Substantial genetic influence on cognitive abilities in twins 80 or more years old.
General and specific cognitive abilities were studied in intact Swedish same-sex twin pairs 80 or more years old for whom neither twin had major cognitive, sensory, or motor impairment. Resemblance for 110 identical twin pairs significantly exceeded resemblance for 130 fraternal same-sex twin pairs for all abilities. Maximum-likelihood model-fitting estimates of heritability were 62 percent for general cognitive ability, 55 percent for verbal ability, 32 percent for spatial ability, 62 percent for speed of processing, and 52 percent for memory. There was also evidence for the significant influence of idiosyncratic experience as the environmental component that most determines individual differences in cognitive abilities late in life.


Promyelocytic leukemia retinoid signaling targets regulate apoptosis,tissue factor and thrombomodulin expression.
Retinoids are involved in cell differentiation, morphogenesis, proliferation and antineoplasic processes. Thus, the retonoic acid receptor (RARalpha) agonist, AM80, regulates tissue factor (TF), thrombomodulin (TM) expression and granulocytic differentiation in promyelocytic cells, while the RARgamma-selective retinoid, CD437, inhibits in vitro cell proliferation and induces apoptosis. The mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K) pathways constitute key integration points along the signal transduction cascades that link diverse extracellular stimuli to proliferation, differentiation and survival. PI3K and MEK/ERK kinase-dependent pathways were examined as potential targets of retinoid signaling. Likewise, by using specific inhibitors, the role of those kinases in retinoid-induced granulocytic differentiation, apoptosis, and TF and TM expression n NB4 cells were analyzed. AM80-treated NB4 cells had increased PI3K activity and phosphoinositide turnover. High steady-state pERK-1/-2 activity levels were not significantly changed by AM80. Yet, PI3K inhibitor LY294002 significantly reduced AM80-elicted ERK-1/-2 activity. Thus, the PI3K pathway might contribute to elevated ERK-1/-2 activity in NB4 cells. Inhibition of the PI3K and MEK/ERK pathways reversed AM80-induced granulocytic differentiation, TF down-regulation and TM induction. Besides, CD437 significantly reduced ERK-1/-2 activity of NB4 cells. Further ERK-1/-2 activity inhibition with the MEK inhibitor, PD98059, increased the retinoid pro-apoptotic effect with an additive effect. Regardless the different regulation of PI3K and MAPK pathways promoted by AM80 and CD437, there is a varying degree of cross-talk between these pathways in the control of the overall response of promyelocytic cells to retinoids. Thus, disruption of targeted pathways, together with specific retinoids, might be an effective therapeutic treatment for acute promyelocytic leukemia.


Self-scrolling MoS2 metallic wires.
Two-dimensional (2D) van der Waals (vdW) materials with strong in-plane chemical bonds and weak interaction in the out-of-plane direction have been acknowledged as a basic building block for designing dimensional materials in 0D, 1D, 2D and 3D forms. Compared to the explosive research on 2D vdW materials, quasi-one-dimensional (quasi-1D) vdW materials have received rare attention, despite the fact that they also present rich physics in electronics and engineering implications. Herein, quasi-1D MoS2 nanoscrolls are directly fabricated from CVD-grown 2D triangular MoS2 sheets. The formation, stability and electronic properties of quasi-1D MoS2 nanoscrolls are studied experimentally and theoretically. The formation of a nanoscroll always starts from the edge of a triangular MoS2 sheet along its armchair orientation. The electronic properties of MoS2 nanoscrolls are systemically studied with optical spectroscopy and electrical transport together with density-functional theory (DFT) calculations. Surprisingly, the carrier mobility and contact properties of MoS2 nanoscroll based field effect transistors (FETs) are distinct from that of 2D MoS2 sheets. The transition from a 2D semiconductor MoS2 sheet to a 1D metallic MoS2 nanoscroll is successfully achieved. It is expected that this method of fabricating MoS2 nanoscrolls will attract wide interest for 1D transition metal dichalcogenides with novel physical and chemical properties.


Repeat prescriptions.
Ninety-six general practitioner recorders undertook an average of 308 consultations in the two weeks reviewed, equivalent to 121 consultations per 1,000 registered patients on the list. The number of patients to whom repeat prescriptions were issued was 10,225.The mean rate of issue of repeat prescriptions was 41.9 per 1,000 list, (346 per 1,000 consultations) though these figures conceal a wide variation between the recorders, 41 per cent of recipients were aged 65+ years and 20 per cent had not been seen by their doctor in the six months prior to receipt. The repeat prescribing rate of individual doctors bears no relation to the workload as measured by the number of consultations undertaken.


What the success of brain imaging implies about the neural code.
The success of fMRI places constraints on the nature of the neural code. The fact that researchers can infer similarities between neural representations, despite fMRI's limitations, implies that certain neural coding schemes are more likely than others. For fMRI to succeed given its low temporal and spatial resolution, the neural code must be smooth at the voxel and functional level such that similar stimuli engender similar internal representations. Through proof and simulation, we determine which coding schemes are plausible given both fMRI's successes and its limitations in measuring neural activity. Deep neural network approaches, which have been forwarded as computational accounts of the ventral stream, are consistent with the success of fMRI, though functional smoothness breaks down in the later network layers. These results have implications for the nature of the neural code and ventral stream, as well as what can be successfully investigated with fMRI.


Nutrient Sensing via mTOR in T Cells Maintains a Tolerogenic Microenvironment.
We have proposed that tolerance can be maintained through the induction, by Treg cells, of a tolerogenic microenvironment within tolerated tissues that inhibits effector cell activity but which supports the generation of further Treg cells by "infectious tolerance." Two important components of this tolerogenic microenvironment depend on metabolism and nutrient sensing. The first is due to the up-regulation of multiple enzymes that consume essential amino acids, which are sensed in naïve T cells primarily via inhibition of the mechanistic target of rapamycin (mTOR) pathway, which in turn encourages their further differentiation into FOXP3(+) Treg cells. The second mechanism is the metabolism of extracellular ATP to adenosine by the ectoenzymes CD39 and CD73. These two enzymes are constitutively co-expressed on Treg cells, but can also be induced on a wide variety of cell types by TGFβ and the adenosine generated can be shown to be a potent inhibitor of T cell proliferation. This review will focus on mechanisms of nutrient sensing in T cells, how these are integrated with TCR and cytokine signals via the mTOR pathway, and what impact this has on intracellular metabolism and subsequently the control of differentiation into different effector or regulatory T cell subsets.


Theoretical approaches of online social network interventions and implications for behavioral change: a systematic review.
The aim of this review was to identify general theoretical frameworks used in online social network interventions for behavioral change. To address this research question, a PRISMA-compliant systematic review was conducted. A systematic review (PROSPERO registration number CRD42014007555) was conducted using 3 electronic databases (PsycINFO, Pubmed, and Embase). Four reviewers screened 1788 abstracts. 15 studies were selected according to the eligibility criteria. Randomized controlled trials and controlled studies were assessed using Cochrane Collaboration's "risk-of-bias" tool, and narrative synthesis. Five eligible articles used the social cognitive theory as a framework to develop interventions targeting behavioral change. Other theoretical frameworks were related to the dynamics of social networks, intention models, and community engagement theories. Only one of the studies selected in the review mentioned a well-known theory from the field of health psychology. Conclusions were that guidelines are lacking in the design of online social network interventions for behavioral change. Existing theories and models from health psychology that are traditionally used for in situ behavioral change should be considered when designing online social network interventions in a health care setting.


[Peculiarities of arterial reconstructions in pyonecrotic lesions of lower limbs].
Presented herein are the results of treating a total of sixty patients suffering from atherosclerosis obliterans of the lower limbs with degree IV chronic ischaemia according to the Fontain-Pokrovsky classification and accompanied by pyonecrotic alterations. The patients were subdivided into two clinically matching groups, each comprising 30 subjects. All patients after two-week conservative preparation underwent various reconstructive surgical operations performed on major arteries of the lower limbs. The local preoperative treatment was of two different types, i. e. consisting of Levomecol ointment used in the control group patients and Metrogyl 1% topical gel applied in the study group patients. Sampled before treatment, inoculations of the wound discharge demonstrated predominantly anaerobic flora in all patients, with the number of bacterial strains having dramatically decreased once Metrogyl gel 1% had been used, whereas application of Levomecol did not significantly influence the structure of the microbial profile. Following surgical treatment we had to perform high amputation of the lower limb in 5 patients of the control group, whereas in the study group patients only one patient required amputation at the foot level. Hence, prior to carrying out reconstructive vascular interventions in patients presenting with pyonecrotic lesions of lower extremities it is preferable to perform debridement of the necrotic foci using topical antibacterial agents, one of which may be Metrogyl 1% gel.


Finding and sharing: new approaches to registries of databases and services for the biomedical sciences.
The recent explosion of biological data and the concomitant proliferation of distributed databases make it challenging for biologists and bioinformaticians to discover the best data resources for their needs, and the most efficient way to access and use them. Despite a rapid acceleration in uptake of syntactic and semantic standards for interoperability, it is still difficult for users to find which databases support the standards and interfaces that they need. To solve these problems, several groups are developing registries of databases that capture key metadata describing the biological scope, utility, accessibility, ease-of-use and existence of web services allowing interoperability between resources. Here, we describe some of these initiatives including a novel formalism, the Database Description Framework, for describing database operations and functionality and encouraging good database practise. We expect such approaches will result in improved discovery, uptake and utilization of data resources. Database URL: http://www.casimir.org.uk/casimir_ddf.


Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase.
The mammalian O-GlcNAc hydrolase (OGA) removes O-GlcNAc from serine and threonine residues on intracellular glycoproteins. OGA activity is sensitive to N-acyl substitutions to O-GlcNAc, with alkyl diazirine-modified O-GlcNAc (O-GlcNDAz) being completely resistant to removal by OGA. Using homology modeling, we identified OGA residues proximal to the N-acyl position of O-GlcNAc substrate. Mutation of one of these residues, C215, results in mutant enzymes that are able to hydrolytically remove O-GlcNDAz from a model compound. Further, the C215A mutant is capable of removing O-GlcNDAz from a peptide substrate. These results can be used to improve metabolism of O-GlcNAc analogs in cells. In addition, the enzyme specificity studies reported here provide new insight into the active site of OGA, an important drug target.


Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial.
Adjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial. Premenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years. In the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p=0.02). In subgroup analysis the risk reduction was most pronounced in patients <40 years of age (HR 0.09, p=0.02). A risk reduction was also seen in women 40-49 years of age or 50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time. In this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women <40 years of age. The effect of tamoxifen was not significantly dependent on time.


Science games and the development of scientific possible selves.
Serious scientific games, especially those that include a virtual apprenticeship component, provide players with realistic experiences in science. This article discusses how science games can influence learning about science and the development of science-oriented possible selves through repeated practice in professional play and through social influences (e.g., peer groups). We first review the theory of possible selves (Markus and Nurius 1986) and discuss the potential of serious scientific games for influencing the development of scientific possible selves. As part of our review, we present a forensic game that inspired our work. Next we present a measure of scientific possible selves and assess its reliability and validity with a sample of middle-school students (N=374). We conclude by discussing the promise of science games and the development of scientific possible selves on both the individual and group levels as a means of inspiring STEM careers among adolescents.


One Hundred Ways to Invent the Sexes: Theoretical and Observed Paths to Dioecy in Plants.
Dioecy, the presence of male and female flowers on separate individuals, is both widespread and uncommon within flowering plants, with only a few percent of dioecious species spread across most major phylogenetic taxa. It is therefore safe to assume that dioecy evolved independently in these different groups, which allows us to ask questions regarding the molecular and developmental mechanisms underlying these independent transitions to dioecy. We start this review by examining the problem from the standpoint of a genetic engineer trying to develop dioecy, discuss various potential solutions, and compare them to models proposed in the past and based on genetic and evolutionary considerations. Next, we present recent information regarding candidate sex determinants in three species, acquired using newly established genomic approaches. Although such specific information is still scarce, it is slowly becoming apparent that various genes or pathways can be altered to evolve dioecy.


Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study.
Arm cuff blood pressure (BP) may overestimate cardiovascular risk. Central aortic BP predicts mortality and could be a better method for patient management. We sought to determine the usefulness of central BP to guide hypertension management. This was a prospective, open-label, blinded-end point study in 286 patients with hypertension randomized to treatment decisions guided by best-practice usual care (n=142; using office, home, and 24-hour ambulatory BP) or, in addition, by central BP intervention (n=144; using SphygmoCor). Therapy was reviewed every 3 months for 12 months, and recommendations were provided to each patient and his/her doctor on antihypertensive medication titration. Outcome measures were as follows: medication quantity (daily defined dose), quality of life, and left ventricular mass (3-dimensional echocardiography). There was 92% compliance with recommendations on medication titration, and quality of life improved in both groups (post hoc P<0.05). For usual care, there was no change in daily defined dose (all P>0.10), but with intervention there was a significant stepwise decrease in daily defined dose from baseline to 3 months (P=0.008) and each subsequent visit (all P<0.001). Intervention was associated with cessation of medication in 23 (16%) patients versus 3 (2%) in usual care (P<0.001). Despite this, there were no differences between groups in left ventricular mass index, 24-hour ambulatory BP, home systolic BP, or aortic stiffness (all P>0.05). We conclude that guidance of hypertension management with central BP results in a significantly different therapeutic pathway than conventional cuff BP, with less use of medication to achieve BP control and no adverse effects on left ventricular mass, aortic stiffness, or quality of life.


Observer-rated retardation but not agitation corresponds to objective motor measures in depression.
To explore the correlations between observer ratings and instrumental parameters across domains of psychomotor functioning in depression. In total, 73 patients with major depressive disorder underwent extensive psychomotor and clinical testing. Psychomotor functioning was assessed with (i) an observer-rated scale (the CORE measure) and also objectively with (ii) 24-h actigraphy, and (iii) a fine motor drawing task. Observer ratings of retardation correlated with instrumental assessments of fine and gross motor functioning. In contrast, observer ratings of agitation did not correlate with observer ratings of retardation or with the instrumental measures. These associations were partly influenced by age and, to a lesser extent, by depression severity. Psychomotor disturbance is a complex concept with different manifestations in depressed patients. Although observer ratings of retardation correspond well with instrumental measures of the motor domains, objective measurement of agitation and other aspects of psychomotor disturbance require further research.


Complexity, fractals, disease time, and cancer.
Despite many years of research, a method to precisely and quantitatively determine cancer disease state remains elusive. Current practice for characterizing solid tumors involves the use of varying systems of tumor grading and staging and thus leaves diagnosis and clinical staging dependent on the experience and skill of the physicians involved. Although numerous disease markers have been identified, no combination of them has yet been found that produces a quantifiable and reliable measure of disease state. Newly developed genomic markers and other measures based on the developing sciences of complexity offer promise that this situation may soon be changed for the better. In this paper, we examine the potential of two measures of complexity, fractal dimension and percolation, for use as components of a yet to be determined "disease time" vector that more accurately quantifies disease state. The measures are applied to a set of micrographs of progressive rat hepatoma and analyzed in terms of their correlation with cell differentiation, ratio of tumor weight to rat body weight and tumor growth time. The results provide some support for the idea that measures of complexity could be important elements of any future cancer "disease time" vector.


Microbiology of the 'G-bacteria' in activated sludge.
This review discusses a group of bacteria, the 'G-bacteria', which have a distinctive morphology of cocci in tetrads, sheets or clusters, that are seen in large numbers in many activated sludge biomass samples. Isolates of 'G-bacteria' that have been grown axenically are phylogenetically diverse. The Gram-negative members include several alpha- and beta-proteobacteria, among which is the genus Amaricoccus, while the Gram-positive 'G-bacteria' contain several members of the actinobacteria. It is probable that other, as yet uncharacterized, 'G-bacteria' exist in activated sludge. The hypothesis that these 'G-bacteria' are detrimental to the process of enhanced biological phosphate removal by competing for substrates anaerobically with the phosphate-accumulating bacteria in such systems, based as it is largely on mixed-culture studies, receives little support from studies using those available in pure culture. The evidence on which these conclusions are founded is discussed, as are the arguments used to explain why these 'G-bacteria' all appear to thrive under conditions found in certain activated sludge systems.


Conferring biological activity to native spider silk: A biofunctionalized protein-based microfiber.
Spider silk is an extraordinary material with physical properties comparable to the best scaffolding/structural materials, and as a fiber it can be manipulated with ease into a variety of configurations. Our work here demonstrates that natural spider silk fibers can also be used to organize biological components on and in devices through rapid and simple means. Micron scale spider silk fibers (5-10 μm in diameter) were surface modified with a variety of biological entities engineered with pentaglutamine tags via microbial transglutaminase (mTG). Enzymes, enzyme pathways, antibodies, and fluorescent proteins were all assembled onto spider silk fibers using this biomolecular engineering/biofabrication process. Additionally, arrangement of biofunctionalized fiber should in of itself generate a secondary level of biomolecular organization. Toward this end, as proofs of principle, spatially defined arrangement of biofunctionalized spider silk fiber was shown to generate effects specific to silk position in two cases. In one instance, arrangement perpendicular to a flow produced selective head and neck carcinoma cell capture on silk with antibodies complexed to conjugated protein G. In a second scenario, asymmetric bacterial chemotaxis arose from asymmetric conjugation of enzymes to arranged silk. Overall, the biofabrication processes used here were rapid, required no complex chemistries, were biologically benign, and also the resulting engineered silk microfibers were flexible, readily manipulated and functionally active. Deployed here in microfluidic environments, biofunctional spider silk fiber provides a means to convey complex biological functions over a range of scales, further extending its potential as a biomaterial in biotechnological settings. Biotechnol. Bioeng. 2017;114: 83-95. © 2016 Wiley Periodicals, Inc.


