Human ribosomal RNA genes: orientation of the tandem array and conservation of the 5' end.
The multiple copies of the human ribosomal RNA genes (rDNA) are arranged as tandem repeat clusters that map to the middle of the short arms of chromosomes 13, 14, 15, 21, and 22. Concerted evolution of the gene family is thought to be mediated by interchromosomal recombination between rDNA repeat units, but such events would also result in conservation of the sequences distal to the rDNA on these five pairs of chromosomes. To test this possibility, a DNA fragment spanning the junction between rDNA and distal flanking sequence has been cloned and characterized. Restriction maps, sequence data, and gene mapping studies demonstrate that (i) the rRNA genes are transcribed in a telomere-to-centromere direction, (ii) the 5' end of the cluster and the adjacent non-rDNA sequences are conserved on the five pairs of chromosomes, and (iii) the 5' end of the cluster is positioned about 3.7 kb upstream from the transcription initiation site of the first repeat unit. The data support a model of concerted evolution by interchromosomal recombination.


Generation of diverse biological forms through combinatorial interactions between tissue polarity and growth.
A major problem in biology is to understand how complex tissue shapes may arise through growth. In many cases this process involves preferential growth along particular orientations raising the question of how these orientations are specified. One view is that orientations are specified through stresses in the tissue (axiality-based system). Another possibility is that orientations can be specified independently of stresses through molecular signalling (polarity-based system). The axiality-based system has recently been explored through computational modelling. Here we develop and apply a polarity-based system which we call the Growing Polarised Tissue (GPT) framework. Tissue is treated as a continuous material within which regionally expressed factors under genetic control may interact and propagate. Polarity is established by signals that propagate through the tissue and is anchored in regions termed tissue polarity organisers that are also under genetic control. Rates of growth parallel or perpendicular to the local polarity may then be specified through a regulatory network. The resulting growth depends on how specified growth patterns interact within the constraints of mechanically connected tissue. This constraint leads to the emergence of features such as curvature that were not directly specified by the regulatory networks. Resultant growth feeds back to influence spatial arrangements and local orientations of tissue, allowing complex shapes to emerge from simple rules. Moreover, asymmetries may emerge through interactions between polarity fields. We illustrate the value of the GPT-framework for understanding morphogenesis by applying it to a growing Snapdragon flower and indicate how the underlying hypotheses may be tested by computational simulation. We propose that combinatorial intractions between orientations and rates of growth, which are a key feature of polarity-based systems, have been exploited during evolution to generate a range of observed biological shapes.


Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis.
Caspase-2, the most evolutionarily conserved member in the human caspase family, may play important roles in stress-induced apoptosis, cell cycle regulation, and tumor suppression. In biochemical assays, caspase-2 uniquely prefers a pentapeptide (such as VDVAD) rather than a tetrapeptide, as required for efficient cleavage by other caspases. We investigated the molecular basis for pentapeptide specificity using peptide analog inhibitors and substrates that vary at the P5 position. We determined the crystal structures of apo caspase-2, caspase-2 in complex with peptide inhibitors VDVAD-CHO, ADVAD-CHO, and DVAD-CHO, and a T380A mutant of caspase-2 in complex with VDVAD-CHO. Two residues, Thr-380 and Tyr-420, are identified to be critical for the P5 residue recognition; mutation of the two residues reduces the catalytic efficiency by about 4- and 40-fold, respectively. The structures also provide a series of snapshots of caspase-2 in different catalytic states, shedding light on the mechanism of capase-2 activation, substrate binding, and catalysis. By comparing the apo and inhibited caspase-2 structures, we propose that the disruption of a non-conserved salt bridge between Glu-217 and the invariant Arg-378 is important for the activation of caspase-2. These findings broaden our understanding of caspase-2 substrate specificity and catalysis.


HIV-1 infection is characterized by profound depletion of CD161+ Th17 cells and gradual decline in regulatory T cells.
CD4 T-cell depletion is central to HIV pathogenesis. However, the relative impact of HIV on Th17 and regulatory T cell (Treg) subsets remains unclear. CD161 CD4 cells are a recently identified, gut-homing Th17 precursor population. The balance between pro-inflammatory Th17 and immunoregulatory Tregs may be critical in HIV pathogenesis. This study addressed changes in CD161, Th17 and Treg subsets during untreated HIV infection. Peripheral blood mononuclear cells were isolated from HIV-infected and HIV-uninfected individuals and stained to characterize CD161 CD4 cells, Th17 cells [by elaboration of interleukin (IL)-17A], Tregs (CD3CD4CD25FoxP3 cells) and CD8 activation (CD38/HLA-DR cells). In-vitro infectability of CD161 and Th17 cells by HIV was assessed in healthy donor CD4 cells by intracellular p24 expression. Peripheral blood Th17 cells were depleted 10-fold in HIV-infected, compared to HIV-uninfected individuals (P < 0.0001) across a range of disease stages, accompanied by a significant reduction of CD161 T cells (P = 0.024). Both Th17 cells and CD161 CD4 T cells were permissive to HIV replication in vitro. Profound loss of Th17 cells before the onset of advanced disease contrasted with a gradual decline in absolute Tregs during HIV disease progression in untreated individuals followed longitudinally (R = 0.71, P = 0.003). Loss of Tregs was associated with increased immune activation (R = -0.33, P = 0.03). HIV-infected individuals showed profound loss of Th17 cells, which may impair mucosal immunity, and reduced CD161 CD4 cells, which may limit Th17 reconstitution. A gradual decline in Tregs during disease progression was associated with increased immune activation.


Nonlinear and bistable reflection minima at lambda = 10.6 microm in an attenuated total reflection configuration with a highly doped n-GaAs film.
n-GaAs can be so highly doped that its plasma frequency is larger than the associated frequency of a CO2 laser emission line, leading to a negative real part of the dielectric permittivity. We studied linear and nonlinear reflection properties of structures composed of such thin highly doped n-GaAs film in an attenuated total reflection (ATR) configuration. We show that deep reflection minima coincide with the excitation of Brewster-type modes of the multilayer structure. These minima feature strong nonlinear and bistable behavior and are sensitive to geometrical and material parameters. The proposed ATR configuration can be used to determine doping concentrations with an accuracy of better than 1 partper thousand and different deformation potentials of the higher-conduction bands in n-GaAs.


Effectiveness of external respiratory surrogates for in vivo liver motion estimation.
Due to low frame rate of MRI and high radiation damage from fluoroscopy and CT, liver motion estimation using external respiratory surrogate signals seems to be a better approach to track liver motion in real-time for liver tumor treatments in radiotherapy and thermotherapy. This work proposes a liver motion estimation method based on external respiratory surrogate signals. Animal experiments are also conducted to investigate related issues, such as the sensor arrangement, multisensor fusion, and the effective time period. Liver motion and abdominal motion are both induced by respiration and are proved to be highly correlated. Contrary to the difficult direct measurement of the liver motion, the abdominal motion can be easily accessed. Based on this idea, our study is split into the model-fitting stage and the motion estimation stage. In the first stage, the correlation between the surrogates and the liver motion is studied and established via linear regression method. In the second stage, the liver motion is estimated by the surrogate signals with the correlation model. Animal experiments on cases of single surrogate signal, multisurrogate signals, and long-term surrogate signals are conducted and discussed to verify the practical use of this approach. The results show that the best single sensor location is at the middle of the upper abdomen, while multisurrogate models are generally better than the single ones. The estimation error is reduced from 0.6 mm for the single surrogate models to 0.4 mm for the multisurrogate models. The long-term validity of the estimation models is quite satisfactory within the period of 10 min with the estimation error less than 1.4 mm. External respiratory surrogate signals from the abdomen motion produces good performance for liver motion estimation in real-time. Multisurrogate signals enhance estimation accuracy, and the estimation model can maintain its accuracy for at least 10 min. This approach can be used in practical applications such as the liver tumor treatment in radiotherapy and thermotherapy.


Towards gene therapy of postoperative adhesions: fiber and transcriptional modifications enhance adenovirus targeting towards human adhesion cells.
Postoperative abdominal/pelvic peritoneal adhesions are a major source of morbidity (bowel obstruction, infertility, ectopic gestation as well as chronic pelvic pain) in women. In this study, we screened various transduction and transcription modifications of adenovirus (Ad) to identify those that support maximal Ad-mediated gene delivery to human adhesion fibroblasts, which in turn would enhance the efficacy of this novel treatment/preventative strategy for postoperative adhesions. We transduced primary cultures of human peritoneal adhesion fibroblasts with fiber-modified Ad vectors Ad5-RGD-luc, Ad5-Sigma-luc, Ad5/3-luc and Ad5-CAV2-luc as well as transcriptional targeting viruses Ad5-survivin-luc, Ad5-heparanase-luc, Ad5-mesothelin (MSLN)-CRAd-luc and Ad5-secretory leukoprotease inhibitor (SLPI)-luc, and compared their activity to wild-type Ad5-luc. At 48 h, luciferase activity was measured and normalized to the total protein content in the cells. Among the fiber-modified Ad vectors, Ad5-Sigma-luc and among the transcriptional targeting modified Ad vectors, Ad5-MSLN-CRAd-luc showed significantly increased expression levels of luciferase activity at 5, 10 and 50 plaque forming units/cell in adhesion fibroblast cells compared with wild-type Ad5-luc (p < 0.05). Specific modifications of Ad improve their gene delivery efficiency towards human peritoneal adhesion fibroblasts. Developing a safe localized method to prevent/treat postoperative adhesion formation would have a major impact on women health.


