Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: a canonical microcircuit for inhibition?
GABAergic interneurons play a major role in the function of the mammalian neocortex, but their circuit connectivity is still poorly understood. We used two-photon RuBi-Glutamate uncaging to optically map how the largest population of cortical interneurons, the parvalbumin-positive cells (PV+), are connected to pyramidal cells (PCs) in mouse neocortex. We found locally dense connectivity from PV+ interneurons onto PCs across cortical areas and layers. In many experiments, all nearby PV+ cells were connected to every local PC sampled. In agreement with this, we found no evidence for connection specificity, as PV+ interneurons contacted PC pairs similarly regardless of whether they were synaptically connected or not. We conclude that the microcircuit architecture for PV+ interneurons, and probably neocortical inhibition in general, is an unspecific, densely homogenous matrix covering all nearby pyramidal cells.


Humoral hypercalcemia caused by a rat Leydig-cell tumor is associated with suppressed parathyroid hormone secretion and increased urinary cAMP excretion.
We studied the effect of a transplantable Leydig-cell tumor (Rice H-500) on serum calcium, parathyroid hormone (PTH), and urinary cAMP in intact Fischer-344 rats. The tumor caused rapid and severe hypercalcemia (control = 10.5 +/- 0.1 mg/dl [mean +/- S.E.] vs. 14.6 +/- 0.9 at day 12 post tumor inoculation) without evidence of metastasis. Progressive renal impairment and death generally occurred within 15 days of tumor inoculation. Serum PTH declined from control values before hypercalcemia occurred and was significantly reduced in tumor-bearing hypercalcemic rats (mean = 60 +/- 8% of control values). Urinary cAMP excretion was increased in tumor-bearing rats (mean at day 12 post inoculation = 12.2 +/- 1.4 nmol/dl creatinine clearance vs. control = 6.2 +/- 0.2) and correlated positively with serum calcium. The Rice H-500 Leydig-cell tumor appears to secrete a humoral factor capable of causing hypercalcemia. This factor may also increase urinary cAMP excretion in a manner analogous to PTH, but it is not detected by PTH radioimmunoassay.


Primary tumour immune response and lymph node yields in colon cancer.
The mechanism underlying improved survival in non-metastatic colon cancer with higher lymph node (LN) yield is unknown. This study aimed to identify whether molecular features in the primary tumour were predictive of LN yield. Clinical, genomic, transcriptomic, proteomic and methylation data of non-metastatic, colon cancers studied in The Cancer Genome Atlas were interrogated for associations with LN yield. Based on maximal survival effects, patients were segregated into high (>15) and low (≤15) LN yield. Gene set enrichment analysis was performed on transcriptomic changes to identify biological processes associated with LN yield. Correlations were validated in an independent set of Stage II colon cancers. High LN yield was found predictive of overall and disease-free survival. There was no association of higher LN yield and increasing nodal positivity. High LN yield was strongly linked with gene expression changes associated with the adaptive and dendritic cell immune response. This association was most prominent in node-negative cancers. Analogous findings were reproduced in the validation dataset. The study shows a strong association of an activated immune response in tumours with a high LN yield. Immunogenic tumours have a better prognosis, likely explaining the survival benefit with higher LN yields.


Characterization of clonogenic multiple myeloma cells.
The identity of the cells responsible for the initiation and maintenance of multiple myeloma (MM) remains unclear largely because of the difficulty growing MM cells in vitro and in vivo. MM cell lines and clinical specimens are characterized by malignant plasma cells that express the cell surface antigen syndecan-1 (CD138); however, CD138 expression is limited to terminally differentiated plasma cells during B-cell development. Moreover, circulating B cells that are clonally related to MM plasma cells have been reported in some patients with MM. We found that human MM cell lines contained small (< 5%) subpopulations that lacked CD138 expression and had greater clonogenic potential in vitro than corresponding CD138+ plasma cells. CD138- cells from clinical MM samples were similarly clonogenic both in vitro and in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, whereas CD138+ cells were not. Furthermore, CD138- cells from both cell lines and clinical samples phenotypically resembled postgerminal center B cells, and their clonogenic growth was inhibited by the anti-CD20 monoclonal antibody rituximab. These data suggest that MM "stem cells" are CD138- B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells.


Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.
The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction). Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma. Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.


The validity and reliability of 1-Hz and 5-Hz global positioning systems for linear, multidirectional, and soccer-specific activities.
The study aimed to analyze the validity and reliability of commercially available nondifferential Global Positioning System (NdGPS) devices for measures of total distance during linear, multidirectional and soccer-specific motion at 1-Hz and 5-Hz sampling frequencies. Linear (32 trials), multidirectional (192 trials) and soccer-specific courses (40 trials) were created to test the validity (mean ± 90% confidence intervals), reliability (mean ± 90% confidence intervals) and bias (mean ± 90% confidence intervals) of the NdGPS devices against measured distance. Standard error of the estimate established validity, reliability was determined using typical error and percentage bias was established. The 1-Hz and 5-Hz data ranged from 1.3% ± 0.76 to 3.1% ± 1.37 for validity and 2.03% ± 1.31 to 5.31% ± 1.2 for reliability for measures of linear and soccer-specific motion. For multidirectional activity, data ranged from 1.8% ± 0.8 to 6.88% ± 2.99 for validity and from 3.08% ± 1.34 to 7.71% ± 1.65 for reliability. The 1-Hz underestimated some complex courses by up to 11%. 1-Hz and 5-Hz NdGPS could be used to quantify distance in soccer and similar field-based team sports. Both 1-Hz and 5-Hz have a threshold beyond which reliability is compromised. 1-Hz also underestimates distance and is less valid in more complex courses.


[The use of transgenic animals in biomedical research in Germany. Part 2: Ethical evaluation of the use of transgenic animals in biomedical research and perspectives for the changeover in research to research animal-free methods].
As a rule, transgenic animals are being used in in vivo experiments to examine gene functions, their regulation or the contribution of genetic alterations to the development of diseases. Many transgenic animals already are affected in their wellbeing due to the genetic modification alone regardless of the procedures performed with them. Moreover, it is to be questioned whether the experimental use of transgenic animals led to results that were of such outstanding scientific relevance that they legitimated the suffering of the animals. In order to point to possible approaches to avoiding the use of transgenic animals in the areas of research identified, subsequent investigations aimed at collecting information on non-animal test methods that might be applied in pursuing the aforesaid questions. In particular, these were non-animal test methods that make use of genetic techniques. Amongst these are in vitro cell culture methods with genetically modified cells, such as the so called Transfected Cell Array, as well as in vitro test methods, in which specifically targeted genes can be turned on or off selectively for example by the so-called RNA interference technique or by antisense oligonucleotide genes. Since such technologies can also be applied to cell cultures with human cells, investigations with these methods enable direct information on the function of human genes. Even though a one to one replacement of animal experiments with transgenic animals by non-animal test methods is considered unlikely, from the point of view of animal welfare the broad spectrum of already available non animal test methods with which to study the function of genes and genetically caused pathophysiological reactions proves that waiving of animal tests with transgenic animals is possible without impeding biomedical research. Even if it cannot be totally excluded that some very specific questions linked to the respective animal experiment might not be pursued for the time being, nevertheless research that would be restricted to modern and ethically acceptable in vitro test methods would certainly conceive its very own questions to pursue and solve the problems currently faced by biomedical research. It is against this background that it is to be welcomed that the German Federal Government currently actively promotes the further development of genetechnological non-animal test methods. In order to ensure that these funding measures will make an effective contribution to reducing animal experiments, as spelled out by the government itself, the conversion of genetechnological research, just like biomedical research as a whole, to non-animal testing methods should be supported by concrete political actions. From the point of view of the German Animal Welfare Federation the following issues are to be requested: (1)In order to enable a fast and comprehensive advancement of promising genetechnological non-animal test methods, it should be ensured that public funding is provided with an adequate budget and over a sufficiently long period of time. (2)The legislator should initiate broad discussions on the question if society would be willing to dispense with certain pieces of knowledge if they would necessarily have to be gained at the expense of a certain degree of animal suffering. As the case may be, in the German Animal Welfare Act it should be laid down that certain procedures should not be considered acceptable as such. (3)As long as animal experiments with transgenic animals continue to be performed, concrete legal measures should be laid down in the German Animal Welfare Act to ensure that the distress of the animals (taking into account all factors relevant for transgenic animals) and the expected benefit of the research project are determined objectively so that the outcome of the ethical evaluation process becomes comprehensible. (4)The legislator should provide the authorities responsible for the licensing of research projects with concrete instructions in order to ensure that all aspects relevant for the welfare of the animals are fully taken into account when evaluating the ethical acceptability and scientific indispensability of projects and that special attention is given to research projects with transgenic animals. (5)The German Decree on the Reporting of Laboratory Animals should be amended to ensure that all individual transgenic animals are included in the official statistical reports regardless of whether they end up being used in scientific procedures or not. From the point of view of animal welfare it is possible to redesign biomedical research to do without transgenic animals without impeding necessary scientific progress. The survey in hand sought to make a contribution to providing a scientifically sound background for initiating these discussions.


Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders.
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.


Laparoscopic Hiatal Hernia Repair in 221 Patients: Outcomes and Experience.
Hiatal hernia is a common condition often associated with symptomatic gastroesophageal reflux disease (GERD). The objectives of this study were to examine the efficacy and safety of laparoscopic hiatal hernia repair (LHHR) with biologic mesh to reduce and/or alleviate GERD symptoms and associated hiatal hernia recurrence. We retrospectively reviewed consecutive LHHR procedures with biologic mesh performed by a single surgeon from July 2009 to October 2014. The primary efficacy outcome measures were relief from GERD symptoms, as measured according to the GERD-health-related quality-of-life (GERD-HRQL) scale and hiatal hernia recurrence. A secondary outcome measure was overall safety of the procedure. A total of 221 patients underwent LHHR with biologic mesh during the study period, and pre- and postoperative GERD-HRQL studies were available for 172 of them. At baseline (preoperative), the mean GERD-HRQL score for all procedures was 18.5 ± 14.4. At follow-up (mean, 14.5 ± 11.0 months [range, 2.0-56.0]), the score showed a statistically significant decline to a mean of 4.4 ± 7.5 (P < .0001). To date, 8 patients (3.6%, 8/221) have had a documented anatomic hiatal hernia recurrence. However, a secondary hiatal hernia repair reoperation was necessary in only 1 patient. Most complications were minor (dysphagia, nausea and vomiting). However, there was 1 death caused by a hemorrhage that occurred 1 week after surgery. Laparoscopic hiatal hernia repair using biologic mesh, both with and without a simultaneous bariatric or antireflux procedure, is an efficacious and safe therapeutic option for management of hiatal hernia, prevention of recurrence, and relief of symptomatic GERD.


Destabilization of fast-ion-induced long sawteeth by localized current drive in the JET tokamak.
In a tokamak fusion reactor the energetic alpha particles will transiently stabilize the magnetohydrodynamic activity causing sawtooth oscillations. The crash events terminating long sawtooth free periods can provide seed islands for neoclassical tearing modes [Phys. Rev. Lett. 88, 105001 (2002)]]. To shorten the sawtooth periods localized current drive near the q=1 surface is a possibility. This Letter provides the first experimental evidence for the effectiveness of this method in the different physics regime associated with fast-ion-induced long sawteeth on the JET tokamak.


Modeling gross primary production of agro-forestry ecosystems by assimilation of satellite-derived information in a process-based model.
In this paper we present results obtained in the framework of a regional-scale analysis of the carbon budget of poplar plantations in Northern Italy. We explored the ability of the process-based model BIOME-BGC to estimate the gross primary production (GPP) using an inverse modeling approach exploiting eddy covariance and satellite data. We firstly present a version of BIOME-BGC coupled with the radiative transfer models PROSPECT and SAILH (named PROSAILH-BGC) with the aims of i) improving the BIOME-BGC description of the radiative transfer regime within the canopy and ii) allowing the assimilation of remotely-sensed vegetation index time series, such as MODIS NDVI, into the model. Secondly, we present a two-step model inversion for optimization of model parameters. In the first step, some key ecophysiological parameters were optimized against data collected by an eddy covariance flux tower. In the second step, important information about phenological dates and about standing biomass were optimized against MODIS NDVI. Results obtained showed that the PROSAILH-BGC allowed simulation of MODIS NDVI with good accuracy and that we described better the canopy radiation regime. The inverse modeling approach was demonstrated to be useful for the optimization of ecophysiological model parameters, phenological dates and parameters related to the standing biomass, allowing good accuracy of daily and annual GPP predictions. In summary, this study showed that assimilation of eddy covariance and remote sensing data in a process model may provide important information for modeling gross primary production at regional scale.


Exercise and depressive symptoms in adolescents: a longitudinal cohort study.
Physical activity (PA) may have a positive effect on depressed mood. However, whether it can act as a protective factor against developing depressive symptoms in adolescence is largely unknown. To investigate the association between objectively measured PA and depressive symptoms during 3 years of adolescence. We performed a longitudinal study between November 1, 2005, and January 31, 2010, of a community-based sample from Cambridgeshire and Suffolk, United Kingdom, that included 736 participants (mean [SD] age, 14.5 years [6 months]). The follow-up period was approximately 3 years after baseline (the ROOTS study). Linear regression models were fitted using physical activity energy expenditure (PAEE) and moderate and vigorous physical activity (MVPA) as the predictors and depressive symptoms as the outcome variable. Binomial logistic regression models were also fitted using PAEE and MVPA as the predictors and clinical depression as the outcome measure. Exercise. Individually calibrated heart rate and movement sensing were used to measure PA at baseline only. Physical activity summary measures included total PAEE and time spent in MVPA. These measures were divided into weekend and weekday activity. All participants also completed the Mood and Feelings Questionnaire, a self-report measure of current depressive symptoms, and took part in a Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview at baseline and 3 years later. Depressive symptoms at 3-year follow-up were not significantly predicted by any of the 4 PA measures at baseline: weekend MVPA (unstandardized β = 0.02; 95% CI, -0.15 to 0.20; P = .79), weekday MVPA (β = 0.00; 95% CI, -0.17 to 0.17; P = .99), weekend PAEE (β = 0.03; 95% CI, -0.14 to 0.20; P = .75), and weekday PAEE (β = -0.03; 95% CI, -0.20 to 0.14; P = .71). This was also true for major depressive disorder diagnoses at follow-up: weekend MVPA (odds ratio [OR], 1.37; 95% CI, 0.76-2.48; P = .30), weekday MVPA (OR, 1.33; 95% CI, 0.74-2.37; P = .34), weekend PAEE (OR, 1.19; 95% CI, 0.67-2.10; P = .56), and weekday PAEE (OR, 0.92; 95% CI, 0.52-1.63; P = .78). No longitudinal association between objectively measured PA and the development of depressive symptoms was observed in this large population-based sample. These results do not support the hypothesis that PA protects against developing depressive symptoms in adolescence.


ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis.
To examine the expression of ADAMTS-7 during the progression of osteoarthritis (OA), defining its role in the pathogenesis of OA, and elucidating the molecular events involved. ADAMTS-7 expression in cartilage of a rat OA model was assayed using immunohistochemistry. Cartilage-specific ADAMTS-7 transgenic mice and ADAMTS-7 small interfering (si)RNA knockdown mice were generated and used to analyse OA progression in both spontaneous and surgically induced OA models. Cartilage degradation and OA was evaluated using Safranin-O staining, immunohistochemistry, ELISA and western blotting. In addition, mRNA expression of tumour necrosis factor (TNF)-α and metalloproteinases known to be involved in cartilage degeneration in OA was analysed. Furthermore, the transactivation of ADAMTS-7 by TNF-α and its downstream NF-κB signalling was measured using reporter gene assay. ADAMTS-7 expression was elevated during disease progression in the surgically induced rat OA model. Targeted overexpression of ADAMTS-7 in chondrocytes led to chondrodysplasia characterised by short-limbed dwarfism and a delay in endochondral ossification in 'young mice' and a spontaneous OA-like phenotype in 'aged' mice. In addition, overexpression of ADAMTS-7 led to exaggerated breakdown of cartilage and accelerated OA progression, while knockdown of ADAMTS-7 attenuated degradation of cartilage matrix and protected against OA development, in surgically induced OA models. ADAMTS-7 upregulated TNF-α and metalloproteinases associated with OA; in addition, TNF-α induced ADAMTS-7 through NF-κB signalling. ADAMTS-7 and TNF-α form a positive feedback loop in the regulation of cartilage degradation and OA progression, making them potential molecular targets for prevention and treatment of joint degenerative diseases, including OA.


Comparison of surgical bypass with angioplasty and stenting of superficial femoral artery disease.
To evaluate the contemporary outcome of femoral-popliteal bypass compared with angioplasty and stenting in patients with symptomatic peripheral arterial disease (PAD) in terms of patency and reintervention rates. We identified all patients evaluated at the Johns Hopkins Bayview Medical Center with the presumptive diagnosis of PAD from September 2005 to September 2010. In this group, we selected all symptomatic patients after failing medical management who received percutaneous transluminal angioplasty/stenting of the superficial femoral artery or femoral-popliteal bypass. We compared the overall patency and reintervention rates between the two groups as well as patency within TransAtlantic Inter-Society Consensus (TASC) II subgroups. Descriptive analyses were performed using χ(2) and two-sided t-tests. The Mann-Whitney U test was used to compare distributions of continuous variables and the Fisher exact test for categorical variables. Cox proportional hazard model was used to examine the treatment effect within each lesion type, using bypass as the reference group. Out of 1237 patients evaluated at Johns Hopkins Bayview Medical Center for PAD from September 2005 to September 2010, we identified 104 symptomatic patients who received percutaneous transluminal angioplasty/stenting of the superficial femoral artery or femoral-popliteal bypass after failing medical management. There were 61 male patients (56%), and the mean age was 68 years in both groups. Both treatment groups had similar risk factors. Overall, 77% of patients with TASC II A and B lesions underwent angioplasty and stenting, whereas 73% of patients with TASC C and D lesions underwent bypass (P < .01). The primary patency at 24 months was better for the stent group 67% (95% confidence interval [CI], 0.52-0.78) vs bypass group 49% (95% CI, 0.32-0.64; P = .05). The rate of reintervention within the 2-year period was higher in the bypass group compared with the stent group (54% vs 31%; P = .02). TASC A and B lesions combined demonstrated a reduced hazard of patency failure compared with TASC C or D lesions combined (hazard ratio, 2.42; 95% CI, 1.26, 4.65; P < .01). This is the first study that documents higher reintervention rates for femoral-popliteal bypass compared with angioplasty and stenting. We believe that the main reason for this finding is the fact that the bypass patients had significantly more advanced disease. This, emphasizes that one must consider the patient population undergoing intervention when comparing revascularization procedures. A prospective randomized trial is needed to determine the overall better treatment option.