In Standing, Corticospinal Excitability Is Proportional to COP Velocity Whereas M1 Excitability Is Participant-Specific.
Reductions in the base of support (BOS) make standing difficult and require adjustments in the neural control of sway. In healthy young adults, we determined the effects of reductions in mediolateral (ML) BOS on peroneus longus (PL) motor evoked potential (MEP), intracortical facilitation (ICF), short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI) using transcranial magnetic stimulation (TMS). We also examined whether participant-specific neural excitability influences the responses to increasing standing difficulty. Repeated measures ANOVA revealed that with increasing standing difficulty MEP size increased, SICI decreased (both p < 0.05) and ICF trended to decrease (p = 0.07). LICI decreased only in a sub-set of participants, demonstrating atypical facilitation. Spearman's Rank Correlation showed a relationship of ρ = 0.50 (p = 0.001) between MEP size and ML center of pressure (COP) velocity. Measures of M1 excitability did not correlate with COP velocity. LICI and ICF measured in the control task correlated with changes in LICI and ICF, i.e., the magnitude of response to increasing standing difficulty. Therefore, corticospinal excitability as measured by MEP size contributes to ML sway control while cortical facilitation and inhibition are likely involved in other aspects of sway control while standing. Additionally, neural excitability in standing is determined by an interaction between task difficulty and participant-specific neural excitability.


Novel genes and mutations in patients affected by recurrent pregnancy loss.
Recurrent pregnancy loss is a frequently occurring human infertility-related disease affecting ~1% of women. It has been estimated that the cause remains unexplained in >50% cases which strongly suggests that genetic factors may contribute towards the phenotype. Concerning its molecular aetiology numerous studies have had limited success in identifying the disease's genetic causes. This might have been due to the fact that hundreds of genes are involved in each physiological step necessary for guaranteeing reproductive success in mammals. In such scenario, next generation sequencing provides a potentially interesting tool for research into recurrent pregnancy loss causative mutations. The present study involved whole-exome sequencing and an innovative bioinformatics analysis, for the first time, in 49 unrelated women affected by recurrent pregnancy loss. We identified 27 coding variants (22 genes) potentially related to the phenotype (41% of patients). The affected genes, which were enriched by potentially deleterious sequence variants, belonged to distinct molecular cascades playing key roles in implantation/pregnancy biology. Using a quantum chemical approach method we established that mutations in MMP-10 and FGA proteins led to substantial energetic modifications suggesting an impact on their functions and/or stability. The next generation sequencing and bioinformatics approaches presented here represent an efficient way to find mutations, having potentially moderate/strong functional effects, associated with recurrent pregnancy loss aetiology. We consider that some of these variants (and genes) represent probable future biomarkers for recurrent pregnancy loss.


Digestion degree is a key factor to regulate the printability of pure tendon decellularized extracellular matrix bio-ink in extrusion-based 3D cell printing.
Improving the printability of pure, decellularized extracellular matrix (dECM) bio-ink without altering its physiological components has been a challenge in three-dimensional (3D) cell printing. To improve the printability of the bio-ink, we first investigated the digestion process of the powdered dECM material obtained from porcine tendons. We manifested the digestion process of tendon derived dECM powders, which includes dissolution, gelatinization and solubilization. After a short dissolution period (around 10 min), we observed a 'High viscosity slurry' status (3 h) of the dECM precursors, i.e. the gelatinization process, followed by the solubilization processes, i.e. a 'Medium viscosity slurry' period (12 h) and a 'Low viscosity slurry' period (72 h). The 'Medium viscosity slurry' status of the dECM bio-ink was inhomogeneous and could not be extruded out from the barrel after the pH value was neutralized to 7.4. Although the 'Low viscosity slurry' status of the dECM bio-ink has been reported to be extrudable, it has poor printability. This study explores the printability of the 'High viscosity slurry' status of the dECM bio-ink, which has not been addressed thus far. The results demonstrate that this less digested status of the dECM bio-ink yields higher shape fidelity and stacking accuracy than the traditional over-digested status of the dECM bio-ink; this indicates better printability of this less digested dECM bio-ink. We compared the performance of the two bio-inks using cell viability tests for 3D cell printing. Bone marrow mesenchymal stem cells derived from rats was printed using the 'High viscosity slurry' status of the dECM bio-ink, yielding high cellular viability lasting for 7 d after printing. Thus, the 'High viscosity slurry' status of tendon dECM bio-ink can be utilized to fabricate complicated 3D organoid structures; it also shows promise for applications such as regenerative medicine and biomimetic tissue engineering.


The social cost of contacts: Theory and evidence for the first wave of the COVID-19 pandemic in Germany.
Building on the epidemiological SIR model, we present an economic model with heterogeneous individuals deriving utility from social contacts creating infection risks. Focusing on social distancing of individuals susceptible to an infection we theoretically characterize the gap between private and social cost of contacts. Our main contribution is to quantify this gap by calibrating the model with unique survey data from Germany on social distancing and impure altruism from the beginning of the COVID-19 pandemic. The optimal policy is to drastically reduce contacts at the beginning to almost eradicate the epidemic and keep them at levels that contain the pandemic at a low prevalence level. We find that also in laissez faire, private protection efforts by forward-looking, risk averse individuals would have stabilized the epidemic, but at a much higher prevalence of infection than optimal. Altruistic motives increase individual protection efforts, but a substantial gap to the social optimum remains.


Effect of Anagliptin on Glycemic and Lipid Profile in Patients With Type 2 Diabetes Mellitus.
Anagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor expected to improve the lipid profile as well as glycemic control. However, findings from large-scale prospective trials have not been obtained. We performed a multicenter prospective trial in patients with type 2 diabetes receiving anagliptin to evaluate its effect on glycemic control and the lipid profile. A total of 95 patients received anagliptin at 200 mg twice daily. Markers of glucose and lipid metabolism were measured at baseline and after 12 and 24 weeks of administration, and the absolute changes and percent changes were determined. Both HbA1c and plasma glucose were significantly decreased by anagliptin therapy. Regarding the lipid profile, total cholesterol (TC) showed a significant decrease at 12 weeks, while TC, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were significantly decreased at 24 weeks. Multivariate analysis revealed that female sex was an independent predictor of greater reduction of TC, LDL-C, and HDL-C, while a baseline TC level ≥ 200 mg/dL predicted greater reduction of TC and a baseline HDL-C level ≥ 40 mg/dL predicted greater reduction of LDL-C and HDL-C. This study suggested that anagliptin significantly reduced TC, LDL-C, and HDL-C levels, as well as improving glycemic control, particularly in female patients.


Islet cell autoimmunity and transplantation tolerance: two distinct mechanisms?
Recent advances in islet transplantation have enabled physicians to cure type 1 autoimmune diabetes, but at the cost of lifelong immunosuppression with its attendant side effects and long-term health risks. To eliminate the need for immunosuppression, researchers have developed methods for inducing tolerance to transplanted allografts. Tolerance-based transplantation using costimulation blockade has proven remarkably successful in many animal model systems. The most widely used animal model system for studying islet transplantation in type 1-like autoimmune diabetes is the NOD mouse. Unfortunately, this strain has proven resistant to costimulation blockade-based transplantation tolerance protocols that are successful in chemically diabetic mice given islet grafts. It has been assumed that resistance to transplantation tolerance in the NOD mouse is (1) related to autoimmunity directed against its pancreatic beta cells, (2) a consequence of that autoimmunity, and (3) under the control of the same genes that control autoimmunity. In this review, we provide arguments to challenge these assumptions. We describe a new animal model and a new conceptual framework based on data indicating that the mechanisms responsible for resistance to transplantation tolerance and beta cell autoimmunity are not identical. We believe that the recent discoveries we describe will have important implications for the development of tolerance-based transplantation therapies and their translation from the laboratory to the clinic.


Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children.
BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.


18S-NemaBase: Curated 18S rRNA Database of Nematode Sequences.
Nematodes are the most abundant and diverse animals on the planet but lack representation in biodiversity research. This presents a problem for studying nematode diversity, particularly when molecular tools (i.e., barcoding and metabarcoding) rely on well-populated and curated reference databases, which are absent for nematodes. To improve molecular identification and the assessment of nematode diversity, we created and curated an 18S rRNA database specific to nematodes (18S-NemaBase) using sequences sourced from the most recent publicly available 18S rRNA SILVA v138 database. As part of the curation process, taxonomic strings were standardized to contain a fixed number of taxonomic ranks relevant to nematology and updated for the most recent accepted nematode classifications. In addition, apparent erroneous sequences were removed. To test the efficacy and accuracy of 18S-NemaBase, we compared it to an older but also curated SILVA v111 and the newest SILVA v138 by assigning taxonomies and analyzing the diversity of a nematode dataset from the Western Nebraska Sandhills. We showed that 18S-NemaBase provided more accurate taxonomic assignments and diversity assessments than either version of SILVA, with a much easier workflow and no need for manual corrections. Additionally, observed diversity further improved when 18S-NemaBase was supplemented with reference sequences from nematodes present in the study site. Although the 18S-NemaBase is a step in the right direction, a concerted effort to increase the number of high-quality, accessible, full-length nematode reference sequences is more important now than ever.