Investigating the effect of anxiety sensitivity, gender and negative interpretative bias on the perception of chest pain.
Research suggests that anxiety sensitivity may be an important component in the negative response to pain sensations, especially those with cardiopulmonary origin. Furthermore, there is experimental evidence to suggest that such effects may be stronger in women than men. The primary aim of the current investigation was to determine the relative roles that anxiety sensitivity and gender have on the pain reports of patients referred to a hospital clinic with chest pain. A total of 78 female and 76 male adults were recruited on entry to a Rapid Access Medical Clinic. All patients had been referred with chest pain, and were administered a range of pain and anxiety measures prior to diagnosis. Results indicate that males were more likely to receive a diagnosis of cardiac chest pain, whereas females were more likely to receive a diagnosis of non-cardiac chest pain. Additionally, anxiety sensitivity was related to pain in women but not men. Finally, evidence was found for the mediating effect of negative interpretative bias on the relationship between anxiety sensitivity and pain. However, this mediating effect was only found in women. These results not only confirm that anxiety sensitivity is related to greater negative pain responses in women, but that this may be due to an increased tendency to negatively interpret sensations.


Immunization practices of pediatricians for children younger than five years in coastal South India.
Immunization helps in controlling infectious diseases. Child immunization is an important component of child survival programs in India, which mainly follows the National Immunization Schedule. Also, many of the injection practices followed are not safe. To study the practices of pediatricians toward the immunization of children younger than 5 years and injection-related waste management. Cross-sectional study carried out in the city of Mangalore, a rapidly developing city in southern India. All the practicing pediatricians were included in the study and an interview was done on prior appointment using pretested interview schedule in March 2012, after obtaining clearance from the institutional ethics committee. Data were analyzed using the Statistical Package for Social Sciences version 11.5. Among the 54 practicing pediatricians in Mangalore, 42 were included in this study after exclusion criteria were applied. Among them, 71.4% were following the National Immunization Schedule, 5% did not prefer to give combination vaccines, 17% reported vaccine failure at least once in their practice, and 85.7% motivated the parents for future doses. Distance to the clinic and affordability were the major reasons for loss of follow-up. Only 38.1% used auto-disabled syringes, 11.9% did not observe the children following the immunization, and 45.2% did not use color coding for disposal of injection-related wastes. Mechanical hub cutters were preferred by 41% of the respondents. The study showed the diversity in immunization practices. The National Immunization Schedule is the most commonly followed schedule. However, the safety of the injection practices was limited.


Cytosolic transmitter concentration regulates vesicle cycling at hippocampal GABAergic terminals.
Sustained synaptic transmission requires vesicle recycling and refilling with transmitter, two processes considered to proceed independently. Contrary to this assumption, we show here that depletion of cytosolic transmitter at GABAergic synapses reversibly reduces the number of recycling vesicles. Using paired recordings in hippocampal cultures, we show that repetitive activity causes two phases of reduction of the postsynaptic response. The first involves the classical depletion of the readily releasable and recycling pools, while the second reflects impairment of vesicle filling as GABA is consumed, since it can only be reversed by uptake of GABA or its precursors, glutamate or glutamine. Surprisingly, this second phase is associated with reduced quantal release, a faster depression rate and lower FM5-95 labeling, suggesting that the size of the cycling vesicular pool is regulated by cytosolic transmitter availability. Regulation of vesicular cycling may represent a general mechanism of presynaptic plasticity, matching synaptic release to transmitter supply.


Developing a novel test to detect cancer genes from microarray data.
DNA microarray technology can simultaneously screen thousands of gene expression profiles, transforming how genetics is applied in medicine. However, the lack of normality in microarray data renders common statistical methods ineffective. We propose a novel statistical method which does not require stringent assumptions but is still more powerful than some of its competitors. Using both simulation studies and clinical data, we show that our novel method outperforms previous methods. The limiting distribution for the proposed test is obtained for under null and alternative hypotheses. The proposed test will help make cancer treatment and gene therapy more successful, and it may facilitate research regarding cancer vaccinations. The proposed test may also help in the development of a prediction model in genetic profiling studies built on a subset of differentially expressed genes and the clinical data to assess the accuracy of the clinical prediction.


Methodological considerations in assessment of language lateralisation with fMRI: a systematic review.
The involvement of the right and left hemispheres in mediating language functions has been measured in a variety of ways over the centuries since the relative dominance of the left hemisphere was first known. Functional magnetic resonance imaging (fMRI) presents a useful non-invasive method of assessing lateralisation that is being increasingly used in clinical practice and research. However, the methods used in the fMRI laterality literature currently are highly variable, making systematic comparisons across studies difficult. Here we consider the different methods of quantifying and classifying laterality that have been used in fMRI studies since 2000, with the aim of determining which give the most robust and reliable measurement. Recommendations are made with a view to informing future research to increase standardisation in fMRI laterality protocols. In particular, the findings reinforce the importance of threshold-independent methods for calculating laterality indices, and the benefits of assessing heterogeneity of language laterality across multiple regions of interest and tasks. This systematic review was registered as a protocol on Open Science Framework: https://osf.io/hyvc4/.


Paradigms of Protist/Bacteria Symbioses Affecting Human Health: Acanthamoeba species and Trichomonas vaginalis.
Ever since the publication of the seminal paper by Lynn Margulis in 1967 proposing the theory of the endosymbiotic origin of organelles, the study of the symbiotic relationships between unicellular eukaryotes and prokaryotes has received ever-growing attention by microbiologists and evolutionists alike. While the evolutionary significance of the endosymbiotic associations within protists has emerged and is intensively studied, the impact of these relationships on human health has been seldom taken into account. Microbial endosymbioses involving human eukaryotic pathogens are not common, and the sexually transmitted obligate parasite Trichomonas vaginalis and the free-living opportunistic pathogen Acanthamoeba represent two unique cases in this regard, to date. The reasons of this peculiarity for T. vaginalis and Acanthamoeba may be due to their lifestyles, characterized by bacteria-rich environments. However, this characteristic does not fully explain the reason why no bacterial endosymbiont has yet been detected in unicellular eukaryotic human pathogens other than in T. vaginalis and Acanthamoeba, albeit sparse and poorly investigated examples of morphological identification of bacteria-like microorganisms associated with Giardia and Entamoeba were reported in the past. In this review article we will present the body of experimental evidences revealing the profound effects of these examples of protist/bacteria symbiosis on the pathogenesis of the microbial species involved, and ultimately their impact on human health.


Influence of cigarette smoking on crocidolite-induced ferritin release by human alveolar macrophages.
Alveolar macrophages (AMs) mobilize iron from the surface of iron-containing minerals such as asbestos and synthesize ferritin for intracellular iron storage or secretion. Although the synthesis of iron-free ferritin (apoferritin) provides antioxidant protection, the secretion of iron-containing ferritin by AMs could increase the availability of catalytic iron in the lungs. Cigarette smoking may promote the secretion of ferritin by AMs after iron acquisition from mineral sources, because smokers' AMs are iron loaded. The first objective of this study was to determine whether ferritin secretion/release by AMs after in vitro exposure to crocidolite asbestos is enhanced by cigarette smoking. The second objective was to assess whether exogenous ferritin-bound iron could enhance the toxicity of crocidolite to lung cells in vitro. AMs recovered from nonsmokers (n = 8) or smokers (n = 8) were exposed to crocidolite or titanium dioxide (TiO2)(1 x 10(6) AMs, 50 to 200 microg/mL) for up to 18 hours. AMs exposed to crocidolite but not TiO2 showed increased cell content of iron and ferritin and increased cell supernatant ferritin concentrations. Increases in iron and ferritin content were similar for AMs recovered from smokers and those recovered from nonsmokers; however, increases in supernatant ferritin were >7-fold greater for smokers' AMs than for nonsmokers' AMs (P < .001). Exposure of A549 cells, a lung cancer-derived cell line, to crocidolite (50 to 200 microg/mL, 18 hours) caused dose-dependent cell death as indicated by lactate dehydrogenase release. The addition of ferritin (> or = 500 mg/mL) but not apoferritin to culture media enhanced crocidolite-induced LDH release (P < .01). These findings suggest that cigarette smoking and crocidolite exposure have synergistic effects that promote ferritin release by AMs, which could catalyze oxidative injury to other alveolar cells.


Improved outcome after relapse in children with acute myeloid leukaemia.
In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event-free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty-six percentage achieved remission with survival after relapse (5 years) 34 +/- 4%. Of 122 patients who received re-induction therapy, 77% entered remission with 40 +/- 5% survival. Remission rates were similar for different re-induction regimens but fludarabine, cytarabine, granulocyte colony-stimulating factor-based therapy had low treatment-related mortality. Prognostic factors for survival were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (<1 year in CR1), survival was 21 +/- 5% compared with 48 +/- 6% in late relapse. For children receiving re-induction therapy, survival in early relapse was 29 +/- 6% and 51 +/- 6% in late. Patients treated in CR1 with SCT, autologous SCT or chemotherapy had a survival of 18 +/- 9, 5 +/- 5 and 41 +/- 5%, respectively. Survival was 62 +/- 6% in 64 children given SCT as part of their relapse therapy. A significant proportion of children with relapsed AML can be cured, even those with early relapse. Children who receive re-induction therapy, enter remission and proceed to SCT can achieve a cure rate of 60%.