BAD, a proapoptotic member of the BCL2 family, is a potential therapeutic target in hepatocellular carcinoma.
Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib.


The Trajectory of Nutritional Status and Physical Activity before and after Transcatheter Aortic Valve Implantation.
It is suggested that older patients waiting for an elective surgical procedure have a poor nutritional status and low physical activity level. It is unknown if this hypothesis is true and if these conditions improve after a medical procedure. We aimed to determine the trajectory of both conditions before and after transcatheter aortic valve implantation (TAVI). Included patients (n = 112, age 81 ± 5 years, 58% male) received three home visits (preprocedural, one and six months postprocedural). Nutritional status was determined with the mini nutritional assessment—short form (MNA-SF) and physical activity using an ankle-worn monitor (Stepwatch). The median MNA-SF score was 13 (11−14), and 27% of the patients were at risk of malnutrition before the procedure. Physical activity was 6273 ± 3007 steps/day, and 69% of the patients did not meet the physical activity guidelines (>7100 steps/day). We observed that nutritional status and physical activity did not significantly change after the procedure (β 0.02 [95% CI −0.03, 0.07] points/months on the MNA-SF and β 16 [95% CI −47, 79] steps/month, respectively). To conclude, many preprocedural TAVI patients should improve their nutritional status or activity level. Both conditions do not improve naturally after a cardiac procedure.


Pharmacokinetics and pharmacodynamics of drug interactions involving HIV-1 protease inhibitors.
Therapeutic agents used to inhibit the HIV-1 protease are integral to the effective suppression of HIV virus replication by use of synergistic combination therapy. This is inherently dependent on the achievement of effective plasma concentrations of the drug in its active form, and sustaining such levels for the duration of a dosing interval without exceeding thresholds of toxicity. The issues determining the absorption, biotransformation, distribution to and activity at the intended site, and elimination, are myriad and complex. Studies at molecular, cell, and tissue levels are useful for predicting the possible fate of these agents at in vivo, but the wide interindividual variability shown in whole-body pharmacokinetic studies is illustrative of the difficulty in making general statements rather than more guarded recommendations. This paper summarizes the current state of understanding of the major interactions between protease inhibitors themselves and other important commonly used agents in the management of HIV disease, based on data from clinical pharmacokinetic studies.


Biomaterials: where we have been and where we are going.
Since its inception just over a half century ago, the field of biomaterials has seen a consistent growth with a steady introduction of new ideas and productive branches. This review describes where we have been, the state of the art today, and where we might be in 10 or 20 years. Herein, we highlight some of the latest advancements in biomaterials that aim to control biological responses and ultimately heal. This new generation of biomaterials includes surface modification of materials to overcome nonspecific protein adsorption in vivo, precision immobilization of signaling groups on surfaces, development of synthetic materials with controlled properties for drug and cell carriers, biologically inspired materials that mimic natural processes, and design of sophisticated three-dimensional (3-D) architectures to produce well-defined patterns for diagnostics, e.g., biological microelectromechanical systems (bioMEMs), and tissue engineering.


CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD.
Regulatory T cells (Tregs) play essential roles in maintaining immunological self-tolerance and preventing autoimmunity. The adoptive transfer of antigen-specific Tregs has been expected to be a potent therapeutic method for autoimmune diseases, severe allergy, and rejection in organ transplantation. However, effective Treg therapy has not yet been established because of the difficulty in preparing a limited number of antigen-specific Tregs. Chimeric antigen receptor (CAR) T cells have been shown to be a powerful therapeutic method for treating B cell lymphomas, but application of CAR to Treg-mediated therapy has not yet been established. Here, we generated CD19-targeted CAR (CD19-CAR) Tregs from human PBMCs (hPBMCs) and optimized the fraction of the Treg source as CD4+CD25+CD127loCD45RA+CD45RO-. CD19-CAR Tregs could be expanded in vitro while maintaining Treg properties, including high expression of the latent form of TGF-β. CD19-CAR Tregs suppressed IgG antibody production and differentiation of B cells via a TGF-β-dependent mechanism. Unlike conventional CD19-CAR CD8+ T cells, CD19-CAR Tregs suppressed antibody production in immunodeficient mice that were reconstituted with hPBMCs, reducing the risk of graft-versus-host disease. Therefore, the adoptive transfer of CD19-CAR Tregs may provide a novel therapeutic method for treating autoantibody-mediated autoimmune diseases.


S. mansoni bolsters anti-viral immunity in the murine respiratory tract.
The human intestinal parasite Schistosoma mansoni causes a chronic disease, schistosomiasis or bilharzia. According to the current literature, the parasite induces vigorous immune responses that are controlled by Th2 helper cells at the expense of Th1 helper cells. The latter cell type is, however, indispensable for anti-viral immune responses. Remarkably, there is no reliable literature among 230 million patients worldwide describing defective anti-viral immune responses in the upper respiratory tract, for instance against influenza A virus or against respiratory syncitial virus (RSV). We therefore re-examined the immune response to a human isolate of S. mansoni and challenged mice in the chronic phase of schistosomiasis with influenza A virus, or with pneumonia virus of mice (PVM), a mouse virus to model RSV infections. We found that mice with chronic schistosomiasis had significant, systemic immune responses induced by Th1, Th2, and Th17 helper cells. High serum levels of TNF-α, IFN-γ, IL-5, IL-13, IL-2, IL-17, and GM-CSF were found after mating and oviposition. The lungs of diseased mice showed low-grade inflammation, with goblet cell hyperplasia and excessive mucus secretion, which was alleviated by treatment with an anti-TNF-α agent (Etanercept). Mice with chronic schistosomiasis were to a relative, but significant extent protected from a secondary viral respiratory challenge. The protection correlated with the onset of oviposition and TNF-α-mediated goblet cell hyperplasia and mucus secretion, suggesting that these mechanisms are involved in enhanced immune protection to respiratory viruses during chronic murine schistosomiasis. Indeed, also in a model of allergic airway inflammation mice were protected from a viral respiratory challenge with PVM.


A critical compilation of Henry's law constant temperature dependence relations for organic compounds in dilute aqueous solutions.
A comprehensive compilation of published studies reporting directly measured experimental determinations of Henry's law constant (HLC) temperature dependence relationships for organic compounds in dilute, non-saline aqueous solutions under ambient conditions was conducted. From this effort, 55 such studies (covering 204 organic compounds) were identified, critically reviewed, summarized and discussed. Of the 204 compounds, 57 were studied in more than one investigation. For the 57 'multi-studied' compounds, relatively good agreement (averaging within 20-30%) was found between the results from different investigations. Given such results, a 'consensus' relationship (i.e., an average temperature dependence relation) was generated for each of the multi-studied compounds. Overall, considering relations established for 197 of the 204 compounds investigated (the results for the other 7 compounds being excluded due to poor correlation coefficients), the average slope of the temperature dependence line was found to correspond to an increase in HLC values by a factor of 1.88 (i.e., an 88% increase) per 10 degrees C rise in temperature (thermodynamically equivalent to an average enthalpy of volatilization of 47 kJ/mole). The associated range found for the temperature dependence slope corresponds to an increase in HLC values by a factor ranging from 1.12 to 3.55 (i.e., a 12-255% increase) per 10 degrees C rise (equivalent enthalpy of volatilization range: 8-93 kJ/mole). The wide range of slope values found indicates that serious errors may result if one applies the commonly cited 'rule of thumb' that HLC values double per 10 degrees C rise in temperature to a specific compound. In light of this finding, when faced with a lack of data, a prudent course for practitioners to take appears to be conducting a laboratory study to determine the exact temperature dependence for the compound(s) of interest.


