Diffusion Tensor Imaging and Fiber Tractography in Children with Craniosynostosis Syndromes.
Patients with craniosynostosis syndromes caused by mutations in FGFR-2, FGFR-3, and TWIST1 genes are characterized by having prematurely fused skull sutures and skull base synchondroses, which result in a skull deformity and are accompanied by brain anomalies, including altered white matter microarchitecture. In this study, the reliability and reproducibility of DTI fiber tractography was investigated in these patients. The outcomes were compared with those of controls. DTI datasets were acquired with a 1.5T MR imaging system with 25 diffusion gradient orientations (voxel size = 1.8 × 1.8 × 3.0 mm(3), b-value = 1000 s/mm(2)). White matter tracts studied included the following: corpus callosum, cingulate gyrus, fornix, corticospinal tracts, and medial cerebellar peduncle. Tract pathways were reconstructed with ExploreDTI in 58 surgically treated patients with craniosynostosis syndromes and 7 controls (age range, 6-18 years). Because of the brain deformity and abnormal ventricular shape and size, DTI fiber tractography was challenging to perform in patients with craniosynostosis syndromes. To provide reliable tracts, we adapted standard tracking protocols. Fractional anisotropy was equal to that in controls (0.44 versus 0.45 ± 0.02, P = .536), whereas mean, axial, and radial diffusivity parameters of the mean white matter were increased in patients with craniosynostosis syndromes (P < .001). No craniosynostosis syndrome-specific difference in DTI properties was seen for any of the fiber tracts studied in this work. Performing DTI fiber tractography in patients with craniosynostosis syndromes was difficult due to partial volume effects caused by an anisotropic voxel size and deformed brain structures. Although these patients have a normal fiber organization, increased diffusivity parameters suggest abnormal microstructural tissue properties of the investigated white matter tracts.


Genomic fingerprinting by arbitrarily primed polymerase chain reaction resolves Borrelia burgdorferi into three distinct phyletic groups.
The causative agent of Lyme disease, Borrelia burgdorferi, was first identified by Burgdorfer et al. in 1982 (W. Burgdorfer, A. G. Barbour, S. F. Hayes, J. L. Benach, E. Grunwaldt, and J. P. Davis, Science 216:1317-1319, 1982) and was isolated by Barbour et al. in 1983 (A. G. Barbour, W. Burgdorfer, S. E. Hayes, O. Peter, and A. Aeschlimann, Curr. Microbiol. 8:123-126, 1983). Since then, a large number of isolates have been collected, and there have been questions regarding the relationships among the various strains. Using genomic fingerprinting by an arbitrarily primed polymerase chain reaction, we resolved into three groups a collection of Eurasian and North American isolates of spirochetes that are generally categorized as B. burgdorferi. Group I strains have been identified in both North America and Eurasia, while strains belonging to Borrelia groups II and III have been found only in Eurasia. These same three groups have also been delineated by Baranton et al. (G. Baranton, D. Postic, I. Saint Girons, P. Boerlin, J.-C. Piffaretti, M. Assous, and P. A. D. Grimont, Int. J. Syst. Bacteriol. 42:370-375, 1992) by independent methods. Two isolates are distinct from all of the other strains in our collection but are clearly members of the genus Borrelia.


Proteomic Analyses Detect Higher Expression of C-Type Lectins in Imidacloprid-Resistant Colorado Potato Beetle Leptinotarsa decemlineata Say.
The Colorado potato beetle (CPB) is one of the most adaptable insect pests to both plant toxins and synthetic insecticides. Resistance in CPB is reported for over 50 classes of insecticides, and mechanisms of insecticide-resistance include enhanced detoxification enzymes, ABC transporters and target site mutations. Adaptation to insecticides is also associated with changes in behaviour, energy metabolism and other physiological processes seemingly unrelated to resistance but partially explained through genomic analyses. In the present study, in place of genomics, we applied 2-dimensional (2-D) gel and mass spectrometry to investigate protein differences in abdominal and midgut tissue of insecticide-susceptible (S) and -resistant (R) CPB. The proteomic analyses measured constitutive differences in several proteins, but the highest match was identified as a C-type lectin (CTL), a component of innate immunity in insects. The constitutive expression of the CTL was greater in the multi-resistant (LI) strain, and the same spot was measured in both midgut and abdominal tissue. Exposure to the neonicotinoid insecticide, imidacloprid, increased the CTL spot found in the midgut but not in the abdominal tissue of the laboratory (Lab) strain. No increase in protein levels in the midgut tissue was observed in the LI or a field strain (NB) tolerant to neonicotinoids. With the exception of biopesticides, such as Bacillus thuringiensis (Bt), no previous studies have documented differences in the immune response by CTLs in insects exposed to synthetic insecticides or the fitness costs associated with expression levels of immune-related genes in insecticide-resistant strains. This study demonstrates again how CPB has been successful at adapting to insecticides, plant defenses as well as pathogens.