Comparison of the reaction progress of calcineurin with Mn2+ and Mg2+.
Activation of calcineurin by Mn2+ and Mg2+ was compared using a heavy atom isotope analogue of the substrate p-nitrophenyl phosphate (pNPP). Heavy atom isotope effects were measured for Mg2+ activation and compared to published results of the isotope effects with Mn2+ as the activating metal. Isotope effects were measured for the kinetic parameter Vmax/Km at the nonbridging oxygen atoms [18(V/K)nonbridge]; at the position of bond cleavage in the bridging oxygen atom [18(V/K)bridge]; and at the nitrogen atom in the nitrophenol leaving group [15(V/K)]. The isotope effects increased in magnitude upon changing from an optimal pH to a nonoptimal pH; the 18(V/K)bridge effect increased from 1.0154 (+/-0.0007) to 1.0198 (+/-0.0002), and the 15(V/K) effect increased from 1.0018 (+/-0. 0002) to 1.0021 (+/-0.0003). The value for 18(V/K)nonbridge is 0. 9910 (+/-0.0003) at pH 7.0. As with Mn2+, the 18(V/K)nonbridge isotope effect indicated that the dianion was the substrate for catalysis, and that a dissociative transition state was operative for the phosphoryl transfer. Comparison to results for Mn2+ activation suggested that chemistry was more rate-limiting with Mg2+ than with Mn2+. Changing the activating metal concentration showed opposite trends with increasing Mg2+ increasing the commitment factor and seemingly making the chemistry less rate-limiting. The influence of viscosity was evaluated as well to gauge the role of chemistry. The activation of calcineurin-catalyzed hydrolysis of pNPP1 by Mg2+ or Mn2+ at pH 7.0 was compared in the presence of viscogens, glycerol and poly(ethylene glycol). Increasing glycerol caused different effects with the two activators. With Mn2+ as the activator, calcineurin activity showed a normal response with kcat and kcat/Km decreasing with viscosity. There was an inverse response with Mg2+ as the activator as values of kcat/Km increased with viscosity. From values of the normalized kcat/Km with Mn2+, the chemistry was found to be partially rate-limiting, consistent with previous heavy atom isotope studies (22). The effect observed for Mg2+ seems consistent with a change in the rate-limiting step for the two different metals at pH 7.0.


Role of water in aging of human butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging.
Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond.


ADP-ribosylation factors modulate the cell surface transport of G protein-coupled receptors.
ADP-ribosylation factors (ARFs) regulate vesicular traffic through recruiting coat proteins. However, their functions in the anterograde transport of nascent G protein-coupled receptors (GPCRs) from the endoplasmic reticulum to the plasma membrane remain poorly explored. Here we show that treatment with brefeldin A, an inhibitor of guanine nucleotide exchange on ARFs, markedly attenuated the cell surface numbers of alpha(2B)-adrenergic receptor (AR), beta(2)-AR, angiotensin II type 1 receptor, and chemokine (CXC motif) receptor 4. Functional inhibition of individual ARF GTPases by transient expression of the GDP-bound, GTP-bound, and guanine nucleotide-deficient mutants showed that the five human ARFs differentially modulated receptor cell surface expression and that the ARF1 mutants produced the most profound inhibitory effect. Furthermore, expression of the ARF1 GTPase-activating protein (GAP) ARFGAP1 significantly blocked receptor transport. Interestingly, the GDP- and GTP-bound ARF1 mutants arrested the receptors in distinct intracellular compartments. Consistent with the reduced receptor cell surface expression, extracellular signal-regulated kinase 1 and 2 activation by receptor agonists was significantly attenuated by the GDP-bound mutant ARF1T31N. Moreover, coimmunoprecipitation showed that alpha(2B)-AR associated with ARF1 and glutathione transferase pull-down assay indicated that the alpha(2B)-AR C terminus directly interacted with ARF1. These data show that ARF1 GTPase is involved in the regulation of cell surface expression of GPCRs at multiple transport steps.


Managed and Unmanaged Pinus sylvestris Forest Stands Harbour Similar Diversity and Composition of the Phyllosphere and Soil Fungi.
The aim was to assess fungal communities associated with living needles and soil of Pinus sylvestris in managed and unmanaged forest stands to get a better understanding of whether and how different intensities of forest management affects fungal diversity and community composition under the north temperate forest zone conditions. The study was carried out in three national parks in Lithuania. Each included five study sites in managed stands and five in unmanaged stands. At each site, three random soil cores and five random last-year needle samples were collected. Following DNA isolation, a DNA fragment of the ITS2 rRNA gene region of each sample was individually amplified and subjected to high-throughput sequencing. Analysis of 195,808 high-quality reads showed the presence of 1909 fungal taxa. Richness and composition of fungal taxa were similar in each substrate (needles and soil) in managed vs. unmanaged sites. The most common fungi in needles were Coleosporium campanulae (12.4% of all fungal sequences), Unidentified sp. 3980_1 (12.4%), Unidentified sp. 3980_4 (4.1%) and Sydowia polyspora (3.1%). In soil: Unidentified sp. 3980_21 (8.6%), Umbelopsis nana (8.2%), Archaeorhizomyces sp. 3980_5 (8.1%) and Penicillium spinulosum (6.3%). The results demonstrated that managed and unmanaged P. sylvestris stands support similar diversity and composition of fungal communities associated with living needles and soil.


Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain.
Neuregulin-1 (NRG-1) plays important roles in the development and plasticity of the brain, and it has recently been identified as a susceptibility gene for schizophrenia. Though there are rodent data, little is known about its distribution in the human brain. The aim of this study was to ascertain the localization of NRG-1 and its mRNA in multiple regions of the normal adult human brain. We investigated NRG-1 mRNA in 11 subjects using in situ hybridization and northern analysis, and NRG-1 protein in six subjects using immunohistochemistry and Western blotting. NRG-1 mRNA was present as bands of approximately 2, 3 and 6 kb. It was clearly detected in the prefrontal cortex (middle laminae), hippocampal formation (except CA1), cerebellum, oculomotor nucleus, superior colliculus, red nucleus and substantia nigra pars compacta. At the cellular level, NRG1 mRNA was abundant in hippocampal and cortical pyramidal neurons and some interneurons, and in cerebellar Purkinje cells and Golgi cells. NRG-1 protein was detected as bands of approximately 140, 110, 95 and 60 kD. Immunohistochemistry revealed NRG-1 in many cell populations, consistent with the mRNA data, being prominent in pyramidal neurons, Purkinje cells, several brainstem nuclei, and white matter neurons. Moderate NRG-1 immunoreactivity was also observed in cerebellar and dentate gyrus granule cells, and some glia. Within neurons, NRG-1 staining was primarily somatodendritic; in the cell body staining was granular, with clustering close to the plasma and nuclear membranes. There was also labeling of some fiber tracts, and local areas of neuropil (e.g. in the dentate nucleus) suggestive of a pre-synaptic location of NRG-1. The data show a widespread expression of NRG-1 in the adult human brain, including, but not limited to, brain areas and cell populations implicated in schizophrenia. Using these normative data, future studies can ascertain whether the role of NRG-1 in the disease is mediated, or accompanied, via alterations in its expression.


Knowledge and attitude of ICU nurses, students and patients towards the Austrian organ donation law.
A survey on the knowledge and attitudes towards the Austrian organ donation legislation (an opt-out solution) of selected groups of the Austrian population taking into account factors such as age, gender, level of education, affiliation to healthcare professions and health related studies was conducted. An online survey among 3 target groups (ICU nurses, health science students and non health science students) was performed and results were compared to the answers from transplantation patients to a paper questionnaire. A total of 8415 persons were asked to participate in the survey and 2025 (24%) persons correctly completed the questionnaire. 1945 online responses (ICU nurses n = 185; students of health sciences n = 1277; students of non-health science related courses n = 483) were analysed and data were compared to 80 manually filled-in responses from patients from a previous study. 84% of participants state that they know the Austrian organ donation legislation; this percentage varies significantly (p < 0.05) within the target groups and is influenced by demographic variables of the participants. 74% think that the law is good and 79% do not favour a change. Opinions and attitudes towards the legal situation are positively influenced by the affiliation to healthcare professions and health-related fields of study. Interviewed persons who were aware of the legislation before the survey had a more positive attitude towards the existing legislation (77% versus 74%, p < 0.05). The information level on Austrian organ donation legislation is high. ICU nurses and those who did not know the law before were most critical towards the existing legislation. Therefore education to increase knowledge in the general population and goal-oriented efforts to increase awareness in the target groups should be emphasized.