Recent developments in prognostic and predictive testing in uveal melanoma.
To provide an update on the rapidly evolving methods for assessing prognosis and predicting response to targeted molecular therapy in uveal melanoma. The techniques for assessing prognosis in uveal melanoma have evolved from simple physical features, such as tumor size, location, and cell morphology, to the slightly more sophisticated counting of chromosomal gains and losses. More recently, gene expression profiling has provided a highly accurate and biologically informative gold standard for molecular prognostication. The latest step in the evolution of molecular testing has been the recent discovery of major driver mutations that allow predictive testing of response to targeted molecular therapies. Mutations in GNAQ and GNA11 are early events that promote cell proliferation, and these mutations are sensitive to MAPK kinase, PKC, and AKT inhibitors. Mutations in BAP1, SF3B1, and EIF1AX are later events that are largely mutually exclusive. Mutations in BAP1 are strongly associated with metastasis, whereas those in SF3B1 and EIF1AX are associated with good prognosis. Uveal melanomas with BAP1 mutations demonstrate sensitivity to epigenetic modulators, such as histone deacetylase inhibitors. Clinical trials are now available to evaluate the efficacy of these targeted molecular agents in patients with uveal melanoma. Molecular prognostic testing and enrollment of high-risk patients into clinical trials of targeted molecular therapy are rapidly becoming the standard of care in the management of uveal melanoma.


Diastereoselective synthesis of epoxide-fused benzoquinolizidine derivatives using intramolecular domino aza-Michael addition/Darzens reaction.
An efficient and diastereoselective strategy based on an intramolecular domino aza-Michael/Darzens reaction to synthesize epoxide-fused benzoquinolizidines has been described. Three bonds (1 C-C, 1 C-N and 1 C-O), three rings and three chiral centers can be constructed in a single pot under very mild conditions. All the products were isolated in only one diastereomer with 40-80% yields.


Destabilization of the VCP-Ufd1-Npl4 complex is associated with decreased levels of ERAD substrates.
p97/VCP associated with Ufd1-Npl4 is considered a key player in ER-associated degradation (ERAD). RNA interference (RNAi) of one component of the Ufd1-Npl4 heterodimer destabilizes the VCP-Ufd1-Npl4 complex inducing proteasome-dependent degradation of the other component and releasing free VCP. In contrast to RNAi of VCP, RNAi of Ufd1 or Npl4 depleting approximately 90% of the VCP-Ufd1-Npl4 complexes does not induce unfolded protein response, indicating that the Ufd1-Npl4 dimer is not involved in the regulation of ER function by VCP. RNAi of Ufd1 or Npl4 is associated with a 2-fold increase in the levels of polyubiquitinated proteins, which form dispersed aggregates often associated with calnexin-positive structures. However, contrary to the effects of proteasome inhibition, RNAi of Ufd1 or Npl4 does not induce an accumulation of alpha-TCR and delta-CD3, two ERAD substrates overexpressed in HeLa cells. Instead, a 60-70% decrease in their levels is observed. The decrease in alpha-TCR levels is associated with a 50% decrease of its half-life. Upregulation of the putative channel forming protein, derlin-1, may contribute to the increased degradation of ERAD substrates. To explain our findings, we propose a model, where association of emerging ERAD substrates with VCP-Ufd1-Npl4 is not required for their degradation but has a regulatory role.


Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia.
To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia. Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m(2)/d (3.6 mg/m(2)/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined. Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m(2)/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m(2). Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease. Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.


Human cytosolic 5'-nucleotidase I: characterization and role in nucleoside analog resistance.
Nucleoside analogs are important in the treatment of hematologic malignancies, solid tumors, and viral infections. Their metabolism to the triphosphate form is central to their chemotherapeutic efficacy. Although the nucleoside kinases responsible for the phosphorylation of these compounds have been well described, the nucleotidases that may mediate drug resistance through dephosphorylation remain obscure. We have cloned and characterized a novel human cytosolic 5'-nucleotidase (cN-I) that potentially may have an important role in nucleoside analog metabolism. It is expressed at a high level in skeletal and heart muscle, at an intermediate level in pancreas and brain, and at a low level in kidney, testis, and uterus. The recombinant cN-I showed high affinity toward dCMP and lower affinity toward AMP and IMP. ADP was necessary for maximal catalytic activity. Expression of cN-I in Jurkat and HEK 293 cells conferred resistance to 2-chloro-2'-deoxyadenosine, with a 49-fold increase in the IC(50) in HEK 293 and a greater than 400-fold increase in the IC(50) in Jurkat cells. Expression of cN-I also conferred a 22-fold increase in the IC(50) to 2',3'-difluorodeoxycytidine in HEK 293 cells and an 82-fold increase in the IC(50) to 2',3'-dideoxycytidine in Jurkat cells. These data indicate that cN-I may play an important role in the regulation of physiological pyrimidine nucleotide pools and may also alter the therapeutic efficacy of certain nucleoside analogs.


Clinical aspects of hantavirus infections in Bulgaria.
Hantaviruses cause two distinct human diseases: hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus pulmonary syndrome (HPS) in America. In Europe, mainly Puumala, Dobrava and Seoul viruses cause HFRS. A total of 23 cases of HFRS were detected in Bulgaria over a 2‑year period 2013-2014. The aim of the study was to present epidemiology, clinical manifestations and laboratory findings of these patients. Patients with HFRS were diagnosed using PCR, ELISA and immunoblotting tests. Dobrava-Belgrade virus (DOBV) was revealed as etiological agent in 16 (69.6%) patients and Puumala virus (PUUV) in 7 (30.4%) patients. All 23 patients were men aged 22-66 years of which 6 (26.1%) patients originated from regions in northern and western Bulgaria previously thought to be non-endemic. Patients with HFRS, despite the infecting hantavirus, manifested acute renal failure, asthenia and less pronounced hemorrhagic syndrome. Patients with DOBV infection were much more likely to present with arthromyalgia, severe headache, severe to moderately severe asthenoadynamia, abdominal pain, vomiting, hypotension, nervous system disorders as well as kidney enlargement, leucopenia and higher levels of blood creatinine, requiring hemodialysis procedures more often and for a longer period of time than patients with PUUV infection. The present report describes for the first time comparative analysis of epidemiological features, clinical manifestations and laboratory findings of DOBV and PUUV infections in Bulgaria.


Spatial variation of au coverage as the driving force for nanoscopic pattern formation.
Au induced faceting of a 4 degrees vicinal Si(001) surface was studied with chemical resolution using soft x-ray photoemission electron microscopy. For the first time a direct and quantitative determination of the local Au coverage in situ and during deposition was possible. Au atoms, necessary for the expansion of (001) terraces, are accummulated from a lattice gas, resulting in a phase separation between Au enriched terraces and Au depleted step bunches. During a second stage Au also adsorbs on the step bunches and transforms them into (119) facets. A simple Monte Carlo simulation shows that the initial coverage difference between terraces and bunches determines the regularity of the formed mesoscopic grating.


Dimethyl fumarate (DMF) vs. monoethyl fumarate (MEF) salts for the treatment of plaque psoriasis: a review of clinical data.
Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.


Quantum-dot-based cell motility assay.
Because of their favorable physical and photochemical properties, colloidal CdSe/ZnS-semiconductor nanocrystals (commonly known as quantum dots) have enormous potential for use in biological imaging. In this report, we present an assay that uses quantum dots as markers to quantify cell motility. Cells that are seeded onto a homogeneous layer of quantum dots engulf and absorb the nanocrystals and, as a consequence, leave behind a fluorescence-free trail. By subsequently determining the ratio of cell area to fluorescence-free track area, we show that it is possible to differentiate between invasive and noninvasive cancer cells. Because this assay uses simple fluorescence detection, requires no significant data processing, and can be used in live-cell studies, it has the potential to be a powerful new tool for discriminating between invasive and noninvasive cancer cell lines or for studying cell signaling events involved in migration.


Specificity and sensitivity of chest radiographs in the diagnosis of paediatric pulmonary tuberculosis and the value of additional high-kilovolt radiographs.
Tuberculosis (TB) remains the most common notifiable infectious disease in South Africa. The diagnosis of pulmonary TB in children is often very difficult because of the non-specific radiological signs and inter-observer variation in the interpretation of radiographs. The frontal high-kilovolt (kV) radiograph has been used to assess the effect of TB adenopathy on the tracheobronchial tree and to detect endobronchial lesions. The aims of the present study were to assess the specificity and sensitivity of chest radiographs in the diagnosis of pulmonary TB and to assess whether the addition of the high-kV radiograph affects these parameters. The study group consisted of paediatric patients suspected of having pulmonary TB over a 6-year period. These patients had clinical, bacteriological and radiographic examinations. Radiographs were examined by one experienced radiologist in two sittings separated by a 6-week interval. On the first sitting, only standard radiographs were examined and, on the second sitting, these were supplemented with high-kV radiographs. Differences in the detection of each recognized radiological feature of pulmonary TB before and after the addition of the high-kV film were analysed for statistical significance. The frequency of radiographic findings in our study compared favourably with other reports. No statistically significant differences for the detection of radiographic features consistent with pulmonary TB, or for the diagnosis of pulmonary TB, were demonstrated between the two sittings. Specificity increased from 74.4% to 86.6% with the addition of the high-kV view and sensitivity remained constant at 38.8%. The present study does not support the routine use of the frontal high-kV radiograph for the diagnosis of pulmonary TB. This paper also confirms the findings of others, that standard chest radiographs are a poor indicator of pulmonary TB in children.