Image quality and radiation exposure with prospectively ECG-triggered axial scanning for coronary CT angiography: the multicenter, multivendor, randomized PROTECTION-III study.
The purpose of this study was to evaluate image quality and radiation dose using a prospectively electrocardiogram (ECG)-triggered axial scan protocol compared with standard retrospective ECG-gated helical scanning for coronary computed tomography angiography. Concerns have been raised regarding radiation exposure during coronary computed tomography angiography. Although the use of prospectively ECG-triggered axial scan protocols may effectively lower radiation dose compared with helical scanning, it is unknown whether image quality is maintained in a clinical setting. In a prospective, multicenter, multivendor trial, 400 patients with low and stable heart rates were randomized to either an axial or a helical coronary computed tomography angiography scan protocol. The primary endpoint was to demonstrate noninferiority in image quality with the axial scan protocol, which was assessed on a 4-point scale (1 = nondiagnostic, 4 = excellent image quality). Secondary endpoints included radiation dose and the rate of downstream testing during 30-day follow-up. Image quality in patients scanned with the axial scan protocol (score 3.36 ± 0.59) was not inferior compared with helical scan protocols (3.37 ± 0.59) (p for noninferiority <0.004). Axial scanning was associated with a 69% reduction in radiation exposure (dose-length product [estimated effective dose] 252 ± 147 mGy · cm [3.5 ± 2.1 mSv] vs. 802 ± 419 mGy · cm [11.2 ± 5.9 mSv] for axial vs. helical scan protocols, p < 0.001). The rate of downstream testing did not differ (13.8% vs. 15.9% for axial vs. helical scan protocols, p = 0.555). In patients with stable and low heart rates, the prospectively ECG-triggered axial scan protocol maintained image quality but reduced radiation exposure by 69% compared with helical scanning. Axial computed tomography data acquisition should be strongly recommended in suitable patients to avoid unnecessarily high radiation exposure.


Breast carcinoma in situ in 167 women--incidence, mode of presentation, therapy and follow-up.
In the city of Malmö, in southern Sweden, 1693 women were diagnosed as having breast carcinoma during 1976 through 1984. Of these, 167 women had pure in situ breast carcinoma (9.9%). One hundred and thirty-two had ductal carcinoma in situ (DCIS) alone or in combination with lobular carcinoma in situ (LCIS), intracystic carcinoma and/or Paget's disease of the nipple. Thirty-three had pure LCIS and two had pure intracystic carcinomas. The incidence of breast carcinoma in situ (CIS) in women 20 years of age or older was 18.7 per 10(5) woman years with high rates of DCIS for all ages above 40, whereas a decline in incidence rate was seen for LCIS in the postmenopausal age groups. The ratio of DCIS to LCIS was 4:1. Of the 132 patients with DCIS, 46% were asymptomatic and were diagnosed by mammography, 35% presented with clinical symptoms, and 19% of the cases were incidental findings in breasts operated on for benign lesions. Mammography had been performed on all patients with DCIS and contributed to diagnosis in 75%. Sixty-one per cent of all DCIS lesions had microcalcifications suspicious for carcinoma. Eighty-nine of 132 patients with DCIS underwent fine-needle aspiration biopsy (FNAB) before surgical biopsy. FNAB was suspicious or diagnostic for carcinoma in 57/89 (64%). Of 33 cases with LCIS all but one were incidental findings. In one of 28 cases with LCIS examined by mammography there was suspicion of carcinoma. Sixteen per cent of the patients with DCIS were treated by a breast-conserving operation (BCO), the remaining patients by mastectomy (ME) (52%) or subcutaneous mastectomy (SCM) (33%) with immediate reconstruction. Thirty-three per cent of the patients with LCIS were treated by BCO, the remaining patients by ME (18%) or SCM (49%) with immediate reconstruction. Only one patient had radiotherapy postoperatively. In 60% of all CIS cases where an excisional biopsy had been performed there were further foci of CIS in the final ME/SCM specimen. After a median follow-up of 7 years for the DCIS group, three patients out of 21 treated by BCO had invasive carcinoma appearing ipsilaterally. They were alive and without symptoms of recurrent disease 2.5 to 6 years following further surgery. One patient treated by SCM died from generalized ductal breast carcinoma. In the LCIS group (median follow-up 8 years) one patient out of 11 had an invasive tubular carcinoma diagnosed 4 years after BCO. Eight years later she was alive and well after bilateral SCM.


The attitudes of patients and staff towards aspects of health promotion interventions in mental health services in Sweden.
The present study investigates attitudes towards aspects of health promotion in mental health services, as rated by patients and staff. The aim of the study was to investigate similarities and differences in attitudes towards health promotion interventions among patients and staff in mental health services, using a newly developed questionnaire, the Health Promotion Intervention Questionnaire (HPIQ). The study has a cross-sectional design and a sample of 141 patients and 140 staff were recruited to the study. The response rate was 59% for the patients and 50% for the staff. The participants were asked to rate the attitudes of the 19 items included in the HPIQ. The result showed that patients and staff in some cases share similar attitudes regarding aspects of health promotion intervention. According to both groups, empowerment is the most important intervention in health promotion. Significant differences between the ratings of patients and staff appeared regarding all subscales of HPIQ. Patients rated alliance and educational support significantly higher than staff and staff-rated empowerment and practical support significantly higher than patients. Based on these findings, it is of importance to meet patients' desire for information and knowledge in an interactive manner with an empowerment approach to promote health in mental health services.


Aging and Network Properties: Stability Over Time and Links with Learning during Working Memory Training.
Growing evidence suggests that healthy aging affects the configuration of large-scale functional brain networks. This includes reducing network modularity and local efficiency. However, the stability of these effects over time and their potential role in learning remain poorly understood. The goal of the present study was to further clarify previously reported age effects on "resting-state" networks, to test their reliability over time, and to assess their relation to subsequent learning during training. Resting-state fMRI data from 23 young (YA) and 20 older adults (OA) were acquired in 2 sessions 2 weeks apart. Graph-theoretic analyses identified both consistencies in network structure and differences in module composition between YA and OA, suggesting topological changes and less stability of functional network configuration with aging. Brain-wide, OA showed lower modularity and local efficiency compared to YA, consistent with the idea of age-related functional dedifferentiation, and these effects were replicable over time. At the level of individual networks, OA consistently showed greater participation and lower local efficiency and within-network connectivity in the cingulo-opercular network, as well as lower intra-network connectivity in the default-mode network and greater participation of the somato-sensorimotor network, suggesting age-related differential effects at the level of specialized brain modules. Finally, brain-wide network properties showed associations, albeit limited, with learning rates, as assessed with 10 days of computerized working memory training administered after the resting-state sessions, suggesting that baseline network configuration may influence subsequent learning outcomes. Identification of neural mechanisms associated with learning-induced plasticity is important for further clarifying whether and how such changes predict the magnitude and maintenance of training gains, as well as the extent and limits of cognitive transfer in both younger and older adults.


The patient-as-partner approach in health care: a conceptual framework for a necessary transition.
The prevalence of chronic diseases today calls for new ways of working with patients to manage their care. Although patient-centered approaches have contributed to significant advances in care and to treatments that more fully respect patients' preferences, values, and personal experiences, the reality is that health care professionals still hold a monopoly on the role of healer. Patients live with their conditions every day and are experts when it comes to their own experiences of illness; this expertise should be welcomed, valued, and fostered by other members of the care team. The patient-as-partner approach embodies the ideal of making the patient a bona fide member of the health care team, a true partner in his or her care. Since 2010, the University of Montreal, through the Direction of Collaboration and Patient Partnership, has embraced this approach. Patients are not only active members of their own health care team but also are involved in research and provide valuable training to health sciences students. Including patients as full partners in the health care team entails a significant shift in both the medical practice and medical education cultures. In this perspective, the authors describe this innovative approach to patient care, including the conceptual framework used in its development and the main achievements of patient partners in education, health care, and research.


Evidence-based complementary and alternative veterinary medicine--a contradiction in terms?
Complementary and Alternative Medicine (CAM) like acupuncture, herbal medicine and homeopathy is increasingly used in the treatment of human and animal disease. On the other hand, CAM is discussed controversially, especially in the context of Evidence-Based Veterinary Medicine (EBVM). This paper provides a balanced analysis of the currently available data on CAM in human and veterinary medicine. In conclusion, little rigorous research data concerning the efficacy and safety of CAM has been published. However, acupuncture is gaining increasing acceptance in academic medicine, based on several metaanalyses that show efficacy for specific conditions. In practice, decisions concerning CAM therapies should also be based on the best available evidence provided by scientifically valid data. This implies that CAM interventions must be validated by stringent high quality research to obtain an objective and replicable overview of efficacy and safety. Nevertheless, trials should be designed according to important aspects of CAM therapies (e.g. individual treatment). In conclusion, Evidence-Based Alternative Veterinary Medicine is not a contradiction in terms.


Genomic determinants of speciation and spread of the Mycobacterium tuberculosis complex.
Models on how bacterial lineages differentiate increase our understanding of early bacterial speciation events and the genetic loci involved. Here, we analyze the population genomics events leading to the emergence of the tuberculosis pathogen. The emergence is characterized by a combination of recombination events involving core pathogenesis functions and purifying selection on early diverging loci. We identify the phoR gene, the sensor kinase of a two-component system involved in virulence, as a key functional player subject to pervasive positive selection after the divergence of the Mycobacterium tuberculosis complex from its ancestor. Previous evidence showed that phoR mutations played a central role in the adaptation of the pathogen to different host species. Now, we show that phoR mutations have been under selection during the early spread of human tuberculosis, during later expansions, and in ongoing transmission events. Our results show that linking pathogen evolution across evolutionary and epidemiological time scales points to past and present virulence determinants.