Central venous catheterization: a prospective, randomized, double-blind study.
Central venous catheters (CVCs) are extensively used worldwide. Mechanical, infectious and thrombotic complications are well described with their use and may be associated with prolonged hospitalization, increased medical costs and mortality. CVCs account for an estimated 90% of all catheter-related bloodstream infections (CRBSI) and a host of risk factors for CVC-related infections have been documented. The duration of use of CVCs remains controversial and the length of time such devices can safely be left in place has not been fully and objectively addressed in the critically ill patient. Antimicrobial-impregnated catheters have been introduced in an attempt to limit catheter-related infection (CRI) and increase the time that CVCs can safely be left in situ. Recent meta-analyses concluded that antimicrobial-impregnated CVCs appear to be effective in reducing CRI. The authors conducted a prospective, randomized, double-blind study at Johannesburg Hospital over a 4-year period. The study entailed a comparison of standard triple-lumen versus antimicrobial impregnated CVCs on the rate of CRI. Our aim was to determine whether we could safely increase the duration of catheter insertion time from our standard practice of seven days to 14 days, to assess the influence of the antimicrobial impregnated catheter on the incidence of CRI, and to elucidate the epidemiology and risks of CRI. One hundred and eighteen critically ill patients were included in the study which spanned 34 951.5 catheter hours (3.99 catheter years). It was found that antimicrobial catheters did not provide any significant benefit over standard catheters, which the authors feel can safely be left in place for up to 14 days with appropriate infection control measures. The most common source of CRI was the skin. The administration of parenteral nutrition and the site of catheter insertion (internal jugular vein vs subclavian vein) were not noted to be risk factors for CRI. There was no clinical evidence of thrombotic complication in either of the study groups. This study offers direction for the use of CVCs in critically ill patients and addresses many of the controversies that exist.


Congestive heart failure in horses: 14 cases (1984-2001).
To identify clinical signs, underlying cardiac conditions, echocardiographic findings, and prognosis for horses with congestive heart failure. Retrospective study. 14 horses. Signalment; history; clinical signs; clinicopathologic, echocardiographic, and radiographic findings; treatment; and outcome were determined by reviewing medical records. All 14 horses were examined because of a heart murmur; tachycardia was identified in all 14. Twelve horses had echocardiographic evidence of enlargement of 1 or more chambers of the heart. Other common clinical findings included jugular distention or pulsation, crackles, cough, tachypnea, and ventral edema. Nine horses had signs consistent with heart failure for > 6 days. Underlying causes for heart failure included congenital defects, traumatic vascular rupture, pericarditis, pulmonary hypertension secondary to heaves, and valvular dysplasia. Seven horses were euthanatized after diagnosis of heart failure; 5 were discharged but were euthanatized or died of complications of heart disease within 1 year after discharge. The remaining 2 horses were discharged but lost to follow-up. Results suggest that congestive heart failure is rare in horses. A loud heart murmur accompanied by either jugular distention or pulsation, tachycardia, respiratory abnormalities (crackles, cough, tachypnea), and ventral edema were the most common clinical signs. Echocardiography was useful in determining the underlying cause in affected horses. The long-term prognosis for horses with congestive heart failure was grave.


Clinical tests to diagnose lumbar spondylolysis and spondylolisthesis: A systematic review.
The aim of this paper was to systematically review the diagnostic ability of clinical tests to detect lumbar spondylolysis and spondylolisthesis. A systematic literature search of six databases, with no language restrictions, from 1950 to 2014 was concluded on February 1, 2014. Clinical tests were required to be compared against imaging reference standards and report, or allow computation, of common diagnostic values. The systematic search yielded a total of 5164 articles with 57 retained for full-text examination, from which 4 met the full inclusion criteria for the review. Study heterogeneity precluded a meta-analysis of included studies. Fifteen different clinical tests were evaluated for their ability to diagnose lumbar spondylolisthesis and one test for its ability to diagnose lumbar spondylolysis. The one-legged hyperextension test demonstrated low to moderate sensitivity (50%-73%) and low specificity (17%-32%) to diagnose lumbar spondylolysis, while the lumbar spinous process palpation test was the optimal diagnostic test for lumbar spondylolisthesis; returning high specificity (87%-100%) and moderate to high sensitivity (60-88) values. Lumbar spondylolysis and spondylolisthesis are identifiable causes of LBP in athletes. There appears to be utility to lumbar spinous process palpation for the diagnosis of lumbar spondylolisthesis, however the one-legged hyperextension test has virtually no value in diagnosing patients with spondylolysis.


Diagnostic value underlies asymmetric updating of impressions in the morality and ability domains.
While positive behavioral information is diagnostic when evaluating a person's abilities, negative information is diagnostic when evaluating morality. Although social psychology has considered these two domains as orthogonal and distinct from one another, we demonstrate that this asymmetry in diagnosticity can be explained by a single parsimonious principle--the perceived frequency of behaviors in these domains. Less frequent behaviors (e.g., high ability and low morality) are weighed more heavily in evaluations. We show that this statistical principle of frequency-derived diagnosticity is evident in human participants at both behavioral and neural levels of analysis. Specifically, activity in right ventrolateral prefrontal cortex increased preferentially when participants updated impressions based on diagnostic behaviors, and further, activity in this region covaried parametrically with the perceived frequency of behaviors. Activity in left ventrolateral PFC, left inferior frontal gyrus, and left superior temporal sulcus showed similar patterns of diagnosticity and sensitivity, though additional analyses confirmed that these regions responded primarily to updates based on immoral behaviors.


Cardiovascular Risk Factors in Children and Adolescents with Subclinical Hypothyroidism.
Subclinical hypothyroidism (SCH) is a commonly encountered entity in day-to-day clinical practice and has been associated with adverse cardiovascular risk profile in adults and children. Data on children and adolescents with SCH, from India, are limited. This study was a cross-sectional case-control study, conducted at a tertiary care center in Northeast India. Twenty-seven children and adolescents aged 11 ± 2.4 years with SCH and thyroid-stimulating hormone >7.5 mIU/L were included in the study along with 20 age-, gender-, and height-matched controls. Multiple clinical, biochemical, and radiological cardiovascular risk factors were assessed and compared between the two groups. Body mass index (BMI) (P = 0.048), waist circumference (P = 0.008), waist to height ratio (P = 0.007), low-density lipoprotein cholesterol (P = 0.04), triglycerides (TGs) (P = 0.038), TGs to high-density lipoprotein (HDL) cholesterol ratio (P = 0.005), non-HDL cholesterol (P = 0.019), fasting insulin (P = 0.006), and homeostasis model assessment of insulin resistance (P = 0.007) were found to be significantly higher while free T4 (P = 0.002) and HDL cholesterol (P = 0.019) were found to be significantly lower in SCH subjects compared to controls. On multiple regression analysis, BMI was found to have significant association with multiple cardiovascular risk factors. Children and adolescents with SCH were found to have adverse cardiovascular risk profile. Long-term follow-up studies are required to assess the clinical significance of these findings and requirement for therapy.


Artificial liver support: quo vadis?
Approximately 2 million persons worldwide die each year from hepatic failure. Because of the scarcity of donor organs, artificial liver support systems are being developed with the aim of either supporting patients with borderline functional liver cell mass until an appropriate organ becomes available for transplantation or until their livers recover from injury. A literature review was performed using MEDLINE, PubMed, EMBASE, and library searches. Only major liver support techniques are included in this review. A number of extracorporeal liver assist systems are in various stages of clinical development. Published data indicate that patients with acute and acute-on-chronic liver failure may benefit from treatment with some of these therapeutic measures. Results from large prospective randomized trials have shown that treatment with MARS® and PROMETHEUS® may not confer a survival advantage, despite positive effects on blood toxemia and improvement in hepatic encephalopathy. Currently, hemofiltration using albumin-leaking membranes is being explored as a novel promising approach to blood purification in liver failure. Developing an effective liver assist technology has proven difficult, because of the complexity of liver functions that must be replaced, as well as heterogeneity of the patient population. Non-biological systems may have a role in the treatment of specific forms of liver failure where the primary goal is to provide blood detoxification/purification. Biological systems appear to hold promise for treating liver failure where the primary objective is to provide whole liver functions which are impaired or lost.


Photosensitiser-gold nanoparticle conjugates for photodynamic therapy of cancer.
Gold nanoparticles (AuNPs) have been extensively studied within biomedicine due to their biocompatibility and low toxicity. In particular, AuNPs have been widely used to deliver photosensitiser agents for photodynamic therapy (PDT) of cancer. Here we review the state-of-the-art for the functionalisation of the gold nanoparticle surface with both photosensitisers and targeting ligands for the active targeting of cancer cell surface receptors. From the initial use of the AuNPs as a simple carrier of the photosensitiser for PDT, the field has significantly advanced to include: the use of PEGylated modification to provide aqueous compatibility and stealth properties for in vivo use; gold metal-surface enhanced singlet oxygen generation; functionalisation of the AuNP surface with biological ligands to specifically target over-expressed receptors on the surface of cancer cells and; the creation of nanorods and nanostars to enable combined PDT and photothermal therapies. These versatile AuNPs have significantly enhanced the efficacy of traditional photosensitisers for both in vitro and in vivo cancer therapy. From this review it is apparent that AuNPs have an important future in the treatment of cancer.


A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.
The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.