Cryo-EM structure of a 3D DNA-origami object.
A key goal for nanotechnology is to design synthetic objects that may ultimately achieve functionalities known today only from natural macromolecular complexes. Molecular self-assembly with DNA has shown potential for creating user-defined 3D scaffolds, but the level of attainable positional accuracy has been unclear. Here we report the cryo-EM structure and a full pseudoatomic model of a discrete DNA object that is almost twice the size of a prokaryotic ribosome. The structure provides a variety of stable, previously undescribed DNA topologies for future use in nanotechnology and experimental evidence that discrete 3D DNA scaffolds allow the positioning of user-defined structural motifs with an accuracy that is similar to that observed in natural macromolecules. Thereby, our results indicate an attractive route to fabricate nanoscale devices that achieve complex functionalities by DNA-templated design steered by structural feedback.


Modification point depth and genome growth in genetic programming.
The evolutionary computation community has shown increasing interest in arbitrary-length representations, particularly in the field of genetic programming. A serious stumbling block to the scalability of such representations has been bloat: uncontrolled genome growth during an evolutionary run. Bloat appears across the evolutionary computation spectrum, but genetic programming has given it by far the most attention. Most genetic programming models explain this phenomenon as a result of the growth of introns, areas in an individual which serve no functional purpose. This paper presents evidence which directly contradicts intron theories as applied to tree-based genetic programming. The paper then uses data drawn from this evidence to propose a new model of genome growth. In this model, bloat in genetic programming is a function of the mean depth of the modification (crossover or mutation) point. Points far from the root are correspondingly less likely to hurt the child's survivability in the next generation. The modification point is in turn strongly correlated to average parent tree size and to removed subtree size, both of which are directly linked to the size of the resulting child.


Behavioural risks in male dogs with minimal lifetime exposure to gonadal hormones may complicate population-control benefits of desexing.
Castration of dogs is a widespread practise with clear justification in population control and knock-on benefits for animal welfare. Deleterious behavioural consequences of castration are believed to be negligible. Gonadectomy is widely recommended as part of a multi-factorial approach to prevent problems including aggression in dogs. However, the consequences of early castration on health are still being debated. The current study focused on the reported behaviour of 6,235 male dogs castrated before 520 weeks of life for reasons other than behavioural management, and calculated their percentage lifetime exposure to gonadal hormones (PLGH) as a proportion of their age at the time of being reported to the online Canine Behavioral Assessment and Research Questionnaire (C-BARQ). Forty behaviors differed between entire and castrated dogs, of which 25 were associated with PLGH and 14 with age-at-castration (AAC). Only 2 behaviours, indoor urine marking and howling when left alone, were significantly more likely in dogs with longer PLGH. In contrast, longer PLGH was associated with significantly reduced reporting of 26 (mostly unwelcome) behaviours. Of these, 8 related to fearfulness and 7 to aggression. The current data suggest that dogs' tendency to show numerous behaviours can be influenced by the timing of castration. They indicate how dog behaviour matures when gonadal hormones are allowed to have their effect. The differences reported here between undesirable behaviours of castrated and intact dogs were in the range of 5.04% and 12.31%, suggesting that, for some dogs, partial or complete denial of puberty may reduce indoor urine-marking but have many other undesirable consequences. Veterinarians may use these data to discuss unwelcome consequences with owners of male dogs before castration.


The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue.
Recently, the existence of significant deposits of brown adipose tissue (BAT) in human adults was confirmed. Its role in the human metabolism is unknown but could be substantial. Inhibition of the cannabinoid receptor-1 (CB1) by the antagonist rimonabant (SR141716) has been associated with activation of BAT thermogenesis and weight loss in mice and rats. The role of peripheral and central CB1 in the activation of BAT merits further investigation. Here we developed a technique for quantifying CB1 in BAT by PET. Sections of rat BAT and subcutaneous white adipose tissue (WAT) were stained for CB1 and uncoupling protein-1 by immunofluorescent staining. Binding of the radiolabeled CB1 antagonist (3R,5R)-5-(3-(18F-fluoromethoxy)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)-phenyl)pyrrolidin-2-one ((18)F-FMPEP-d2) to BAT in vivo and in vitro was assessed in rats by PET. We found that CB1 was colocalized with uncoupling protein-1 in BAT, but neither protein was found in WAT. Binding of the radiotracer to BAT sections (but not WAT) in vitro was high and displaceable by pretreatment with rimonabant. Deposits of BAT in rats had significant binding of (18)F-FMPEP-d2 in vivo, indicating high CB1 density. WAT deposits were negative for (18)F-FMPEP-d2, consistent with the immunofluorescent staining and in vitro results. (18)F-FMPEP-d2 PET can quantify CB1 density noninvasively in vivo in rats. CB1 is therefore a promising surrogate imaging biomarker for assessing the presence of BAT deposits as well as for elucidating the mechanism of CB1 antagonist-mediated weight loss.


[Neuroscience of cursive handwriting: a computational appraoch].
Based on the minimum torque change model (MTCM), Wada and Kawato (1995) proposed a computational model of cursive handwriting which includes the following assumptions. The brain represents via-points that the hand passes through in a trajectory. Cursive handwriting consists of consecutive reaching movements. The via-points for handwriting are retrieved from memory during actual handwriting. Mathematically extracted via-points based on MTCM proved to be practically identical to motor primitives measured by EMG suggesting that drastic directional changes in muscle movement may be determining the location of via-points. Based on computational model, we examined the via-points in the cursive handwriting of a patient with parietal lobe involvement accompaning agraphia. While the control subject showed basically the same numbers and locations in via-points regardless of the velocity of hand movement, the patient's number and locations of via-points differed depending on the velocity of hand movement. The results suggest that the control subject retrieved necessary via-points based on the velocity of handwriting. The results also may reflect the neuropsychological nature of agraphic hand writing in a patient with parietal lobe damage.


Red Blood Cell DHA Is Inversely Associated with Risk of Incident Alzheimer's Disease and All-Cause Dementia: Framingham Offspring Study.
Docosahexaenoic acid (DHA) might help prevent Alzheimer's disease (AD). Red blood cell (RBC) status of DHA is an objective measure of long-term dietary DHA intake. In this prospective observational study conducted within the Framingham Offspring Cohort (1490 dementia-free participants aged ≥65 years old), we examined the association of RBC DHA with incident AD, testing for an interaction with APOE-ε4 carriership. During the follow-up (median, 7.2 years), 131 cases of AD were documented. In fully adjusted models, risk for incident AD in the highest RBC DHA quintile (Q5) was 49% lower compared with the lowest quintile (Q1) (Hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.27, 0.96). An increase in RBC DHA from Q1 to Q5 was predicted to provide an estimated 4.7 additional years of life free of AD. We observed an interaction DHA × APOE-ε4 carriership for AD. Borderline statistical significance for a lower risk of AD was observed per standard deviation increase in RBC DHA (HR: 0.71, 95% CI: 0.51, 1.00, p = 0.053) in APOE-ε4 carriers, but not in non-carriers (HR: 0.85, 95% CI: 0.65, 1.11, p = 0.240). These findings add to the increasing body of literature suggesting a robust association worth exploring dietary DHA as one strategy to prevent or delay AD.


Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study.
To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.


Reference data set for camera spectral sensitivity estimation.
In this article, we describe a spectral sensitivity measurement procedure at the National Physical Laboratory, London, with the aim of obtaining ground truth spectral sensitivity functions for Nikon D5100 and Sigma SD1 Merill cameras. The novelty of our data is that the potential measurement errors are estimated at each wavelength. We determine how well the measured spectral sensitivity functions represent the actual camera sensitivity functions (as a function of wavelength). The second contribution of this paper is to test the performance of various leading sensor estimation techniques implemented from the literature using measured and synthetic data and also evaluate them based on ground truth data for the two cameras. We conclude that the estimation techniques tested are not sufficiently accurate when compared with our measured ground truth data and that there remains significant scope to improve estimation algorithms for spectral estimation. To help in this endeavor, we will make all our data available online for the community.


Effect of storage temperature and media composition on the survivability of Bifidobacterium breve NCIMB 702257 in a malt hydrolisate.
The aim of this study was to evaluate the survivability of Bifidobacterium breve NCIMB 702257 in a three malt-based media supplemented with cysteine and yeast extract, and to determine the protective effect of these growth factors. A number of parameterised mathematical models were used to predict of kinetics of viability and total acidity during storage at different temperatures. Results demonstrated a good fit to the experimental mathematical model. The Arrhenius equations showed only reasonable fits and the polynomial plots contained a large area without data between 4 and 25 degrees C. In addition, it was shown that cysteine promotes growth and acid production by bifidobacteria, but does not extend survivability. On the other hand, increasing the yeast extract content of the fermentation media enhances the survivability of B. breve. To our knowledge, this is the first study to address the modelling of the survivability of probiotic bacteria in a cereal based fermentation media at different temperatures, introducing a more quantitative approach to the study of the shelf-life of a probiotic product.