Proteomics analysis of Psychotria leaf nodule symbiosis: improved genome annotation and metabolic predictions.
Several plant species of the genus Psychotria (Rubiaceae) harbor Burkholderia sp. bacteria within specialized leaf nodules. The bacteria are transmitted vertically between plant generations and have not yet been cultured outside of their host. This symbiosis is considered to be obligatory because plants devoid of symbionts fail to develop into mature individuals. The genome of 'Candidatus Burkholderia kirkii' has been sequenced recently and has revealed evidence of reductive genome evolution, as shown by the proliferation of insertion sequences and the presence of numerous pseudogenes. We employed shotgun proteomics to investigate the expression of 'Ca. B. kirkii' proteins in the leaf nodule. Drawing from this dataset and refined comparative genomics analyses, we designed a new pseudogene prediction algorithm and improved the genome annotation. We also found conclusive evidence that nodule bacteria allocate vast resources to synthesis of secondary metabolites, possibly of the C7N aminocyclitol family. Expression of a putative 2-epi-5-valiolone synthase, a key enzyme of the C7N aminocyclitol synthesis, is high in the nodule population but downregulated in bacteria residing in the shoot apex, suggesting that production of secondary metabolites is particularly important in the leaf nodule.


Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity.
Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer classes of SERMs also exhibit cytotoxic effects in cancers devoid of ERs, indicating a non-estrogenic mechanism of action. Indicative of a potential ER-independent target, reports demonstrate that tamoxifen binds to cannabinoid receptors (CBRs) with affinity in the low μM range and acts as an inverse agonist. To identify cannabinoids with improved pharmacological properties relative to tamoxifen, and further investigate the use of different SERM scaffolds for future cannabinoid drug development, this study characterized the affinity and activity of SERMs in newer structural classes at CBRs. Fourteen SERMs from five structurally distinct classes were screened for binding to human CBRs. Compounds from four of five SERM classes examined bound to CBRs. Subsequent studies fully characterized CBR affinity and activity of one compound from each class. Ospemifine (a triphenylethylene) selectively bound to CB1Rs, while bazedoxifine (an indole) bound to CB2Rs with highest affinity. Nafoxidine (a tetrahydronaphthalene) and raloxifene (RAL; a benzothiaphene) bound to CB1 and CB2Rs non-selectively. All four compounds acted as inverse agonists at CB1 and CB2Rs, reducing basal G-protein activity with IC50 values in the nM to low μM range. Ospemifine, bazedoxifene and RAL also acted as inverse agonists to elevate basal intracellular cAMP levels in intact CHO-hCB2 cells. The four SERMs examined also acted as CB1 and CB2R antagonists in the cAMP assay, producing rightward shifts in the concentration-effect curve of the CBR agonist CP-55,940. In conclusion, newer classes of SERMs exhibit improved pharmacological characteristics (e.g., in CBR affinity and selectivity) relative to initial studies with tamoxifen, and thus suggest that different SERM scaffolds may be useful for development of safe and selective drugs acting via CBRs.


Microfluidic analysis of red blood cell deformability as a means to assess hemin-induced oxidative stress resulting from Plasmodium falciparum intraerythrocytic parasitism.
Hemolytic anemia is one of the hallmarks of malaria and leads to an increase in oxidized heme (hemin) within the plasma of infected individuals. While scavenger proteins sequester much of the circulating heme, it has been hypothesized that extracellular heme may play a central role in malaria pathogenesis. We have previously developed the multiplex fluidic plunger (MFP) device for the measurement of red blood cell (RBC) deformability. Here, we demonstrate that the measurement of changes in RBC deformability is a sensitive method for inferring heme-induced oxidative stress. We further show that extracellular hemin concentration correlates closely with changes in RBC deformability and we confirm that this biophysical change correlates with other indicators of cell stress. Finally, we show that reduced erythrocyte deformability corresponds with both erythrophagocytosis and RBC osmotic fragility. The MFP microfluidic device presents a simple and potentially inexpensive alternative to existing methods for measuring hemolytic cell stress that could ultimately be used to perform clinical assessment of disease progression in severe malaria.


Dissociation of lens fibre gap junctions releases MP70.
MIP and MP70 are putative gap junction components in the plasma membranes of the mammalian lens fibre cells. We show now that MP70 can be solubilized separately from MIP in mild detergent solutions, and that this treatment results in the dissociation of the fibre gap junctions. Solubilized MP70 was isolated as 16.9 S particles by velocity gradient centrifugation and in the electron microscope had the appearance of short double-membrane structures consistent with connexon-pairs. These observations open a new experimental avenue in which to characterize separately the two putative lens gap junction proteins structurally and functionally.


Problems of treatment process selection for relief agency water supplies in an emergency.
There is currently limited public information available concerning methods for the selection of appropriate water treatment technologies for application in acute phase emergency water and sanitation responses. Considering the number of available emergency water treatment and supply options, it is speculated that a framework methodology offering guidance in the form of a selection process would offer advantages. This process would relate a defined set of emergency factors to a selection of available water treatment and supply options, described by a basic, but complete, set of technical and operational characteristics. It is suggested that, whilst not a complete process, the proposed framework methodology is sufficient to lead to the identification and selection of appropriate options for deployment. Furthermore the support of critical decision making by a logical framework, could help shape and justify the actions of agencies and workers in the field.


Facilitation of the induction of long-term potentiation by GABAB receptors.
Long-term potentiation (LTP), an in vitro model of learning, was induced in hippocampal slices by 5-hertz stimulation. During induction, gamma-aminobutyric acid A (GABAA) inhibition decreased, causing the N-methyl-D-aspartate receptor-mediated excitation to increase. 2-OH Saclofen, a GABAB receptor antagonist, prevented the reduction of inhibition, the increase of excitation, and the induction of LTP. Therefore, disinhibition caused by GABAB receptors is required for induction of LTP by 5-hertz stimulation. GABAB receptor modulation of synaptic plasticity occurs at frequencies in the range of the endogenous hippocampal theta rhythm, which has been shown to modulate LTP in vivo.


HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer.
Histone deacetylases (HDACs) are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC), but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21(WAF1/Cip1) and p27(Kip1) expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21(WAF1/Cip1) transcriptional activity through Sp1-binding sites in the p21(WAF1/Cip1) promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy.


Outcomes in patients admitted for rehabilitation with spinal cord or cauda equina lesions following degenerative spinal stenosis.
To evaluate outcome measures and the factors affecting them in patients treated between 1,962 and 2,000 at Loewenstein Rehabilitation Hospital, Israel. This retrospective cohort study included 262 patients with spinal neurological lesions (spinal cord or cauda equina lesions) following degenerative spinal stenosis. Data were collected retrospectively. Survival was assessed using the Kaplan-Meier method and the relative mortality risk by the Cox model. Neurological recovery was evaluated by the change in Frankel grades, and factors that affect it were assessed by logistic regression. Associations of length of stay in rehabilitation were analyzed with ANOVA. Median age at lesion onset was 61 years and median survival 17.6 years. Age at spinal neurological lesion onset was found to be the only factor with a significant effect on survival. Of the 148 patients who had Frankel grades A, B, or C on admission, 58% achieved recovery to grades D and E. Frankel grade at admission, age, and spinal neurological level had a significant effect on recovery. The mean length of stay was 99.7 days, and only Frankel grade had a significant effect on length of stay. Patients with spinal stenosis and disabling spinal neurological lesions can achieve significant neurological recovery and survive for many years. They require adequate care in a specialist rehabilitation system.


High-throughput continuous hydrothermal flow synthesis of Zn-Ce oxides: unprecedented solubility of Zn in the nanoparticle fluorite lattice.
High-throughput continuous hydrothermal flow synthesis has been used as a rapid and efficient synthetic route to produce a range of crystalline nanopowders in the Ce-Zn oxide binary system. High-resolution powder X-ray diffraction data were obtained for both as-prepared and heat-treated (850 degrees C for 10 h in air) samples using the new robotic beamline I11, located at Diamond Light Source. The influence of the sample composition on the crystal structure and on the optical and physical properties was studied. All the nanomaterials were characterized using Raman spectroscopy, UV-visible spectrophotometry, Brunauer-Emmett-Teller surface area and elemental analysis (via energy-dispersive X-ray spectroscopy). Initially, for 'as-prepared' Ce(1-x)Zn(x)O(y), a phase-pure cerium oxide (fluorite) structure was obtained for nominal values of x=0.1 and 0.2. Biphasic mixtures were obtained for nominal values of x in the range of 0.3-0.9 (inclusive). High-resolution transmission electron microscopy images revealed that the phase-pure nano-CeO(2) (x=0) consisted of ca 3.7 nm well-defined nanoparticles. The nanomaterials produced herein generally had high surface areas (greater than 150 m(2) g(-1)) and possessed combinations of particle properties (e.g. bandgap, crystallinity, size, etc.) that were unobtainable or difficult to achieve by other more conventional synthetic methods.