Long-chain omega-3 fatty acid deficiency in mood disorders: rationale for treatment and prevention.
Major recurrent mood disorders including major depressive disorder (MDD) and bipolar disorder (BD) are associated with significant psychosocial morbidity and excess premature mortality primarily attributable to suicide and coronary heart disease. Limited efficacy and adverse side-effects associated with psychotropic medications used in the treatment of MDD and BD highlight the urgent need to develop safe and efficacious treatments or treatment adjuncts. A body of evidence now indicates that long-chain omega-3 (LCn-3) fatty acid deficiency is a feature associated with MDD and BD. The etiology of LCn-3 deficits in MDD and BD patients may be attributable to both genetic and environmental factors. Dietary LCn-3 supplementation is safe and well-tolerated with chronic administration and corrects LCn-3 deficiency in MDD and BD patients. LCn-3 supplementation has been found to augment the therapeutic efficacy of psychotropic medications in the treatment of mood symptoms and to reduce suicidality. Preliminary studies also suggest that LCn-3 supplementation is efficacious as monotherapy in the treatment and prevention of psychopathology in children and adolescents. LCn-3 supplementation is also associated with reduced risk for developing coronary heart disease. The overall cost-benefit ratio associated with LCn-3 supplementation provides a strong rationale to diagnose and treat LCn-3 deficiency in MDD and BD patients, and to prevent LCn-3 deficiency in subjects at high risk for developing these disorders.


Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery.
Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR(-/-) mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of "telomerase therapy" for such diseases.


[Staging with profiles in offence analysis: diagnostic steps in forensic psychiatry].
Forensic psychiatry is concerned particularly with accurate risk-assessment of offenders' future behaviour. To describe a staging and profiling system that is applicable to mentally-ill patients who have committed an offence. The various steps in forensic psychiatric diagnosis are analysed and discussed. Three diagnostic steps within a treatment trajectory are described: stage 1. psychiatric diagnosis; stage 2. the course of the trajectory; stage 3. supervision (i.e. protection from danger). Each step is divided into profiles. By means of staging and profiling, the treatment plan is integrated into a dynamic model in which each stage contains a set of activities that gradually lead to unique profiles and interventions which incorporate evidence for subsequent diagnostics.


Local tumour hyperthermia as immunotherapy for metastatic cancer.
Abstract Local tumour hyperthermia for cancer treatment is currently used either for ablation purposes as an alternative to surgery or less frequently, in combination with chemotherapy and/or radiation therapy to enhance the effects of those traditional therapies. As it has become apparent that activating the immune system is crucial to successfully treat metastatic cancer, the potential of boosting anti-tumour immunity by heating tumours has become a growing area of cancer research. After reviewing the history of hyperthermia therapy for cancer and introducing methods for inducing local hyperthermia, this review describes different mechanisms by which heating tumours can elicit anti-tumour immune responses, including tumour cell damage, tumour surface molecule changes, heat shock proteins, exosomes, direct effects on immune cells, and changes in the tumour vasculature. We then go over in vivo studies that provide promising results showing that local hyperthermia therapy indeed activates various systemic anti-tumour immune responses that slow growth of untreated tumours. Finally, future research questions that will help bring the use of local hyperthermia as systemic immunotherapy closer to clinical application are discussed.


Reliability and Validity of Three Versions of the Brief Fear of Negative Evaluation Scale in Patients With Systemic Sclerosis: A Scleroderma Patient-Centered Intervention Network Cohort Study.
Fear of negative evaluation is a common concern among individuals with visible differences but has received limited attention in systemic sclerosis (SSc), which can involve substantial changes to appearance. The Brief Fear of Negative Evaluation Scale (BFNE) was specifically designed to evaluate fear of negative evaluation. There are currently 3 versions of the BFNE with strong demonstrated measurement properties: two 8-item versions (BFNE-S, BFNE-8) and one 12-item version (BFNE-II). The present study evaluated these versions in SSc, and identified the most appropriate version for use among SSc patients. Participants were 1,010 patients with SSc enrolled in the Scleroderma Patient-Centered Intervention Network cohort. Multiple group confirmatory factor analysis, Cronbach's alpha, and Pearson's product-moment correlations were used to evaluate structural validity, internal consistency reliability, and convergent and divergent validity, respectively. Confirmatory factor analysis demonstrated that 1-factor models fit acceptably well for the 12-item BFNE-II, the 8-item BFNE-S, and the 8-item BFNE-8. Additionally, all Cronbach's alphas demonstrated excellent internal consistency reliability (BFNE-II = 0.98, BFNE-S = 0.97, BFNE-8 = 0.96), and all versions had comparable associations with measures of social anxiety, body-related attitudes, depression, age, and education. Psychometric support was found for all 3 versions of the BFNE, although the longer 12-item BFNE-II did not improve measurement compared to the shorter 8-item versions (BFNE-S and BFNE-8). Of these 2, the BFNE-S has been more widely studied, with strong validity data in a greater number of populations. Therefore, the BFNE-S is recommended to assess fear of negative evaluation among patients with SSc.


Estimated glomerular filtration rate is an easy predictor of venous thromboembolism in cancer patients undergoing platinum-based chemotherapy.
Reduced estimated glomerular filtration rate (eGFR) has been associated with increased venous thromboembolism (VTE) risk in the general population. VTE incidence significantly increases in cancer patients, especially those undergoing chemotherapy. Despite the evidence that a substantial number of cancer patients have unrecognized renal impairment, as indicated by reduced eGFR in the presence of serum creatinine levels within the reference value, chemotherapy dosage is routinely adjusted for serum creatinine values. Among chemotherapies, platinum-based regimens are associated with the highest rates of VTE. A cohort study was designed to assess the value of pretreatment eGFR in the risk prediction of a first VTE episode in cancer outpatients without previous history of VTE who were scheduled for platinum-based chemotherapy. Methods. Serum creatinine and eGFR were evaluated before the start of standard platinum-based chemotherapy in a cohort of 322 consecutive patients with primary or relapsing/recurrent solid cancers, representative of a general practice population. Results. Patients who experienced a first VTE episode in the course of chemotherapy had lower mean eGFR values compared with patients who remained VTE free. Multivariate Cox analysis demonstrated that eGFR had an independent value for risk prediction of a first VTE episode during treatment, with a 3.15 hazard ratio. Indeed, 14% of patients with reduced eGFR had VTE over 1-year follow-up compared with 6% of patients with normal eGFR values. Conclusion. The results suggest that reductions in eGFR, even in the presence of normal serum creatinine, are associated with an increased VTE risk in cancer outpatients undergoing platinum-based chemotherapy regimens. Determining eGFR before chemotherapy could represent a simple predictor of VTE, at no additional cost to health care systems.


Do patients with obstructive sleep apnea have thick necks?
During physical examination of patients with suspected obstructive sleep apnea (OSA), a comment is frequently made that they appear to have a short and fat neck. To confirm this subjective impression by objective measurements, we studied a group of 123 patients referred to us because of snoring and suspected OSA, all of whom had nocturnal polysomnography and measurements of external and internal neck circumference. The external neck circumference was measured at the level of the superior border of the cricothyroid cartilage. Internal neck circumferences were calculated from the measurements of pharyngeal, glottic, and tracheal areas obtained by the acoustic reflection technique. Internal pharyngeal circumference was further subdivided into the proximal, middle, and distal thirds. The acoustic technique also permitted us to measure the distance between the teeth and the glottic minimum, which reflects the length of the upper airway. Stepwise multiple linear regression analysis revealed that the apnea/hypopnea index (AHI) correlated only with the external neck circumference, the body mass index, and the internal circumference of the distal pharynx; these three variables accounted for 39% of the variability in AHI. We conclude that the external and internal neck circumferences and the degree of obesity are important predictors of sleep apnea; it is possible that obesity produces its effect via fat in the neck. We speculate that the static pharyngeal size modulated by the dynamic loading of the airway due to the weight of fatty tissue of the neck may contribute to the pathogenesis of OSA.


Glycemic Control and Risk of Infections Among People With Type 1 or Type 2 Diabetes in a Large Primary Care Cohort Study.
Diabetes mellitus (DM) increases the risk of infections, but the effect of better control has not been thoroughly investigated. With the use of English primary care data, average glycated hemoglobin (HbA1c) during 2008-2009 was estimated for 85,312 patients with DM ages 40-89 years. Infection rates during 2010-2015 compiled from primary care, linked hospital, and mortality records were estimated across 18 infection categories and further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) by HbA1c categories across all DM, and type 1 and type 2 DM separately. IRRs also were compared with 153,341 age-sex-practice-matched controls without DM. Attributable fractions (AF%) among patients with DM were estimated for an optimal control scenario (HbA1c 6-7% [42-53 mmol/mol]). Long-term infection risk rose with increasing HbA1c for most outcomes. Compared with patients without DM, those with DM and optimal control (HbA1c 6-7% [42-53 mmol/mol], IRR 1.41 [95% CI 1.36-1.47]) and poor control (≥11% [97 mmol/mol], 4.70 [4.24-5.21]) had elevated hospitalization risks for infection. In patients with type 1 DM and poor control, this risk was even greater (IRR 8.47 [5.86-12.24]). Comparisons within patients with DM confirmed the risk of hospitalization with poor control (2.70 [2.43-3.00]) after adjustment for duration and other confounders. AF% of poor control were high for serious infections, particularly bone and joint (46%), endocarditis (26%), tuberculosis (24%), sepsis (21%), infection-related hospitalization (17%), and mortality (16%). Poor glycemic control is powerfully associated with serious infections and should be a high priority.