Case-control analysis of the health and nutrition of orphan schoolchildren in Ethiopia.
To undertake a case-control analysis of the health, nutrition and caring practices of orphans enrolled in primary schools in Ethiopia. Pupils of both sexes aged 7-17 who were randomly selected from Grades 3 and 4 of primary school during a national survey of schoolchildren in Ethiopia and who were classified as an orphan were matched by age, sex and school with non-orphans. Logistic regression was used to compare children in terms of indicators of anthropometric and nutritional status, chronic infections, personal hygiene, diet, caring practices and self-reported sensory disability. Of the 7752 children in the national survey, 1283 (16.9%) had lost either both parents or one parent. Of these orphans, 1048 were uniquely pair matched for the case-control analysis. About 60% of orphans had lost their father, and about 20% each had lost their mother or both parents. Orphans had better anthropometric measurements and indices than non-orphans, although the differences were small, and they were less likely to have a goitre (OR = 0.68, P = 0.011). There were no differences in the odds of infections. Orphans were less likely than non-orphans to have eaten breakfast or fruit and vegetables on the previous day and were more likely to report having trouble seeing and hearing. Orphans were slight better nourished than non-orphans, but this could have been a result of asystematic bias in underestimating the age of orphans. The indicators suggested that orphans were less well cared for than non-orphans, but the differences were small.


Empirical design of a variant quality control pipeline for whole genome sequencing data using replicate discordance.
The success of next-generation sequencing depends on the accuracy of variant calls. Few objective protocols exist for QC following variant calling from whole genome sequencing (WGS) data. After applying QC filtering based on Genome Analysis Tool Kit (GATK) best practices, we used genotype discordance of eight samples that were sequenced twice each to evaluate the proportion of potentially inaccurate variant calls. We designed a QC pipeline involving hard filters to improve replicate genotype concordance, which indicates improved accuracy of genotype calls. Our pipeline analyzes the efficacy of each filtering step. We initially applied this strategy to well-characterized variants from the ClinVar database, and subsequently to the full WGS dataset. The genome-wide biallelic pipeline removed 82.11% of discordant and 14.89% of concordant genotypes, and improved the concordance rate from 98.53% to 99.69%. The variant-level read depth filter most improved the genome-wide biallelic concordance rate. We also adapted this pipeline for triallelic sites, given the increasing proportion of multiallelic sites as sample sizes increase. For triallelic sites containing only SNVs, the concordance rate improved from 97.68% to 99.80%. Our QC pipeline removes many potentially false positive calls that pass in GATK, and may inform future WGS studies prior to variant effect analysis.


Gene expression profiling of macrophages: implications for an immunosuppressive effect of dissolucytotic gold ions.
Gold salts has previously been used in the treatment of rheumatoid arthritis but have been replaced by biologicals such as TNF-α inhibitors. The mechanisms behind the anti-inflammatory effect of metallic gold ions are still unknown, however, recent data showed that charged gold atoms are released from pure metallic gold implants by macrophages via a dissolucytosis membrane, and that gold ions are taken up by local macrophages, mast cells and to some extent fibroblasts. These findings open the question of possible immunomodulatory effects of metallic gold and motivate efforts on a deeper understanding of the effect of metallic gold on key inflammatory cells as macrophages. Human macrophage cells (cell line THP-1) were grown on gold foils and intracellular uptake was analysed by autometallography. The impact of phagocytised gold ions on viability of THP-1 cells was investigated by trypan blue staining and TUNEL assay. The global gene expression profile of THP-1 cells after incorporation of gold ions was studied using microarray analysis comprising approximately 20,000 genes. The gene expression data was confirmed by measurement of secreted proteins. Autometallography showed intracellular uptake of gold ions into THP-1 cells. No significant effect on viability of THP-1 cells was demonstrated. Our data revealed a unique gene expression signature of dissolucytotic THP-1 cells that had taken up gold ions. A large number of regulated genes were functionally related to immunomodulation. Gold ion uptake induced downregulation of genes involved in rheumatoid arthritis such as hepatocyte growth factor, tenascin-C, inhibitor of DNA binding 1 and 3 and matrix metalloproteinase 13. The data obtained in this study offer new insights into the mode of action of gold ions and suggest for the investigation of effects on other key cells and a possible future role of metallic gold as implants in rheumatoid arthritis or other inflammatory conditions.


Kynurenine, a Tryptophan Metabolite That Increases with Age, Induces Muscle Atrophy and Lipid Peroxidation.
The cellular and molecular mechanisms underlying loss of muscle mass with age (sarcopenia) are not well-understood; however, heterochronic parabiosis experiments show that circulating factors are likely to play a role. Kynurenine (KYN) is a circulating tryptophan metabolite that is known to increase with age and is a ligand of the aryl hydrocarbon receptor (Ahr). Here, we tested the hypothesis that KYN activation of Ahr plays a role in muscle loss with aging. Results indicate that KYN treatment of mouse and human myoblasts increased levels of reactive oxygen species (ROS) 2-fold and KYN treatment in vivo reduced muscle size and strength and increased muscle lipid peroxidation in young mice. PCR array data indicate that muscle fiber size reduction with KYN treatment reduces protein synthesis markers whereas ubiquitin ligase gene expression is not significantly increased. KYN is generated by the enzyme indoleamine 2,3-dioxygenase (IDO), and aged mice treated with the IDO inhibitor 1-methyl-D-tryptophan showed an increase in muscle fiber size and muscle strength. Small-molecule inhibition of Ahr in vitro, and Ahr knockout in vivo, did not prevent KYN-induced increases in ROS, suggesting that KYN can directly increase ROS independent of Ahr activation. Protein analysis identified very long-chain acyl-CoA dehydrogenase as a factor activated by KYN that may increase ROS and lipid peroxidation. Our data suggest that IDO inhibition may represent a novel therapeutic approach for the prevention of sarcopenia and possibly other age-associated conditions associated with KYN accumulation such as bone loss and neurodegeneration.


Drinking Contexts and Alcohol Consumption: How Much Alcohol Is Consumed in Different Australian Locations?
The aim of this study was to examine where Australians in different demographic groups and drinker categories consume their alcohol. Results were taken from the Australian arm of the International Alcohol Control study, a telephone survey of 2,020 Australian adults with an oversample of risky drinkers. The 1,789 respondents who reported consuming alcohol in the past 6 months were asked detailed questions about the location of their alcohol consumption and how much alcohol they consumed at each place. Sixty-three percent of all alcohol consumption reported by respondents was consumed in the drinker's own home, with much less consumed at pubs, bars, and nightclubs (12%). This is driven primarily by the number of people who drink in the home and the frequency of these events, with the amount consumed per occasion at home no more than in other people's homes or pubs, and significantly less than at special events. The average consumption on a usual occasion at each of these locations was more than five Australian standard drinks (above the Australian low-risk guideline for episodic drinking). Short-term risky drinkers had the highest proportion of consumption in pubs (19%), but they still consumed 41% of their units in their own home. The majority of alcohol consumed in Australia is consumed in the drinker's own home. Efforts to reduce long-term harms from drinking need to address off-premise drinking and, in particular, drinking in the home.


Estimation of Actual Evapotranspiration by Remote Sensing: Application in Thessaly Plain, Greece.
Remote sensing can assist in improving the estimation of the geographical distribution of evapotranspiration, and consequently water demand in large cultivated areas for irrigation purposes and sustainable water resources management. In the direction of these objectives, the daily actual evapotranspiration was calculated in this study during the summer season of 2001 over the Thessaly plain in Greece, a wide irrigated area of great agricultural importance. Three different methods were adapted and applied: the remotesensing methods by Granger (2000) and Carlson and Buffum (1989) that use satellite data in conjunction with ground meteorological measurements and an adapted FAO (Food and Agriculture Organisation) Penman-Monteith method (Allen at al. 1998), which was selected to be the reference method. The satellite data were used in conjunction with ground data collected on the three closest meteorological stations. All three methods, exploit visible channels 1 and 2 and infrared channels 4 and 5 of NOAA-AVHRR (National Oceanic and Atmospheric Administration - Advanced Very High Resolution Radiometer) sensor images to calculate albedo and NDVI (Normalised Difference Vegetation Index), as well as surface temperatures. The FAO Penman-Monteith and the Granger method have used exclusively NOAA-15 satellite images to obtain mean surface temperatures. For the Carlson-Buffum method a combination of NOAA-14 and ΝΟΑΑ-15 satellite images was used, since the average rate of surface temperature rise during the morning was required. The resulting estimations show that both the Carlson-Buffum and Granger methods follow in general the variations of the reference FAO Penman-Monteith method. Both methods have potential for estimating the spatial distribution of evapotranspiration, whereby the degree of the relative agreement with the reference FAO Penman-Monteith method depends on the crop growth stage. In particular, the Carlson- Buffum method performed better during the first half of the crop development stage, while the Granger method performed better during the remaining of the development stage and the entire maturing stage. The parameter that influences the estimations significantly is the wind speed whose high values result in high underestimates of evapotranspiration. Thus, it should be studied further in future.