A systematic review of effectiveness and cost-effectiveness of school-based identification of children and young people at risk of, or currently experiencing mental health difficulties.
Although school-based programmes for the identification of children and young people (CYP) with mental health difficulties (MHD) have the potential to improve short- and long-term outcomes across a range of mental disorders, the evidence-base on the effectiveness of these programmes is underdeveloped. In this systematic review, we sought to identify and synthesise evidence on the effectiveness and cost-effectiveness of school-based methods to identify students experiencing MHD, as measured by accurate identification, referral rates, and service uptake. Electronic bibliographic databases: MEDLINE, Embase, PsycINFO, ERIC, British Education Index and ASSIA were searched. Comparative studies were included if they assessed the effectiveness or cost-effectiveness of strategies to identify students in formal education aged 3-18 years with MHD, presenting symptoms of mental ill health, or exposed to psychosocial risks that increase the likelihood of developing a MHD. We identified 27 studies describing 44 unique identification programmes. Only one study was a randomised controlled trial. Most studies evaluated the utility of universal screening programmes; where comparison of identification rates was made, the comparator test varied across studies. The heterogeneity of studies, the absence of randomised studies and poor outcome reporting make for a weak evidence-base that only generate tentative conclusions about the effectiveness of school-based identification programmes. Well-designed pragmatic trials that include the evaluation of cost-effectiveness and detailed process evaluations are necessary to establish the accuracy of different identification models, as well as their effectiveness in connecting students to appropriate support in real-world settings.


Accelerated neuronal differentiation toward motor neuron lineage from human embryonic stem cell line (H9).
Motor neurons loss plays a pivotal role in the pathoetiology of various debilitating diseases such as, but not limited to, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy. However, advancement in motor neuron replacement therapy has been significantly constrained by the difficulties in large-scale production at a cost-effective manner. Current methods to derive motor neuron heavily rely on biochemical stimulation, chemical biological screening, and complex physical cues. These existing methods are seriously challenged by extensive time requirements and poor yields. An innovative approach that overcomes prior hurdles and enhances the rate of successful motor neuron transplantation in patients is of critical demand. Iron, a trace element, is indispensable for the normal development and function of the central nervous system. Whether ferric ions promote neuronal differentiation and subsequently promote motor neuron lineage has never been considered. Here, we demonstrate that elevated iron concentration can drastically accelerate the differentiation of human embryonic stem cells (hESCs) toward motor neuron lineage potentially via a transferrin mediated pathway. HB9 expression in 500 nM iron-treated hESCs is approximately twofold higher than the control. Moreover, iron treatment generated more matured and functional motor neuron-like cells that are ∼1.5 times more sensitive to depolarization when compared to the control. Our methodology renders an expedited approach to harvest motor neuron-like cells for disease, traumatic injury regeneration, and drug screening.