Transoceanic migration, spatial dynamics, and population linkages of white sharks.
The large-scale spatial dynamics and population structure of marine top predators are poorly known. We present electronic tag and photographic identification data showing a complex suite of behavioral patterns in white sharks. These include coastal return migrations and the fastest known transoceanic return migration among swimming fauna, which provide direct evidence of a link between widely separated populations in South Africa and Australia. Transoceanic return migration involved a return to the original capture location, dives to depths of 980 meters, and the tolerance of water temperatures as low as 3.4 degrees C. These findings contradict previous ideas that female white sharks do not make transoceanic migrations, and they suggest natal homing behavior.


Phase behaviour of a dispersion of charge-stabilised colloidal spheres with added non-adsorbing interacting polymer chains.
We present a theory for the phase behaviour of mixtures of charge-stabilised colloidal spheres plus interacting polymer chains in good and theta -solvents within the framework of free-volume theory. We use simple but accurate combination rules for the depletion thickness around a colloidal particle and for the osmotic pressure up to the semi-dilute concentration regime. Hence, we obtain expressions for the free energy for mixtures of charged colloidal particles and non-adsorbing interacting polymers. From that, we calculate the phase behaviour, and discuss its topology in dependence on the competition between the charge-induced repulsion and the polymer-induced attraction. The homogeneous mixture of colloids and polymers becomes more stabilised against demixing when increasing the electrostatic repulsion. This charge-induced stabilisation is strongest for small polymer-to-colloid size ratios and is more pronounced for charged colloids mixed with polymers in a good solvent than for polymers in a theta -solvent. For the weakly charged regime we find that the phase diagram becomes salt-concentration-independent in the protein limit for charged colloids plus polymers in a theta -solvent. The liquid window, i.e., the concentration regimes where a colloidal liquid exists, is narrowed down upon increasing the charge-induced repulsion. Also this effect is more pronounced when charged colloids are mixed with polymer chains in a good solvent. In summary, we demonstrate that the solvent quality significantly influences the phase behaviour of mixtures of charged colloids plus non-adsorbing polymers if the range of the screened electrostatic repulsion becomes of the order of the range of the depletion-induced attraction.


Bioengineering and Bioinformatics Summer Institutes: meeting modern challenges in undergraduate summer research.
Summer undergraduate research programs in science and engineering facilitate research progress for faculty and provide a close-ended research experience for students, which can prepare them for careers in industry, medicine, and academia. However, ensuring these outcomes is a challenge when the students arrive ill-prepared for substantive research or if projects are ill-defined or impractical for a typical 10-wk summer. We describe how the new Bioengineering and Bioinformatics Summer Institutes (BBSI), developed in response to a call for proposals by the National Institutes of Health (NIH) and the National Science Foundation (NSF), provide an impetus for the enhancement of traditional undergraduate research experiences with intense didactic training in particular skills and technologies. Such didactic components provide highly focused and qualified students for summer research with the goal of ensuring increased student satisfaction with research and mentor satisfaction with student productivity. As an example, we focus on our experiences with the Penn State Biomaterials and Bionanotechnology Summer Institute (PSU-BBSI), which trains undergraduates in core technologies in surface characterization, computational modeling, cell biology, and fabrication to prepare them for student-centered research projects in the role of materials in guiding cell biology.


Non-averaged human brain potentials in somatic attention: the short-latency cognition-related P40 component.
1. Non-averaged scalp-recorded brain potentials were studied in humans during selective attention to randomly intermixed series of stimuli to fingers. Physiological tests were use for validating the presence or absence of the short-latency cognition-related P40 electrogeneses in parietal cortex in the response to a single-target stimulus (P40 signifies a positive polarity of about 40 ms peak latency). 2. To minimize interference from the electroencephalogram and noise we mapped single brain responses over the scalp and identified P40 topographies by an updated form of the numerical estimator Z for assessment of recorded potentials over time. We found that Z should exceed 0.96 for at least 15 ms for validation of the topographical congruity between the single P40 and an averaged P40 template. 3. Individual responses to 145 target finger stimuli correctly identified by the subject were analysed. P40 occurred only intermittently (34.5%) in a series of targets, but its voltage was unexpectedly large, exceeding the P40 voltage in averaged responses by a factor of about 10. 4. The usual assumption in the averaging method that the single brain responses combined in the average are stable but merely contaminated by unrelated noise was shown to be false for the cognition-related P40, which was considerably underestimated because of its intermittency in the averaged single trials. 5. The reaction time of the subject was on average 19% shorter in the trials in which a P40 was present, thus suggesting that P40 can influence subsequent perceptual processing by the brain in the same trial. 6. The feasibility of identifying specific cognition-related electrogeneses in single brain responses opens up the study of momentary shifts in brain processing strategies thereby allowing the neurophysiology of cognition to be based in real time.


Topological augmentation to infer hidden processes in biological systems.
A common problem in understanding a biochemical system is to infer its correct structure or topology. This topology consists of all relevant state variables-usually molecules and their interactions. Here we present a method called topological augmentation to infer this structure in a statistically rigorous and systematic way from prior knowledge and experimental data. Topological augmentation starts from a simple model that is unable to explain the experimental data and augments its topology by adding new terms that capture the experimental behavior. This process is guided by representing the uncertainty in the model topology through stochastic differential equations whose trajectories contain information about missing model parts. We first apply this semiautomatic procedure to a pharmacokinetic model. This example illustrates that a global sampling of the parameter space is critical for inferring a correct model structure. We also use our method to improve our understanding of glutamine transport in yeast. This analysis shows that transport dynamics is determined by glutamine permeases with two different kinds of kinetics. Topological augmentation can not only be applied to biochemical systems, but also to any system that can be described by ordinary differential equations. Matlab code and examples are available at: http://www.csb.ethz.ch/tools/index


Three-dimensional telomere profiles in papillary thyroid cancer variants: A pilot study.
Besides the two main histologic types of papillary thyroid carcinoma (PTC), the classical PTC (CL-PTC) and the follicular variant PTC (FV-PTC), several other variants are described. The encapsulated FV-PTC variant was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its similarities to benign lesions. Specific molecular signatures, however, are still unavailable. It is well known that improper DNA repair of dysfunctional telomeres may cause telomere-related genome instability. The mechanisms involved in the damaged telomere repair processing may lead to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether a specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and the telomere length of NIFTP overlaps with that of the FTA histotype. In contrast, there was no association between BRAF expression and telomere length in all tested samples. These preliminary findings reinforce the view that NIFTP is closer to non-malignant thyroid nodules and confirm that PTC features short telomeres.


Effect of education on self-efficacy of Turkish patients with chronic obstructive pulmonary disease.
This study was designed to compare the effect of structured education on self-efficacy in patients with chronic obstructive pulmonary disease (COPD). The study was carried out with an experimental group on which a structured education was provided, and a control group on which only educational advice was provided. There were 30 patients in both groups. Control and experimental group measurements were obtained on the COPD Self-Efficacy Scale (CSES). There was a significant difference between control group and experimental group scores on the CSES. Self-efficacy, as it affects managing or avoiding breathing difficulty, was measured before and after the structured education program and the nursing care. Patients' self-efficacy scores significantly improved after the structured education and remained significantly improved 1-month later. Standard nursing care alone was also effective in significantly improving self-efficacy scores, but patients' scores 1-month later were not significantly better than pre-program scores. This study indicates that a planned education program that is more effective in improving self-efficacy in patients with COPD.


Comparing outcomes of donation after cardiac death versus donation after brain death in liver transplant recipients with hepatitis C: a systematic review and meta-analysis.
Liver transplantation (LT) using organs donated after cardiac death (DCD) is increasing due, in large part, to a shortage of organs. The outcome of using DCD organs in recipients with hepatits C virus (HCV) infection remains unclear due to the limited experience and number of publications addressing this issue. To evaluate the clinical outcomes of DCD versus donation after brain death (DBD) in HCV-positive patients undergoing LT. Studies comparing DCD versus DBD LT in HCV-positive patients were identified based on systematic searches of seven electronic databases and multiple sources of gray literature. The search identified 58 citations, including three studies, with 324 patients meeting eligibility criteria. The use of DCD livers was associated with a significantly higher risk of primary nonfunction (RR 5.49 [95% CI 1.53 to 19.64]; P=0.009; I2=0%), while not associated with a significantly different patient survival (RR 0.89 [95% CI 0.37 to 2.11]; P=0.79; I2=51%), graft survival (RR 0.40 [95% CI 0.14 to 1.11]; P=0.08; I2=34%), rate of recurrence of severe HCV infection (RR 2.74 [95% CI 0.36 to 20.92]; P=0.33; I2=84%), retransplantation or liver disease-related death (RR 1.79 [95% CI 0.66 to 4.84]; P=0.25; I2=44%), and biliary complications. While the literature and quality of studies assessing DCD versus DBD grafts are limited, there was significantly more primary nonfunction and a trend toward decreased graft survival, but no significant difference in biliary complications or recipient mortality rates between DCD and DBD LT in patients with HCV infection. There is insufficient literature on the topic to draw any definitive conclusions.