The association between oral contraceptive use and lobular and ductal breast cancer in young women.
Recent reports indicate that the incidence of lobular breast cancer is increasing at a faster rate than ductal breast cancer, which may be due to the differential effects of exogenous hormones by histology. To address this issue, we examined whether the relationship between oral contraceptive use and incident breast cancer differs between lobular and ductal subtypes in young women. A population-based sample of in situ and invasive breast cancer cases between ages 20 and 44 were recruited from Atlanta, GA; Seattle-Puget Sound, WA and central New Jersey. Controls were sampled from the same areas by random-digit dialing, and were frequency matched to the expected case age distribution. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using polytomous logistic regression. Among the 100 lobular cancers, 1,164 ductal cancers, and 1,501 controls, the odds ratios for oral contraceptive ever use were 1.10 (95% CI = 0.68-1.78) for lobular cancers and 1.21 (95% CI = 1.01-1.45) for ductal cancers, adjusted for study site, age at diagnosis, and pap screening history. Our results suggest that the magnitude of the association between ever use of oral contraceptives and breast cancer in young women does not vary strongly by histologic subtype. These results are similar to previous studies that report little difference in the effect of oral contraceptive use on breast cancer by histology.


Adiponectin in eutrophic and obese children as a biomarker to predict metabolic syndrome and each of its components.
Obesity is associated with the rise of noncommunicable diseases worldwide. The pathophysiology behind this disease involves the increase of adipose tissue, being inversely related to adiponectin, but directly related to insulin resistance and metabolic syndrome (MetS). Therefore, this study aimed to determine the relationship between adiponectin levels with each component of MetS in eutrophic and obese Mexican children. A cross sectional study was conducted in 190 school-age children classified as obese and 196 classified as eutrophic. Adiponectin, glucose, insulin, high density lipoprotein cholesterol (HDL-C) and triglycerides were determined from a fasting blood sample. Height, weight, waist circumference, systolic and diastolic blood pressures (BP) were measured; MetS was evaluated with the IDF definition. The study groups were divided according to tertiles of adiponectin, using the higher concentration as a reference. Linear regression analysis was used to assess the association between adiponectin and components of the MetS. Finally, stepwise forward multiple logistic regression analysis controlling for age, gender, basal HOMA-IR values and BMI was performed to determine the odds ratio of developing MetS according to adiponectin tertiles. Anthropometric and metabolic measurements were statistically different between eutrophic and obese children with and without MetS (P <0.001). The prevalence of MetS in obese populations was 13%. Adiponectin concentrations were 15.5 ± 6.1, 12.0 ± 4.8, 12.4 ± 4.9 and 9.4 ± 2.8 μg/mL for eutrophic and obese subjects, obese without MetS, and obese with MetS, respectively (P <0.001). Obese children with low values of adiponectin exhibited a higher frequency of MetS components: abdominal obesity, 49%; high systolic BP, 3%; high diastolic BP, 2%; impaired fasting glucose, 17%; hypertriglyceridemia, 31%; and low HDL-C values, 42%. Adjusted odds ratio of presenting MetS according to adiponectin categories was 10.9 (95% CI 2.05; 48.16) when the first tertile was compared with the third. In this sample of eutrophic and obese Mexican children we found that adiponectin concentrations and MetS components have an inversely proportional relationship, which supports the idea that this hormone could be a biomarker for identifying individuals with risk of developing MetS.


Skeletal muscle fiber-type distribution and habitual physical activity in daily life.
The capacity to perform physical activity largely depends on physical fitness. Muscle fiber-type distribution (Muscle(FTD)) is associated with physical fitness and may influence the capacity to perform physical activity. The purpose of this study was to determine whether habitual physical activity in daily life (PA(DL)) and Muscle(FTD) are related. Thirty-eight healthy non-athletes (31 women, 7 men) were recruited. PA(DL) was measured twice for 14 days using a tri-axial accelerometer for movement registration (Tracmor). From Tracmor output, the proportion of time subjects were physically active at low, moderate, and high intensities was determined (%Low, %Moderate, and %High, respectively). A total activity index (PA(index)) and sub-scores on work, leisure-time and sports were obtained using the Baecke questionnaire. Muscle(FTD) was determined using immuno-fluorescence against respective myosin heavy chain isoforms. No relationship was observed between PA(DL) and Muscle(FTD). %Low, %Moderate, and %High, as well as PA(index) and its sub-scores, were not related to Muscle(FTD) either. The time spent on sports was associated with the proportion of type I and II(X) fibers (P=0.06 and P<0.01, respectively). In conclusion, Muscle(FTD) probably cannot explain why some people are more prone to engaging in physical activities than others.


Complete genome sequence of Bacteroides salanitronis type strain (BL78).
Bacteroides salanitronis Lan et al. 2006 is a species of the genus Bacteroides, which belongs to the family Bacteroidaceae. The species is of interest because it was isolated from the gut of a chicken and the growing awareness that the anaerobic microflora of the cecum is of benefit for the host and may impact poultry farming. The 4,308,663 bp long genome consists of a 4.24 Mbp chromosome and three plasmids (6 kbp, 19 kbp, 40 kbp) containing 3,737 protein-coding and 101 RNA genes and is a part of the Genomic Encyclopedia of Bacteria and Archaea project.


Factors influencing GAP-43 gene expression in PC12 pheochromocytoma cells.
We have studied factors controlling message levels for the neuronal growth- and plasticity-associated protein, GAP-43. Following exposure of PC12 cells to various effectors, cytoplasmic RNA was isolated and analyzed by Northern transfer and autoradiography using a GAP-43 cDNA probe. Induction by NGF is apparent after 3 hr exposure and reaches maximal levels at 24 hr. Beyond 24 hr, levels remain constant in the continued presence of NGF. Induction is insensitive to variations in culture conditions, such as plating density or substrate, which influence NGF-induced neurite outgrowth. Other inducers, in order of decreasing efficacy, are FGF, dBcAMP, TPA, K+, and EGF. Insulin and retinoic acid are ineffective. Dexamethasone partially inhibited basal expression as well as induction by NGF, FGF, dBcAMP, and TPA. The methyltransferase inhibitor 5'-S-(2-methyl-propyl)adenosine completely inhibited induction by NGF, FGF, and dBcAMP. Inhibition of protein synthesis by cycloheximide partially decreased induction by NGF, FGF, and TPA but slightly enhanced dBcAMP induction. Complete down-regulation of protein kinase C by chronic TPA treatment completely eliminated the TPA response but slightly enhanced induction by NGF. These findings and the results of additivity experiments in which cells were stimulated with various combinations of NGF, dBcAMP and TPA suggest that NGF induction of GAP-43 RNA (1) does not involve activation of protein kinase C but (2) may be mediated partially via activation of protein kinase A.


Electromagnetic noise inhibits radiofrequency radiation-induced DNA damage and reactive oxygen species increase in human lens epithelial cells.
The goal of this study was to investigate whether superposing of electromagnetic noise could block or attenuate DNA damage and intracellular reactive oxygen species (ROS) increase of cultured human lens epithelial cells (HLECs) induced by acute exposure to 1.8 GHz radiofrequency field (RF) of the Global System for Mobile Communications (GSM). An sXc-1800 RF exposure system was used to produce a GSM signal at 1.8 GHz (217 Hz amplitude-modulated) with the specific absorption rate (SAR) of 1, 2, 3, and 4 W/kg. After 2 h of intermittent exposure, the ROS level was assessed by the fluorescent probe, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). DNA damage to HLECs was examined by alkaline comet assay and the phosphorylated form of histone variant H2AX (gammaH2AX) foci formation assay. After exposure to 1.8 GHz RF for 2 h, HLECs exhibited significant intracellular ROS increase in the 2, 3, and 4 W/kg groups. RF radiation at the SAR of 3 W/kg and 4 W/kg could induce significant DNA damage, examined by alkaline comet assay, which was used to detect mainly single strand breaks (SSBs), while no statistical difference in double strand breaks (DSBs), evaluated by gammaH2AX foci, was found between RF exposure (SAR: 3 and 4 W/kg) and sham exposure groups. When RF was superposed with 2 muT electromagnetic noise could block RF-induced ROS increase and DNA damage. DNA damage induced by 1.8 GHz radiofrequency field for 2 h, which was mainly SSBs, may be associated with the increased ROS production. Electromagnetic noise could block RF-induced ROS formation and DNA damage.


Repeated GenomiPhi, phi29 DNA polymerase-based rolling circle amplification, is useful for generation of large amounts of plasmid DNA.
The GenomiPhi DNA Amplification Kit (Amersham Biosciences Co., Piscataway, NJ, USA) uses a novel, isothermal DNA amplification technique for production of microgram quantities of DNA from picograms of starting material. In this study, we tested whether repeated reactions using the kit would enhance high-fidelity amplification of a small amount (10 ng) of plasmid DNA containing enhanced green fluorescent protein (EGFP) cDNA. Approximately 4.7 x 10(9)-fold amplification of plasmid DNA was achieved after 3 repeated reactions, and the RCA products were sufficient for EGFP expression in cells. Based on the preliminary results, repeated reactions using the kit appears feasible for amplification of the entire genome of organisms or cells (such a sperms and oocytes) carrying very small amounts of DNA.