Climate adaptation and speciation: particular focus on reproductive barriers in Ficedula flycatchers.
Climate adaptation is surprisingly rarely reported as a cause for the build-up of reproductive isolation between diverging populations. In this review, we summarize evidence for effects of climate adaptation on pre- and postzygotic isolation between emerging species with a particular focus on pied (Ficedula hypoleuca) and collared (Ficedula albicollis) flycatchers as a model for research on speciation. Effects of climate adaptation on prezygotic isolation or extrinsic selection against hybrids have been documented in several taxa, but the combined action of climate adaptation and sexual selection is particularly well explored in Ficedula flycatchers. There is a general lack of evidence for divergent climate adaptation causing intrinsic postzygotic isolation. However, we argue that the profound effects of divergence in climate adaptation on the whole biochemical machinery of organisms and hence many underlying genes should increase the likelihood of genetic incompatibilities arising as side effects. Fast temperature-dependent co-evolution between mitochondrial and nuclear genomes may be particularly likely to lead to hybrid sterility. Thus, how climate adaptation relates to reproductive isolation is best explored in relation to fast-evolving barriers to gene flow, while more research on later stages of divergence is needed to achieve a complete understanding of climate-driven speciation.


Throwing Skills.
Traditionally, motor learning scientists have evaluated the process of learning a new motor skill by considering the skill as a whole. Yet, motor skills comprise various phases, and in the motor learning literature, it is not clear whether new learners show similar or different learning across various phases. We provide exploratory data on learning movement phases by novices, using baseball pitching as the learning task. Eight participants (four male, four female, M age = 23.7 years, SD = 2.4) performed five trials each in the pretest followed by three blocks of 10 trials each in the acquisition phase. Finally, two retention tests of five trials were conducted by each participant 10 minutes and seven days after the last acquisition block, respectively. Intra- and interlimb coordination of upper and lower body segments were measured as dependent variables. We found significant differences between the stride phase and the other phases at pretest, during the acquisition phase, and on both retention tests across all kinematic variables. Participants experienced more trouble coordinating the stride phase than the other phases of pitching, perhaps because the stride phase is the only phase in which the participants had to move their upper and lower body parts simultaneously. We discuss implications for motor learning generally.


Body weight is more important than family history of hypertension for left ventricular function.
Left ventricular function was studied in young men with a positive family history of hypertension for two generations (n = 15). The findings were compared with three control groups: one age-, sex-, and weight-matched group with a negative family history of hypertension (n = 14); one normotensive control group unselected as regards family history of hypertension (n = 27); and one group also unselected regarding family history of hypertension but selected with blood pressure criteria to have mild blood pressure elevation (n = 59). The group with a positive family history of hypertension, in comparison with the normotensive control group, was heavier, had higher blood pressure, increased left ventricular wall thickness, increased left ventricular mass, and signs of changes in diastolic and systolic left ventricular function. There were no differences in these variables between the group with a positive family history and the other two control groups. Data clearly indicated that subjects with a positive family history of hypertension, as well as subjects with mild blood pressure elevation, were heavier than the normotensive control group. It is not possible to judge, with available data, if the changes in left ventricular morphology and function in the two groups with a different family history of hypertension and in the group with mild blood pressure elevation occurred as a physiological response to the increase in afterload or if the neurohormonal and metabolic disturbances leading to the condition of slight overweight also affected left ventricular function.


Difference in the clinical characteristic and prognosis of colitis-associated cancer and sporadic neoplasia in ulcerative colitis patients.
Although various studies have been conducted on colitis-associated cancer (CAC), few have assessed the differences in the clinical and endoscopic features, treatment, and prognosis of CAC and sporadic neoplasia (SN) in the inflamed mucosa of ulcerative colitis (UC) patients. To compare the characteristics of CAC and SN within the previously or currently inflamed mucosa. Between 1997 and 2017, we retrospectively analyzed the endoscopic chart data of 348 colonic lesions from 266 UC patients. Non-dysplastic lesions and lesions located outside the inflamed mucosa were excluded. The diagnosis of CAC or SN was confirmed by conventional histopathological and immunohistochemical evaluation of p53 and Ki67. In total, 74 patients with CAC (97 lesions) and 46 with SN (58) were enrolled. The proportions of patients with a younger age of onset of UC, with chronic persistent UC, and with severe inflamed mucosa were significantly higher in the CAC group. In the SN group, no flat lesions were found, whereas 26% of the lesions in the CAC group were flat. Sixteen patients died during a median follow-up of 6.1 years (interquartile range (IQR) 1.8-11.1)in the CAC group, whereas 1 patient died during a median follow-up 3.2 years(IQR 1.4-4.6) in the SN group. Mortality from colorectal cancer was significantly higher (P = 0.015) in the CAC group (12/68; 17.6%) than in the SN group (1/44; 2.3%). The 5-year survival rate was 100% in the SN group and 97% in the CAC group for lesions located in the mucosa or submucosa. Recognizing differences in the characteristics of CAC and SN within the inflamed mucosa is critical to avoid unnecessary total colectomy in patients with SN.


The guide sRNA sequence determines the activity level of box C/D RNPs.
2'-O-rRNA methylation, which is essential in eukaryotes and archaea, is catalysed by the Box C/D RNP complex in an RNA-guided manner. Despite the conservation of the methylation sites, the abundance of site-specific modifications shows variability across species and tissues, suggesting that rRNA methylation may provide a means of controlling gene expression. As all Box C/D RNPs are thought to adopt a similar structure, it remains unclear how the methylation efficiency is regulated. Here, we provide the first structural evidence that, in the context of the Box C/D RNP, the affinity of the catalytic module fibrillarin for the substrate-guide helix is dependent on the RNA sequence outside the methylation site, thus providing a mechanism by which both the substrate and guide RNA sequences determine the degree of methylation. To reach this result, we develop an iterative structure-calculation protocol that exploits the power of integrative structural biology to characterize conformational ensembles.


A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease.
Alzheimer disease (AD) is characterized by functional impairment in the neural elements and circuits underlying cognitive and memory functions. We hypothesized that fornix/hypothalamus deep brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits. We conducted a phase I trial in 6 patients with mild AD receiving ongoing medication treatment. Patients received continuous stimulation for 12 months. Three main lines of investigation were pursued including: (1) mapping the brain areas whose physiological function was modulated by stimulation using standardized low-resolution electromagnetic tomography, (2) assessing whether DBS could correct the regional alterations in cerebral glucose metabolism in AD using positron emission tomography (PET), and 3) measuring the effects of DBS on cognitive function over time using clinical scales and instruments. DBS drove neural activity in the memory circuit, including the entorhinal, and hippocampal areas and activated the brain's default mode network. PET scans showed an early and striking reversal of the impaired glucose utilization in the temporal and parietal lobes that was maintained after 12 months of continuous stimulation. Evaluation of the Alzheimer's Disease Assessment Scale cognitive subscale and the Mini Mental State Examination suggested possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients. There were no serious adverse events. There is an urgent need for novel therapeutic approaches for AD. Modulating pathological brain activity in this illness with DBS merits further investigation.


p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis.
Intact p73 function is shown to be an important determinant of cellular sensitivity to anticancer agents. Inhibition of p73 function by dominant-negative proteins or by mutant p53 abrogates apoptosis and cytotoxicity induced by these agents. A polymorphism encoding either arginine (72R) or proline (72P) at codon 72 of p53 influences inhibition of p73 by a range of p53 mutants identified in squamous cancers. Clinical response following cisplatin-based chemo-radiotherapy for advanced head and neck cancer is influenced by this polymorphism, cancers expressing 72R mutants having lower response rates than those expressing 72P mutants. Polymorphism in p53 may influence individual responsiveness to cancer therapy.


Plant molecular biology in the space station era: utilization of KSC fixation tubes with RNAlater.
Spaceflight experiments involving biological specimens face unique challenges with regard to the on orbit harvest and preservation of material for later ground-based analyses. Preserving plant material for gene expression analyses requires that the tissue be prepared and stored in a manner that maintains the integrity of RNA. The liquid preservative RNAlater (Ambion) provides an effective alternative to conventional freezing strategies, which are limited or unavailable in current spaceflight experiment scenarios. The spaceflight use of RNAlater is enabled by the Kennedy space center fixation tube (KFT), hardware designed to provide the necessary containment of fixatives during the harvest and stowage of biological samples in space. Pairing RNAlater with the KFT system provides a safe and effective strategy for preserving plant material for subsequent molecular analyses, a strategy that has proven effective in several spaceflight experiments. Possible spaceflight scenarios for the use of RNAlater and KFTs are explored and discussed.


Emerging roles of health care providers to mitigate climate change impacts: a perspective from East Harlem, New York.
Professional associations of health care workers are issuing policy statements on climate change and health with greater frequency, calling on their members to act in their duty to protect and fulfill the right to health. These health care providers' perceptions of their roles in the intersection of climate and health, however, have not been well-studied. This article presents results from a qualitative study using focus groups conducted with health care providers serving the low-income, ethnic minority population in East Harlem, New York. The focus groups sought to identify and explore providers' perceived health threats of climate change, as well as their perceived role as frontline disseminators of information and detectors of disease for their patients. Extreme heat events were used to frame the discussion in each group. Three major themes emerged: 1) environmental awareness, 2) an "ecohealth" lens, and 3) heat and health vulnerability. The participants demonstrated their interest in playing a role in climate change adaptation by identifying at-risk patients and helping to tailor clinical care to better serve these individuals.