ADA1, a novel component of the ADA/GCN5 complex, has broader effects than GCN5, ADA2, or ADA3.
The ADA genes encode factors which are proposed to function as transcriptional coactivators. Here we describe the cloning, sequencing, and initial characterization of a novel ADA gene, ADA1. Similar to the previously isolated ada mutants, ada1 mutants display decreases in transcription from various reporters. Furthermore, ADA1 interacts with the other ADAs in the ADA/GCN5 complex as demonstrated by partial purification of the complex and immunoprecipitation experiments. We estimate that the complex has a molecular mass of approximately 2 MDa. Previously, it had been demonstrated that ada5 mutants displayed more severe phenotypic defects than the other ada mutants (G. A. Marcus, J. Horiuchi, N. Silverman, and L. Guarente, Mol. Cell. Biol. 16:3197-3205, 1996; S. M. Roberts and F. Winston, Mol. Cell. Biol. 16:3206-3213, 1996). ada1 mutants display defects similar to those of ada5 mutants and different from those of the other mutants with respect to promoters affected, inositol auxotrophy, and Spt- phenotypes. Thus, the ADAs can be separated into two classes, suggesting that the ADA/GCN5 complex may have two separate functions. We present a speculative model on the possible roles of the ADA/GCN5 complex.


Mechanism of antibacterial activity of liposomal linolenic acid against Helicobacter pylori.
Helicobacter pylori infects approximately half of the world population and is a major cause of gastritis, peptic ulcer, and gastric cancer. Moreover, this bacterium has quickly developed resistance to all major antibiotics. Recently, we developed a novel liposomal linolenic acid (LipoLLA) formulation, which showed potent bactericidal activity against several clinical isolated antibiotic-resistant strains of H. pylori including both the spiral and coccoid form. In addition, LipoLLA had superior in vivo efficacy compared to the standard triple therapy. Our data showed that LipoLLA associated with H. pylori cell membrane. Therefore, in this study, we investigated the possible antibacterial mechanism of LipoLLA against H. pylori. The antibacterial activity of LipoLLA (C18:3) was compared to that of liposomal stearic acid (LipoSA, C18:0) and oleic acid (LipoOA, C18:1). LipoLLA showed the most potent bactericidal effect and completely killed H. pylori within 5 min. The permeability of the outer membrane of H. pylori increased when treated with LipoOA and LipoLLA. Moreover, by detecting released adenosine triphosphate (ATP) from bacteria, we found that bacterial plasma membrane of H. pylori treated with LipoLLA exhibited significantly higher permeability than those treated with LipoOA, resulting in bacteria cell death. Furthermore, LipoLLA caused structural changes in the bacterial membrane within 5 min affecting membrane integrity and leading to leakage of cytoplasmic contents, observed by both transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Our findings showing rapid bactericidal effect of LipoLLA suggest it is a very promising new, effective anti-H. pylori agent.


Antineurodegenerative effect of phenolic extracts and caffeic acid derivatives in romaine lettuce on neuron-like PC-12 cells.
In recent decades, romaine lettuce has been one of the fastest growing vegetables with respect to its consumption and production. An understanding is needed of the effect of major phenolic phytochemicals from romaine lettuce on biological protection for neuron-like PC-12 cells. Phenolics in fresh romaine lettuce were extracted, and then its total phenolics and total antioxidant capacity were measured spectrophotometrically. Neuroprotective effects of phenolic extract of romaine lettuce and its pure caffeic acid derivatives (caffeic, chicoric, chlorogenic, and isochlorogenic acids) in PC-12 cells were evaluated using two different in vitro methods: lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assays. Total phenolics and total antioxidant capacity of 100 g of fresh romaine lettuce averaged 22.7 mg of gallic acid equivalents and 31.0 mg of vitamin C equivalents, respectively. The phenolic extract of romaine lettuce protected PC-12 cells against oxidative stress caused by H(2)O(2) in a dose-dependent manner. Isochlorogenic acid, one of the phenolics in romaine lettuce, showed stronger neuroprotection than the other three caffeic acid derivatives also found in the lettuce. Although romaine lettuce had lower levels of phenolics and antioxidant capacity compared to other common vegetables, its contribution to total antioxidant capacity and antineurodegenerative effect in human diets would be higher because of higher amounts of its daily per capita consumption compared to other common vegetables.


The early commitment of fetal neurons to the limbic cortex.
The limbic-system-associated membrane protein (LAMP) is expressed early in cerebral cortical development by migrating and postmigratory neurons in limbic regions such as the prefrontal and perirhinal cortices (Horton and Levitt, 1988), but not by nonlimbic neurons such as in the primary sensory and motor cortices. In the present study, we used LAMP expression to evaluate the timing and potential cell-lineage and environmental determinants of the commitment of cerebral cortical neurons to limbic and nonlimbic phenotypes. The cerebral wall, containing either presumptive perirhinal or sensorimotor cortex, was removed prior to [embryonic day (E) 12, 14] or just after (E17) the onset of LAMP expression, labeled with fast blue, and placed into cavities in either perirhinal or sensorimotor regions of postnatal day (P) 1 hosts. Host animals were allowed to survive until at least P10, and surviving transplanted cells were counted and evaluated for LAMP expression. Sensorimotor cortical neurons transplanted at E14 or E17, in either homotopic or heterotopic locations, did not express LAMP. In contrast, a high percentage of perirhinal cortical neurons transplanted at either E14 or E17, whether situated in sensorimotor or perirhinal regions of the host, expressed the limbic marker protein. Surprisingly, neurons from E12 donors exhibited patterns of LAMP expression that reflected their new location in the host rather than their embryonic origin. The data suggest that there is an early pliant period in which precursor and early differentiating cells remain uncommitted to a particular cortical regional phenotype. After this period, one aspect of the molecular phenotype (determined by LAMP expression) of neurons destined for sensorimotor and allo- and mesocortical regions has become immutable by environmental factors in the host.


Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software.
High rates of panel-reactive antibody (PRA) may decrease the chance of kidney transplantation and may result in long waiting periods before transplantation. The calculated PRA (cPRA) is performed based on unacceptable HLA antigens. These antigens are identified by a program that was created based on the antibodies that developed against the HLA antigens circulating in serum and on the risk of binding of these antibodies to antigens. The antigen profile of the population and antigen frequencies can be measured, and more realistic cPRA positivity rates may be obtained using this method. We developed a program based on the HLA antigens of 494 blood donors in 2 European Federation for Immunogenetics-accredited Tissue Typing Laboratories in Turkey. Next-generation sequencing-based tissue typing (HLA-A, -B, -C, -DR, -DQ, 4 digits) of the samples was performed. The PRA screening test was performed on 380 patients who were waiting for organ transplant from a cadaver in Istanbul Faculty of Medicine. The single antigen bead assay testing was performed to identify the antibody profiles on 48 hypersensitized patients. The PRA testing results using the current methods were 44.6% ± 18.5%, and the cPRA rate was 86.2% ± 5.1%. The mean PRA positivity of the sensitized patients using the current methods was 44.6%; however, the rate was 86.2% using the cPRA. cPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. In principal, implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match, particularly for hypersensitized patients, by the creation of an unacceptable mismatch program using cPRA software.


Bioprocessing of wheat bran improves in vitro bioaccessibility and colonic metabolism of phenolic compounds.
Ferulic acid (FA) is the most abundant phenolic compound in wheat grain, mainly located in the bran. However, its bioaccessibility from the bran matrix is extremely low. Different bioprocessing techniques involving fermentation or enzymatic and fermentation treatments of wheat bran were developed aiming at improving the bioaccessibility of phenolic compounds in bran-containing breads. The bioaccessibility of ferulic acid, p-coumaric acid, and sinapic acid was assessed with an in vitro model of upper gastrointestinal tract (TIM-1). Colonic metabolism of the phenolic compounds in the nonbioaccessible fraction of the breads was studied with an in vitro model of human colon (TIM-2). The most effective treatment was the combination of enzymes and fermentation that increased the bioaccessibility of FA from 1.1% to 5.5%. The major colonic metabolites were 3-(3-hydroxyphenyl)propionic acid and 3-phenylpropionic acid. Bran bioprocessing increases the bioaccessibility of phenolic compounds as well as the colonic end metabolite 3-phenylpropionic acid.


Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence.
Pathogens that can be transmitted between different host species are of fundamental interest and importance from public health, conservation and economic perspectives, yet systematic quantification of these pathogens is lacking. Here, pathogen characteristics, host range and risk factors determining disease emergence were analysed by constructing a database of disease-causing pathogens of humans and domestic mammals. The database consisted of 1415 pathogens causing disease in humans, 616 in livestock and 374 in domestic carnivores. Multihost pathogens were very prevalent among human pathogens (61.6%) and even more so among domestic mammal pathogens (livestock 77.3%, carnivores 90.0%). Pathogens able to infect human, domestic and wildlife hosts contained a similar proportion of disease-causing pathogens for all three host groups. One hundred and ninety-six pathogens were associated with emerging diseases, 175 in humans, 29 in livestock and 12 in domestic carnivores. Across all these groups, helminths and fungi were relatively unlikely to emerge whereas viruses, particularly RNA viruses, were highly likely to emerge. The ability of a pathogen to infect multiple hosts, particularly hosts in other taxonomic orders or wildlife, were also risk factors for emergence in human and livestock pathogens. There is clearly a need to understand the dynamics of infectious diseases in complex multihost communities in order to mitigate disease threats to public health, livestock economies and wildlife.


Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity.
Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.


An animal model for acute and persistent Epstein-Barr virus infection.
Epstein-Barr virus (EBV) is a human lymphocryptovirus that causes infectious mononucleosis, persists asymptomatically for life in nearly all adults, and is associated with the development of B cell lymphomas and nasopharyngeal carcinomas. A highly similar rhesus lymphocryptovirus naturally endemic in rhesus monkeys was used to orally infect naïve animals from a pathogen-free colony. This animal model reproduced key aspects of human EBV infection, including oral transmission, atypical lymphocytosis, lymphadenopathy, activation of CD23(+) peripheral blood B cells, sustained serologic responses to lytic and latent EBV antigens, latent infection in the peripheral blood, and virus persistence in oropharyngeal secretions. This system may be useful for studying the pathogenesis, prevention, and treatment of EBV infection and associated oncogenesis.


Development and reliability of a system to classify gross motor function in children with cerebral palsy.
To address the need for a standardized system to classify the gross motor function of children with cerebral palsy, the authors developed a five-level classification system analogous to the staging and grading systems used in medicine. Nominal group process and Delphi survey consensus methods were used to examine content validity and revise the classification system until consensus among 48 experts (physical therapists, occupational therapists, and developmental pediatricians with expertise in cerebral palsy) was achieved. Interrater reliability (kappa) was 0.55 for children less than 2 years of age and 0.75 for children 2 to 12 years of age. The classification system has application for clinical practice, research, teaching, and administration.


Relationships between childhood maltreatment, adult health and psychiatric outcomes, and medical utilization.
Childhood maltreatment strongly predicts poor psychiatric and physical health outcomes in adulthood. This overview of the literature shows that individuals who suffer abuse, neglect, or serious family dysfunction as children are more likely to be depressed, to experience other types of psychiatric illness, to have more physical symptoms (both medically explained and unexplained), and to engage in more health-risk behaviors than their nonabused counterparts. The more severe the abuse, the stronger the association with poor outcomes in adulthood. Childhood sexual abuse in particular has been repeatedly associated, in adulthood, with physical complaints such as chronic pain that are likewise associated with depression. Individuals with a history of childhood abuse, particularly sexual abuse, are more likely than individuals with no history of abuse to become high utilizers of medical care and emergency services. Childhood maltreatment is highly prevalent among both men and women, especially in specialty settings such as emergency psychiatric care.


In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents.
Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. We evaluated the in vivo pharmacological profile of a potent and selective PDE10A inhibitor, TAK-063 (1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one). TAK-063 at 0.3 and 1 mg/kg p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP- and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg p.o., strongly suppressed MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced hyperlocomotion, which is often used as a predictive model for antipsychotic-like activity in rodents. Upregulation of striatal cAMP/cGMP levels and the antipsychotic-like effect of TAK-063 were not attenuated after 15 days of pretreatment with TAK-063 in mice. The potential side effect profile of TAK-063 was assessed in rats using the clinical antipsychotics haloperidol, olanzapine, and aripiprazole as controls. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg p.o. At 3 mg/kg p.o., TAK-063 elicited a weak cataleptic response compared with haloperidol and olanzapine. Evaluation of pathway-specific markers (substance P mRNA for the direct pathway and enkephalin mRNA for the indirect pathway) revealed that TAK-063 activated both the direct and indirect pathways of MSNs. These findings suggest that TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles.


Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology.
The complex pathophysiology of autism spectrum disorder encompasses interactions between genetic and environmental factors. On the one hand, hundreds of genes, converging at the functional level on selective biological domains such as epigenetic regulation and synaptic function, have been identified to be either causative or risk factors of autism. On the other hand, exposure to chemicals that are widespread in the environment, such as endocrine disruptors, has been associated with adverse effects on human health, including neurodevelopmental disorders. Interestingly, experimental results suggest an overlap in the regulatory pathways perturbed by genetic mutations and environmental factors, depicting convergences and complex interplays between genetic susceptibility and toxic insults. The pervasive nature of chemical exposure poses pivotal challenges for neurotoxicological studies, regulatory agencies, and policy makers. This highlights an emerging need of developing new integrative models, including biomonitoring, epidemiology, experimental, and computational tools, able to capture real-life scenarios encompassing the interaction between chronic exposure to mixture of substances and individuals' genetic backgrounds. In this review, we address the intertwined roles of genetic lesions and environmental insults. Specifically, we outline the transformative potential of stem cell models, coupled with omics analytical approaches at increasingly single cell resolution, as converging tools to experimentally dissect the pathogenic mechanisms underlying neurodevelopmental disorders, as well as to improve developmental neurotoxicology risk assessment.


Arrayed water-in-oil droplet bilayers for membrane transport analysis.
The water-in-oil droplet bilayer is a simple and useful lipid bilayer system for membrane transport analysis. The droplet interface bilayer is readily formed by the contact of two water-in-oil droplets enwrapped by a phospholipid monolayer. However, the size of individual droplets with femtoliter volumes in a high-throughput manner is difficult to control, resulting in low sensitivity and throughput of membrane transport analysis. To overcome this drawback, in this study, we developed a novel micro-device in which a large number of droplet interface bilayers (>500) are formed at a time by using femtoliter-sized droplet arrays immobilized on a hydrophobic/hydrophilic substrate. The droplet volume was controllable from 3.5 to 350 fL by changing the hydrophobic/hydrophilic pattern on the device, allowing high-throughput analysis of membrane transport mechanisms including membrane permeability to solutes (e.g., ions or small molecules) with or without the aid of transport proteins. Thus, this novel platform broadens the versatility of water-in-oil droplet bilayers and will pave the way for novel analytical and pharmacological applications such as drug screening.


The Mediolateral Excursion of the Meniscal Bearing during Flexion and Extension of the Knee after Medial Mobile-Bearing Unicompartmental Knee Arthroplasty.
This mediolateral excursion of the bearing during knee motion is supposed to be caused by external rotation of the tibia during knee extension. However, to our knowledge, there is no published clinical evidence supporting these hypotheses. The current study aimed to evaluate the mediolateral excursion of the bearing during flexion-extension motion of the knee after medial unicompartmental knee arthroplasty (UKA). In 52 knees, varus/valgus (F-VarVal) or rotational position (F-Rot) of the femoral component and relative location of the bearing were measured with the standing anteroposterior and modified axial view, respectively. We adopted the modified axial radiographs that are simple to assess the bearing position in the flexed knee. The modified axial view showed excellent inter- and intraobserver agreements. F-Rot in the modified axial view and CT showed a high agreement in terms of validity (r = 0.98; p < 0.0001). On average, the bearing showed more medial position in extension than flexion of the knee. No correlation was found between the femoral component positions (F-VarVal and F-Rot) and mediolateral bearing excursion (p = 0.68 and 0.80, respectively). In conclusion, coronal location of bearing according to flexion-extension of the knee is not influenced by the coronal and axial alignment of the femoral component. With simple radiographic method, more medial position of the bearing according to flexion-extension of the knee. Our method could be used to assess axial rotation of the femoral component and spin-out phenomenon of the bearing following the medial UKA.


Measuring nonlinear signal combination using EEG.
Relatively little is known about the processes, both linear and nonlinear, by which signals are combined beyond V1. By presenting two stimulus components simultaneously, flickering at different temporal frequencies (frequency tagging) while measuring steady-state visual evoked potentials, we can assess responses to the individual components, including direct measurements of suppression on each other, and various nonlinear responses to their combination found at intermodulation frequencies. The result is a rather rich dataset of frequencies at which responses can be found. We presented pairs of sinusoidal gratings at different temporal frequencies, forming plaid patterns that were "coherent" (looking like a checkerboard) and "noncoherent" (looking like a pair of transparently overlaid gratings), and found clear intermodulation responses to compound stimuli, indicating nonlinear summation. This might have been attributed to cross-orientation suppression except that the pattern of intermodulation responses differed for coherent and noncoherent patterns, whereas the effects of suppression (measured at the component frequencies) did not. A two-stage model of nonlinear summation involving conjunction detection with a logical AND gate described the data well, capturing the difference between coherent and noncoherent plaids over a wide array of possible response frequencies. Multistimulus frequency-tagged EEG in combination with computational modeling may be a very valuable tool in studying the conjunction of these signals. In the current study the results suggest a second-order mechanism responding selectively to coherent plaid patterns.


Claims to protection: the rise and fall of feminist abolitionism in the League of Nations' Committee on the Traffic in Women and Children, 1919–1936.
This article examines the League of Nations Advisory Committee on the Trafficking of Women and Children (CTW) to assess the impact of international feminists on the interwar anti-sex trafficking movement. It argues that women who were firmly embedded in the transnational and international women's rights movement built a coalition on the CTW to ensure the prominence of the feminist abolitionist position of sex trafficking in the 1920s. This position was defined by calls for equal standards of morality between the sexes, resistance to laws that treated prostitutes as a group and infringed on their human rights, and unwavering demands for the abolition of state-regulated prostitution. Changes in the personnel and bureaucratic structure of the CTW and the rising tide of nationalism served to undermine the feminist abolitionists' position in the League in the 1930s.