Genome-wide map of nuclear protein degradation shows NCoR1 turnover as a key to mitochondrial gene regulation.
Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.


Modeling motivations for non-medical use of prescription drugs.
Non-medical use of prescription drugs (NMUPD) is a growing problem among college-aged individuals. Motivations for use of a substance have been shown to predict consumption behavior across a variety of substances, but research on motivations for engaging in NMUPD is limited. We hypothesize that Confirmatory Factor Analysis (CFA) would support a two-factor latent structure for motivations (self-treatment and recreational) for NMUPD across three classes of drugs (stimulants, tranquilizers and sedatives, and pain relievers). Data were collected from 1016 undergraduates attending a large southeastern university via an online survey. Motivations for use were subjected to a CFA for those participants who reported past-year use of each drug class (tranquilizer and sedative use n=138, pain reliever use n=189, and stimulant use n=258). Model fit varied across drug class. A two-factor model emerged for both pain relievers and stimulants, and each factor was positively correlated with one another and with frequency of use for both drug classes. A two-factor model was not a good fit for tranquilizers and sedatives. Motives for NMUPD are a relatively understudied construct. Although our initial results suggest that a proposed framework consisting of self-treatment and recreational motives might have some utility in explaining the use of stimulants and pain relievers, more research is needed to characterize motives for tranquilizers and sedatives. Additional research is also needed to develop assessment measures that capture the full range of motives for all three classes of NMUPD.


Trends in trigonal prismatic Ln-[1]ferrocenophane complexes and discovery of a Ho3+ single-molecule magnet.
Lanthanide metallocenophanes are an intriguing class of organometallic complexes that feature rare six-coordinate trigonal prismatic coordination environments of 4f elements with close intramolecular proximity to transition metal ions. Herein, we present a systematic study of the structural and magnetic properties of the ferrocenophanes, [LnFc3(THF)2Li2]-, of the late trivalent lanthanide ions (Ln = Gd (1), Ho (2), Er (3), Tm (4), Yb (5), Lu (6)). One major structural trend within this class of complexes is the increasing diferrocenyl (Fc2-) average twist angle with decreasing ionic radius (r ion) of the central Ln ion, resulting in the largest average Fc2- twist angles for the Lu3+ compound 6. Such high sensitivity of the twist angle to changes in r ion is unique to the here presented ferrocenophane complexes and likely due to the large trigonal plane separation enforced by the ligand (>3.2 Å). This geometry also allows the non-Kramers ion Ho3+ to exhibit slow magnetic relaxation in the absence of applied dc fields, rendering compound 2 a rare example of a Ho-based single-molecule magnet (SMM) with barriers to magnetization reversal (U) of 110-131 cm-1. In contrast, compounds featuring Ln ions with prolate electron density (3-5) don't show slow magnetization dynamics under the same conditions. The observed trends in magnetic properties of 2-5 are supported by state-of-the-art ab initio calculations. Finally, the magneto-structural relationship of the trigonal prismatic Ho-[1]ferrocenophane motif was further investigated by axial ligand (THF in 2) exchange to yield [HoFc3(THF*)2Li2]- (2-THF*) and [HoFc3(py)2Li2]- (2-py) motifs. We find that larger average Fc2- twist angles (in 2-THF* and 2-py as compared to in 2) result in faster magnetic relaxation times at a given temperature.


Coarticulation of jaw movements in speech production: is context sensitivity in speech kinematics centrally planned?
Coarticulation in speech production is a phenomenon in which the articulator movements for a given speech sound vary systematically with the surrounding sounds and their associated movements. Although these variations may seem to be planned centrally, without explicit models of the speech articulators, the kinematic patterns that are attributable to central control cannot be distinguished from those that arise because of dynamics and are not represented in the underlying control signals. We address the origins of coarticulation by comparing the results of empirical and modeling studies of jaw motion in speech. The simulated kinematics of sagittal-plane jaw rotation and horizontal jaw translation are compared with the results of empirical studies in which subjects produce speech-like sequences at a normal rate and volume. The simulations examine both "anticipatory" and "carryover" coarticulatory effects. In both cases, the results show that even when no account is taken of context at the level of central control, kinematic patterns vary in amplitude and duration as a function of the magnitude of the preceding or following movement, in the same manner as that observed empirically in coarticulation. Because at least some coarticulatory effects may arise from muscle mechanics and jaw dynamics and not from central control, these factors must be considered before drawing inferences about control in coarticulation.


The prevalence and pattern of cavitated carious lesions in primary dentition among children under 5 years age in Sirsa, Haryana (India).
To determine the prevalence and pattern of cavitated carious lesions in primary dentition in children below 5 years of age in Sirsa, Haryana. The aim of this study was to evaluate the status of dental caries in primary dentition and compute data for planning anticipatory programs in children aged less than 5 years. The study was conducted among children attending the outpatient department of pedodontics, JCD Dental College, Sirsa, Haryana (India) from April to December 2014. This study consisted of 576 children of both sexes (311 males and 265 females) up to 5 years of age. Dentition status and treatment proforma (WHO, 1997) was used to assess the prevalence of cavitated carious lesions. Selection of children for the study was done by simple random sampling method. Chi-square test and t-test were used to compute data for statistical analysis. 33.85% of children in the study population showed presence of cavitated carious lesions. Males showed slightly higher prevalence of cavitated carious lesions than females (P = 0.35). Incidence of caries was higher in mandibular arch in both the sexes (males P = 0.9, females P = 0.7) and in posterior teeth (both sex wise and arch wise). Higher caries prevalence was noticed in maxillary anterior teeth (P = 0.04) and mandibular posterior teeth (P = 0.7). Primary second molars showed highest caries prevalence (P = 0.39) in both the arches and sexes. The mean prevalence of cavitated carious lesions in primary dentition was found to be 33.85%. Males were more affected than females. Mandibular molars and maxillary anterior teeth were the predominantly affected teeth. Mandibular anterior teeth were least affected. The increase in incidence of cavitated carious lesions shows that there is necessity of implementing dental health awareness programs and modifications in types of food consumed are needed to eliminate the cause of decay.


Promotion of mesenchymal-to-epithelial transition by Rac1 inhibition with small molecules accelerates hepatic differentiation of mesenchymal stromal cells.
In vitro differentiation of stem cells into specific cell lineages provides a stable cell supply for cell therapy and tissue engineering. Therefore, understanding the mechanisms underlying such differentiation processes is critical for generating committed lineage-specific cell progenies effectively. We previously developed a two-step protocol to differentiate mesenchymal stromal cells (MSCs) into hepatocyte-like cells. Since hepatic differentiation involves mesenchymal-epithelial transition (MET), we hypothesize that promoting MET could further accelerate the differentiation process. Ras-related C3 botulinum toxin substrate 1 (Rac1) is involved in actin polymerization and its role in MET was investigated in the study. Our results showed that inhibition of Rac1 activation by Rac1-specific inhibitor, NSC23766, led to cells favoring epithelial morphology and being more packed during hepatic differentiation. In addition, Rac1 inhibition accelerated the upregulation of hepatic marker genes accompanied by more mature hepatic functions. Taken together, promotion of MET by inhibiting Rac1 accelerates the hepatic differentiation of MSCs. Our findings open a new prospect of directing the commitment of MSCs by manipulating cell morphology and cytoskeleton arrangement through small molecules. The results provide further insight into scaffold design for rapid production of MSC-differentiated hepatocytes.


The genetics of attention deficit/hyperactivity disorder in adults, a review.
The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.


CD1d-restricted recognition of synthetic glycolipid antigens by human natural killer T cells.
A conserved subset of mature circulating T cells in humans expresses an invariant Valpha24-JalphaQ T cell receptor (TCR)-alpha chain rearrangement and several natural killer (NK) locus-encoded C-type lectins. These human T cells appear to be precise homologues of the subset of NK1.1(+) TCR-alpha/beta+ T cells, often referred to as NK T cells, which was initially identified in mice. Here we show that human NK T cell clones are strongly and specifically activated by the same synthetic glycolipid antigens as have been shown recently to stimulate murine NK T cells. Responses of human NK T cells to these synthetic glycolipids, consisting of certain alpha-anomeric sugars conjugated to an acylated phytosphingosine base, required presentation by antigen-presenting cells expressing the major histocompatibility complex class I-like CD1d protein. Presentation of synthetic glycolipid antigens to human NK T cells required internalization of the glycolipids by the antigen-presenting cell and normal endosomal targeting of CD1d. Recognition of these compounds by human NK T cells triggered proliferation, cytokine release, and cytotoxic activity. These results demonstrate a striking parallel in the specificity of NK T cells in humans and mice, thus providing further insight into the potential mechanisms of immune recognition by NK T cells and the immunological function of this unique T cell subset.