Attraction between neutral dielectrics mediated by multivalent ions in an asymmetric ionic fluid.
We study the interaction between two neutral plane-parallel dielectric bodies in the presence of a highly asymmetric ionic fluid, containing multivalent as well as monovalent (salt) ions. Image charge interactions, due to dielectric discontinuities at the boundaries, as well as effects from ion confinement in the slit region between the surfaces are taken fully into account, leading to image-generated depletion attraction, ion correlation attraction, and steric-like repulsive interactions. We investigate these effects by employing a combination of Monte Carlo simulation methods, including explicit-ion simulations (where all electrostatic interactions are simulated explicitly) and implicit-ion simulations (where monovalent ions are replaced by an effective screened electrostatic potential between multivalent ions), as well as an approximate analytical theory. The latter incorporates strong ion-image charge correlations, which develop in the presence of high valency ions in the mixture. We show that the implicit-ion simulations and the proposed analytical theory can describe the explicit simulation results on a qualitative level, while excellent quantitative agreement can be obtained for sufficiently large monovalent salt concentrations. The resultant attractive interaction between the neutral surfaces is shown to be significant, as compared with the usual van der Waals interactions between semi-infinite dielectrics, and can thus play an important role at the nano scale.


Protective effect of different tetrafluorides on erosion of pellicle-free and pellicle-covered enamel and dentine.
The aim was to analyze the protective effects of titanium, zirconium and hafnium tetrafluorides on erosion of pellicle-free and pellicle-covered enamel and dentine in vitro. Eight groups of 20 specimens each of bovine enamel and bovine dentine were prepared. Half the specimens in each group were immersed in human saliva for 2 h for pellicle formation. Specimens were then left untreated (controls) or were treated for 120 s with TiF(4), ZrF(4) or HfF(4) solutions (0.4 or 1%) or 1.25% AmF/NaF gel. All specimens were eroded by exposure to hydrochloric acid, pH 2.6, for 25 min. Cumulative calcium release into the acid was monitored in consecutive 30-second intervals for 5 min, then at 2-min intervals up to a total erosion time of 25 min using the Arsenazo III procedure. Data were analyzed by ANOVA. 1% TiF(4) solution offered the best protective effect, especially in dentine (reduction of calcium loss about 50% at 25 min). 1% ZrF(4), 1% HfF(4) and 0.4% TiF(4) also reduced calcium loss, but to a lesser extent. Long-term effects were limited to dentine, while reduction of enamel erosion (about 25%) was restricted to 1-min erosion. The fluoride gel had a protective effect only in dentine. The efficacy of the tetrafluorides was influenced by the presence of the pellicle layer, in that the protection against dentine erosion by TiF(4) and ZrF(4) was greater on pellicle-covered specimens. Tetrafluoride solutions, especially 1% TiF(4), could decrease dental erosion, but were more effective on dentine than on enamel.


Affected kindred analysis of human X chromosome exomes to identify novel X-linked intellectual disability genes.
X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders.


ARA9 modifies agonist signaling through an increase in cytosolic aryl hydrocarbon receptor.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of agonists like 2,3, 7,8-tetrachlorodibenzo-p-dioxin. In the current model for AHR signaling, the unliganded receptor is found in the cytosol as part of a complex with a dimer of the 90-kDa heat shock protein and an immunophilin-like molecule, ARA9. In yeast, expression of ARA9 results in an increase in the maximal agonist response and a leftward shift in the AHR dose-response curve. To better understand the mechanism by which ARA9 modifies AHR signal transduction, we performed a series of coexpression experiments in yeast and mammalian cells. Our results demonstrate that ARA9's influence on AHR signaling is not due to inhibition of a membrane pump or modification of the receptor's transactivation properties. Using receptor photoaffinity labeling experiments, we were able to show that ARA9 enhances AHR signal transduction by increasing the available AHR binding sites within the cytosolic compartment of the cell. Our evidence suggests that ARA9's effects are related to its role as a cellular chaperone; i.e. we observed that expression of ARA9 increases the fraction of AHR in the cytosol and also stabilized the receptor under heat stress.


Chemical meningitis caused by spontaneous rupture of spinal teratoma.
Chemical meningitis is a medical condition characterised by sterile meningitis that usually develops in certain patients after neurosurgical procedures. Its acute clinical course and standard laboratory findings are indistinguishable from those of bacterial meningitis. We hereby describe a case who presented with clinico-investigatory profile suggestive of acute bacterial meningitis. Patient showed good response to standard antibiotics and steroids, but deteriorated on stopping steroids. MRI brain showed hyperintense signal in the frontal horns of lateral ventricle on T1 weighted images suggesting presence of fat. MRI spine confirmed presence of ruptured teratoma in lumbo-sacral region which had caused chemical meningitis. Patient responded well to steroid therapy. Tumour histopathology confirmed the diagnosis of mature cystic teratoma.