Toxoplasmosis and mental disorders in the Russian Federation (with special reference to schizophrenia).
The association of latent toxoplasmosis with mental disorders in general and with schizophrenia in particular was noticed in the mid-1950s. In subsequent years, the role of Toxoplasma gondii was established based on its ability to survive for long periods of time in the nerve cells of the brain. The acute manifestations of the infection include psychopathic symptoms resembling those of schizophrenia. In the former USSR, and in other parts of the world, a number of studies were performed with respect to the association of latent toxoplasmosis and schizophrenia. However, with the dissolution of the USSR at the beginning of the 1990s, studies on the subject were halted due to financial problems and have resumed only recently. The reasons for the resumption of such studies in contemporary Russia are related to the progressively increasing incidence of schizophrenia over the last 25-30 years in the country. According to official data, approximately 550 000 persons reported suffering from the disease in 2014. There are reasons to believe that this is only a fraction of the real burden of the disease. Economically, it cost the state no less than approximately US $10 billion. The purpose of the study was to identify the level of toxoplasmosis seroprevalence in patients with verified diagnoses of schizophrenia in comparison to healthy people in Moscow City and in the Moscow region. A total of 155 persons constituted the patients group and 152 healthy people were in the control group. An integrated approach to the diagnosis and comparison of data from the entire spectrum of serological markers of infection was used, including the detection of specific IgM and the determination of IgG concentrations. It was found that among persons with neuropsychiatric disorders, the incidence of cases with latent toxoplasmosis was higher than in the control group. The effect of toxoplasmosis was significant and similar for men and women. Further statistical analyses revealed that among patients with a diagnosis of schizophrenia, the incidence of latent toxoplasmosis was significantly higher than in the control group. These data are in agreement with the results of similar studies in other countries.


Oxidation and adduct formation of xenobiotics in a microfluidic electrochemical cell with boron doped diamond electrodes and an integrated passive gradient rotation mixer.
Reactive xenobiotic metabolites and their adduct formation with biomolecules such as proteins are important to study as they can be detrimental to human health. Here, we present a microfluidic electrochemical cell with integrated micromixer to study phase I and phase II metabolism as well as protein adduct formation of xenobiotics in a purely instrumental approach. The newly developed microfluidic device enables both the generation of reactive metabolites through electrochemical oxidation and subsequent adduct formation with biomolecules in a chemical microreactor. This allows us to study the detoxification of reactive species with glutathione and to predict potential toxicity of xenobiotics as a result of protein modification. Efficient mixing in microfluidic systems is a slow process due to the typically laminar flow conditions in shallow channels. Therefore, a passive gradient rotation micromixer has been designed that is capable of mixing liquids efficiently in a 790 pL volume within tens of milliseconds. The mixing principle relies on turning the concentration gradient that is initially established by bringing together two streams of liquid, to take advantage of the short diffusion distances in the shallow microchannels of thin-layer flow cells. The mixer is located immediately downstream of the working electrode of an electrochemical cell with integrated boron doped diamond electrodes. In conjunction with mass spectrometry, the two microreactors integrated in a single device provide a powerful tool to study the metabolism and toxicity of xenobiotics, which was demonstrated by the investigation of the model compound 1-hydroxypyrene.


Poststroke exercise is as effective as skilled rehabilitation: Effects in young and aged mice.
Stroke is a leading cause of long-term disability, though current rehabilitative strategies fail to yield complete recovery. Focused training of the impaired limb improves functional outcome in rodents, but these strategies require intensive training that is difficult to practice in humans. Because aerobic exercise has been found to induce beneficial changes in the brain, it is a promising rehabilitative strategy after stroke. The current study investigated the effect of voluntary poststroke aerobic exercise on functional outcome in young and aged mice. Mice were trained on a skilled reaching task before receiving focal ischemic stroke and being subdivided into 3 different groups for rehabilitative training: traditional skilled reach rehabilitation, aerobic exercise, and control procedures. Both young and aged mice benefited from aerobic exercise after stroke, though the behavioral profile somewhat differed. Aerobic exercise in young mice yielded poststroke performance levels that were equivalent to preinjury levels. In aged mice, aerobic exercise accelerated improvement in motor performance without an effect on the absolute level of performance compared with controls. Our results suggest that aerobic exercise may be an effective alternative or adjunctive rehabilitative strategy after stroke. Potential mechanisms of this effect need to be further investigated. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Genomic architecture of human neuroanatomical diversity.
Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.


Accurate calculation of the absolute free energy of binding for drug molecules.
Accurate prediction of binding affinities has been a central goal of computational chemistry for decades, yet remains elusive. Despite good progress, the required accuracy for use in a drug-discovery context has not been consistently achieved for drug-like molecules. Here, we perform absolute free energy calculations based on a thermodynamic cycle for a set of diverse inhibitors binding to bromodomain-containing protein 4 (BRD4) and demonstrate that a mean absolute error of 0.6 kcal mol-1 can be achieved. We also show a similar level of accuracy (1.0 kcal mol-1) can be achieved in pseudo prospective approach. Bromodomains are epigenetic mark readers that recognize acetylation motifs and regulate gene transcription, and are currently being investigated as therapeutic targets for cancer and inflammation. The unprecedented accuracy offers the exciting prospect that the binding free energy of drug-like compounds can be predicted for pharmacologically relevant targets.


Behavioural economics in fisheries: A systematic review protocol.
The field of behavioural economics holds several opportunities for integrated fisheries management and conservation and can help researchers and managers alike understand fisher behaviour and decision-making. As the study of the cognitive biases that influence decision-making processes, behavioural economics differentiates itself from the classical field of economics in that it does not assume strictly rational behaviour of its agents, but rather looks for all mechanisms that influence behaviour. This field offers potential applications for fisheries management, for example in relation to behavioural change, but such applications require evidence of these mechanisms applied in a fisheries context. Thus, we have developed a systematic literature review protocol focusing on the primary question: "Which behavioural economics mechanisms influence fisher behaviour?" The aim is to provide a comprehensive overview of these different mechanisms and how they have been applied in the study of fisher behaviour. The review protocol was developed in close collaboration with the International Council for the Exploration of the Sea (ICES) Working Group on Maritime Systems (WGMARS). WGMARS members were therefore considered the key stakeholders for this study, and were consulted to develop a suitable systematic review question and methodology. Three academic databases will be searched using a customized Boolean keyword search string. Research articles deemed eligible for inclusion in the systematic review are those that studied the influence of behavioural-economics mechanisms on the behaviour of marine fishers in any location, and at any scale. Insights from this literature will be collated in order to provide an overview of the relevant behavioural-economics mechanisms and actions, how effective these mechanisms are and at what scale, geographic region and in which fisheries sector they have been applied. Any fisheries management implications identified by the studies under review will also be outlined. Finally, it will be recorded whether or not ethical considerations were made in the reviewed literature, so that in the discussion it will be possible to reflect on the ethics of conducting behavioural-economics research and policy actions in a fisheries context.


Aripiprazole Lauroxil NanoCrystal® Dispersion Technology (Aristada Initio®).
Nonadherence to antipsychotic medications for the treatment of schizophrenia is a widely recognized concern, leading to poorer clinical outcomes and higher treatment costs. Long-acting injectable (LAI) antipsychotics offer an extended dosing interval option for patients, although the current options may require an oral overlap at initiation. Aripiprazole lauroxil is an LAI that offers multiple dosing options but requires oral treatment overlap during initiation for the first 21 consecutive days. As an alternative to oral overlap, a novel nano-crystalline milled dispersion delivery system of aripiprazole lauroxil was recently approved as a one-day regimen to be added to aripiprazole lauroxil treatment.


Role of near work in myopia: findings in a sample of Australian school children.
To examine the association of time spent in near work and reading with spherical equivalent refraction (SER) in a population-based sample of 12-year-old Australian schoolchildren. Data on the time spent in near-work or outdoor activities per week and estimates for the duration of continuous reading and reading distances, were collected in questionnaires (2353 participants, 75.3% response) in the Sydney Myopia Study between 2004 and 2005; 2339 children underwent a comprehensive eye examination, including cycloplegia. Longer time spent on reading for pleasure and reports of close reading distance (< 30 cm) were associated with a more myopic refraction after adjustment for age, sex, ethnicity, and school type (P(trend) = 0.02 and P = 0.0003, respectively). Time spent in individual near-work activities, however, correlated poorly with SER (all r < or = 0.2) and was not significant in multivariate analyses for myopia (SER < or = -0.50 D), with adjustment for age, sex, ethnicity, parental myopia, school type, and outdoor activity. Children of European Caucasian ethnicity reported spending marginally less time in near work than children of East Asian ethnicity (26.0 h/wk vs. 32.5 h/wk, P < 0.0001). East Asian ethnicity, however, was associated with substantially greater odds of having myopia (odds ratio [OR], 11.0; 95% confidence interval [CI], 7.0-17.4). Near work such as close reading distance (< 30 cm) and continuous reading (> 30 minutes) independently increased the odds of having myopia in this sample of children. Although myopia was not significantly associated with time spent in near work after adjustment for other factors, there were significant independent associations with close reading distance and continuous reading. These associations may indicate that the intensity rather than the total duration of near work is an important factor.