Beyond oral hygiene, are capacity-altering, biologically based interventions within the moral domain of dentistry?
Oral diseases such as dental caries (DC) and periodontitis are widely prevalent, and existing approaches to managing these conditions have only a limited effect. Accordingly, there is growing interest in the development of novel biological interventions (including, among others, CRISPR-Cas9) that might, in the future, be used to prevent the development of or cure these conditions. However, in addition to familiar concerns about using biological interventions in children who cannot provide valid consent, it is not clear whether the provision of these interventions would fall within the proper domain of dentistry. In this opinion paper, we defend the view that the provision of reasonably safe and effective novel biological interventions aimed at preventing DC and periodontitis should be understood to fall within the proper domain of dentistry. To do so, we first argue that their use would be consistent with existing practice in dentistry. We then argue that: i) they may substantially increase the recipient's wellbeing and future autonomy; and ii) that their use could constitute a form of indirect preventative medicine by addressing a threat to systemic health.


Back schools for acute and subacute non-specific low-back pain.
Since the introduction of the Swedish back school in 1969, back schools have frequently been used for treating people with low-back pain (LBP). However, the content of back schools has changed and appears to vary widely today. In this review we defined back school as a therapeutic programme given to groups of people, which includes both education and exercise. This is an update of a Cochrane review first published in 1999, and updated in 2004. For this review update, we split the review into two distinct reviews which separated acute from chronic LBP. To assess the effectiveness of back schools on pain and disability for people with acute or subacute non-specific LBP. We also examined the effect on work status and adverse events. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, PubMed and two clinical trials registers up to 4 August 2015. We also checked the reference lists of articles and contacted experts in the field of research on LBP. We included randomised controlled trials (RCTs) or quasi-RCTs that reported on back school for acute or subacute non-specific LBP. The primary outcomes were pain and disability. The secondary outcomes were work status and adverse events. Back school had to be compared with another treatment, a placebo (or sham or attention control) or no treatment. We used the 2009 updated method guidelines for this Cochrane review. Two review authors independently screened the references, assessed the quality of the trials and extracted the data. We set the threshold for low risk of bias, a priori, as six or more of 13 internal validity criteria and no serious flaws (e.g. large drop-out rate). We classified the quality of the evidence into one of four levels (high, moderate, low or very low) using the adapted Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We contacted study authors for additional information. We collected adverse effects information from the trials. The search update identified 273 new references, of which none fulfilled our inclusion criteria. We included four studies (643 participants) in this updated review, which were all included in the previous (2004) update. The quality of the evidence was very low for all outcomes. As data were too clinically heterogeneous to be pooled, we described individual trial results. The results indicate that there is very low quality evidence that back schools are no more effective than a placebo (or sham or attention control) or another treatment (physical therapies, myofascial therapy, joint manipulations, advice) on pain, disability, work status and adverse events at short-term, intermediate-term and long-term follow-up. There is very low quality evidence that shows a statistically significant difference between back schools and a placebo (or sham or attention control) for return to work at short-term follow-up in favour of back school. Very low quality evidence suggests that back school added to a back care programme is more effective than a back care programme alone for disability at short-term follow-up. Very low quality evidence also indicates that there is no difference in terms of adverse events between back school and myofascial therapy, joint manipulation and combined myofascial therapy and joint manipulation. It is uncertain if back schools are effective for acute and subacute non-specific LBP as there is only very low quality evidence available. While large well-conducted studies will likely provide more conclusive findings, back schools are not widely used interventions for acute and subacute LBP and further research into this area may not be a priority.


Involvement of annexin-I in glucose-induced insulin secretion in rat pancreatic islets.
Annexin-I was demonstrated to specifically present in islets and not in exocrine tissues of the rat pancreas and to have a diffuse and homogeneous distribution in all islet cells in our previous study. In the present report, to clarify the functions of annexin-I in rat pancreatic islets, especially in beta-cells, we investigated the role of annexin-I in insulin secretion. Immunoelectron microscopic analysis of pancreatic beta-cells demonstrated that immunogold particles reactive to annexin-I were almost exclusively observed on most of the insulin-containing granules (approximately 90%) and less frequently located in cytosol and other organelles, such as the endoplasmic reticulum and mitochondria. The number of annexin-I gold particles located on insulin granules after oral glucose administration was significantly increased compared with that observed in fasted rats. Moreover, when the isolated islets were stimulated by a high concentration of glucose (20 mM), the phosphorylation of annexin-I was markedly enhanced, and it was synchronized to insulin secretion. This phosphorylation mainly occurred on serine residues. H-7 (100 microM), a potent inhibitor of protein kinase-C, inhibited the phosphorylation to about 90%. These findings suggest that annexin-I might be involved in the regulatory mechanism of glucose-induced insulin secretion in rat pancreatic islets via phosphorylation-dephosphorylation processes.


Focusing on the bright tomorrow? A longitudinal study of organizational identification and projected continuity in a corporate merger.
Past research provides evidence that organizational identification is a key factor predicting employees' behaviours during mergers and acquisitions. In particular, recent studies demonstrate that members of the subordinate merger partner, in contrast to the dominant group, often find it difficult to transfer their identification to the post-merger organization. To understand this difference between dominant and subordinate groups, we examined employees' sense of projected continuity in the future. We argue that projected continuity mediates the differential relationships between pre-merger and post-merger identification and propose that pre-merger identification relates positively to projected continuity in the dominant group but negatively in the subordinate group. As a result, the overall relationship between pre- and post-merger identification should be reduced or eliminated in the subordinate compared with the dominant group. We tested our hypotheses in a survey (N = 492) distributed in a merger of two international pharmaceutical companies at the beginning of the post-merger integration and 15 months later. Results were consistent with our assumptions of a moderated mediation effect. We conclude that a key challenge in merger integration is to support high identifiers in the subordinate group in developing a projected continuity or a focus on 'the bright tomorrow'.


Gender Disparities in Access to Pediatric Renal Transplantation in Europe: Data From the ESPN/ERA-EDTA Registry.
Inequalities between genders in access to transplantation have been demonstrated. We aimed to validate this gender inequality in a large pediatric population and to investigate its causes. This cohort study included 6454 patients starting renal replacement therapy before 18 years old, in 35 countries participating in the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry. We used cumulative incidence competing risk and proportional hazards frailty models to study the time to receive a transplant and hierarchical logistic regression to investigate access to preemptive transplantation. Girls had a slower access to renal transplantation because of a 23% lower probability of receiving preemptive transplantation. We found a longer follow-up time before renal replacement therapy in boys compared with girls despite a similar estimated glomerular filtration rate at first appointment. Girls tend to progress faster toward end-stage renal disease than boys, which may contribute to a shorter time available for pretransplantation workup. Overall, medical factors explained only 70% of the gender difference. In Europe, girls have less access to preemptive transplantation for reasons that are only partially related to medical factors. Nonmedical factors such as patient motivation and parent and physician attitudes toward transplantation and organ donation may contribute to this inequality. Our study should raise awareness for the management of girls with renal diseases.


Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts.
Cultured myofibroblasts are characterized by stress fibers, containing alpha-smooth muscle actin (alpha-SMA) and by supermature focal adhesions (FAs), which are larger than FAs of alpha-SMA-negative fibroblasts. We have investigated the role of alpha-SMA for myofibroblast adhesion and FA maturation. Inverted centrifugation reveals two phases of initial myofibroblast attachment: during the first 2 h of plating microfilament bundles contain essentially cytoplasmic actin and myofibroblast adhesion is similar to that of alpha-SMA-negative fibroblasts. Then, myofibroblasts incorporate alpha-SMA in stress fibers, develop mature FAs and their adhesion capacity is significantly increased. When alpha-SMA expression is induced in 5 d culture by TGFbeta or low serum levels, fibroblast adhesion is further increased correlating with a "supermaturation" of FAs. Treatment of myofibroblasts with alpha-SMA fusion peptide (SMA-FP), which inhibits alpha-SMA-mediated contractile activity, reduces their adhesion to the level of alpha-SMA negative fibroblasts. With the use of flexible micropatterned substrates and EGFP-constructs we show that SMA-FP application leads to a decrease of myofibroblast contraction, shortly followed by disassembly of paxillin- and beta3 integrin-containing FAs; alpha5 integrin distribution is not affected. FRAP of beta3 integrin-EGFP demonstrates an increase of FA protein turnover following SMA-FP treatment. We conclude that the formation and stability of supermature FAs depends on a high alpha-SMA-mediated contractile activity of myofibroblast stress fibers.


System theory and safety models in Swedish, UK, Dutch and Australian road safety strategies.
Road safety strategies represent interventions on a complex social technical system level. An understanding of a theoretical basis and description is required for strategies to be structured and developed. Road safety strategies are described as systems, but have not been related to the theory, principles and basis by which systems have been developed and analysed. Recently, road safety strategies, which have been employed for many years in different countries, have moved to a 'vision zero', or 'safe system' style. The aim of this study was to analyse the successful Swedish, United Kingdom and Dutch road safety strategies against the older, and newer, Australian road safety strategies, with respect to their foundations in system theory and safety models. Analysis of the strategies against these foundations could indicate potential improvements. The content of four modern cases of road safety strategy was compared against each other, reviewed against scientific systems theory and reviewed against types of safety model. The strategies contained substantial similarities, but were different in terms of fundamental constructs and principles, with limited theoretical basis. The results indicate that the modern strategies do not include essential aspects of systems theory that describe relationships and interdependencies between key components. The description of these strategies as systems is therefore not well founded and deserves further development.