contingent on memory context demonstrates that WM and priming represent distinct states in the early visual cortex that play a causal role in memory-based guidance of attention.


Design and characterization of genetically engineered zebrafish aquaporin-3 mutants highly permeable to the cryoprotectant ethylene glycol.
Increasing cell membrane permeability to water and cryoprotectants is critical for the successful cryopreservation of cells with large volumes. Artificial expression of water-selective aquaporins or aquaglyceroporins (GLPs), such as mammalian aquaporin-3 (AQP3), enhances cell permeability to water and cryoprotectants, but it is known that AQP3-mediated water and solute permeation is limited and pH dependent. To exploit further the possibilities of using aquaporins in cryobiology, we investigated the functional properties of zebrafish (Danio rerio) GLPs. Water, glycerol, propylene glycol and ethylene glycol permeability of zebrafish Aqp3a, -3b, -7, -9a, -9b, -10a and -10b, and human AQP3, was examined. Expression in Xenopus laevis oocytes indicated that the permeability of DrAqp3a and -3b to ethylene glycol was higher than for glycerol or propylene glycol under isotonic conditions, unlike other zebrafish GLPs and human AQP3, which were more permeable to glycerol. In addition, dose-response experiments and radiolabeled ethylene glycol uptake assays suggested that oocytes expressing DrAqp3b were permeated by this cryoprotectant more efficiently than those expressing AQP3. Water and ethylene glycol transport through DrAqp3a and -3b were, however, highest at pH 8.5 and completely abolished at pH 6.0. Point mutations in the DrAqp3b amino acid sequence rendered two constructs, DrAqp3b-T85A showing higher water and ethylene glycol permeability at neutral and alkaline pH, and DrAqp3b-H53A/G54H/T85A, no longer inhibited at acidic pH but less permeable than the wild type. Finally, calculation of permeability coefficients for ethylene glycol under concentration gradients confirmed that the two DrAqp3b mutants were more permeable than wild-type DrAqp3b and/or AQP3 at neutral pH, resulting in a 2.6- to 4-fold increase in the oocyte intracellular concentration of ethylene glycol. By single or triple point mutations in the DrAqp3b amino acid sequence, we constructed one mutant with enhanced ethylene glycol permeability and another with reduced pH sensitivity. The DrAqp3b and the two mutant constructs may be useful for application in cryobiology.


English-learning one- to two-year-olds do not show a consonant bias in word learning.
Following the proposal that consonants are more involved than vowels in coding the lexicon (Nespor, Peña & Mehler, 2003), an early lexical consonant bias was found from age 1;2 in French but an equal sensitivity to consonants and vowels from 1;0 to 2;0 in English. As different tasks were used in French and English, we sought to clarify this ambiguity by using an interactive word-learning study similar to that used in French, with British-English-learning toddlers aged 1;4 and 1;11. Children were taught two CVC labels differing on either a consonant or vowel and tested on their pairing of a third object named with one of the previously taught labels, or part of them. In concert with previous research on British-English toddlers, our results provided no evidence of a general consonant bias. The language-specific mechanisms explaining the differential status for consonants and vowels in lexical development are discussed.


Polar extracts from (Tunisian) Acacia salicina Lindl. Study of the antimicrobial and antigenotoxic activities.
Methanolic, aqueous and Total Oligomer Flavonoids (TOF)-enriched extracts obtained from the leaves of Acacia salicina 'Lindl.' were investigated for antibacterial, antimutagenic and antioxidant activities. The antimicrobial activity was tested on the Gram positive and Gram negative reference bacterial strains. The Mutagenic and antimutagenic activities against direct acting mutagens, methylmethane sulfonate (MMS) and 4-nitro-o-phenylenediamine (NOPD), and indirect acting mutagens, 2-aminoanthracene (2-AA) and benzo[a]pyrene (B(a)P) were performed with S. typhimurium TA102 and TA98 assay systems. In addition, the enzymatic and nonenzymatic methods were employed to evaluate the anti-oxidative effects of the tested extracts. A significant effect against the Gram positive and Gram negative reference bacterial strains was observed with all the extracts. The mutagenic and antimutagenic studies revealed that all the extracts decreased the mutagenicity induced by B(a)P (7.5 μg/plate), 2-AA (5 μg/plate), MMS (1.3 mg/plate) and NOPD (10 μg/plate). Likewise, all the extracts showed an important free radical scavenging activity towards the superoxide anion generated by the xanthine/xanthine oxidase assay system, as well as high Trolox Equivalent Antioxidant Capacity (TEAC), against the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS)⁺• radical. TOF-enriched extract exhibited the highest protective effect against free radicals, direct acting-mutagen and metabolically activated S9-dependent mutagens. The present study indicates that the extracts from A. salicina leaves are a significant source of compounds with the antimutagenic and antioxidant activities, and this may be useful for developing potential chemopreventive substances.