De novo DNA methylation through the 5'-segment of the H19 ICR maintains its imprint during early embryogenesis.
Genomic imprinting is a major monoallelic gene expression regulatory mechanism in mammals, and depends on gamete-specific DNA methylation of specialized cis-regulatory elements called imprinting control regions (ICRs). Allele-specific DNA methylation of the ICRs is faithfully maintained at the imprinted loci throughout development, even in early embryos where genomes undergo extensive epigenetic reprogramming, including DNA demethylation, to acquire totipotency. We previously found that an ectopically introduced H19 ICR fragment in transgenic mice acquired paternal allele-specific methylation in the somatic cells of offspring, whereas it was not methylated in sperm, suggesting that its gametic and postfertilization modifications were separable events. We hypothesized that this latter activity might contribute to maintenance of the methylation imprint in early embryos. Here, we demonstrate that methylation of the paternally inherited transgenic H19 ICR commences soon after fertilization in a maternal DNMT3A- and DNMT3L-dependent manner. When its germline methylation was partially obstructed by insertion of insulator sequences, the endogenous paternal H19 ICR also exhibited postfertilization methylation. Finally, we refined the responsible sequences for this activity in transgenic mice and found that deletion of the 5' segment of the endogenous paternal H19 ICR decreased its methylation after fertilization and attenuated Igf2 gene expression. These results demonstrate that this segment of the H19 ICR is essential for its de novo postfertilization DNA methylation, and that this activity contributes to the maintenance of imprinted methylation at the endogenous H19 ICR during early embryogenesis.


Mild Depressive Symptoms During the Third Trimester of Pregnancy Are Associated with Disruptions in Daily Rhythms but Not Subjective Sleep Quality.
Recent research in major depressive disorder suggests that dysregulation of the circadian system may be a core pathophysiological component. In pregnancy, women often experience significant disruptions in their daily rhythms, including changes in day-to-day schedule and sleep habits. Current evidence suggests that these disruptions in daily rhythms may adversely affect underlying circadian rhythmicity. The purpose of our study was to examine whether subjectively rated daily rhythm disruptions were associated with a greater incidence of depressive symptoms during the third trimester. Our study was a cross-sectional design, assessing sleep quality, symptoms of depression, and daily rhythm disruptions in 51 pregnant women in their third trimester. We observed a significant relationship between mild depressive symptoms and disruptions in daily rhythms. While we initially observed a strong correlation between subjective sleep quality and depressive symptoms, this was attenuated after accounting for daily rhythm disruptions. Disruptions in daily social rhythms, eating patterns, and general activity were all significantly associated with depressive symptomatology. Our findings point to a strong correlation between daily rhythm disruptions and prenatal depressive symptoms. Given that these daily rhythms are known to act as zeitgebers, longitudinal studies examining the directionality of this relationship between circadian rhythms and depressive symptoms during pregnancy are warranted.


Detection of SARS-CoV-2 within the healthcare environment: a multi-centre study conducted during the first wave of the COVID-19 outbreak in England.
Understanding how severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spread within the hospital setting is essential in order to protect staff, implement effective infection control measures, and prevent nosocomial transmission. The presence of SARS-CoV-2 in the air and on environmental surfaces around hospitalized patients, with and without respiratory symptoms, was investigated. Environmental sampling was undertaken within eight hospitals in England during the first wave of the coronavirus disease 2019 outbreak. Samples were analysed using reverse transcription polymerase chain reaction (PCR) and virus isolation assays. SARS-CoV-2 RNA was detected on 30 (8.9%) of 336 environmental surfaces. Cycle threshold values ranged from 28.8 to 39.1, equating to 2.2 x 105 to 59 genomic copies/swab. Concomitant bacterial counts were low, suggesting that the cleaning performed by nursing and domestic staff across all eight hospitals was effective. SARS-CoV-2 RNA was detected in four of 55 air samples taken <1 m from four different patients. In all cases, the concentration of viral RNA was low and ranged from <10 to 460 genomic copies/m3 air. Infectious virus was not recovered from any of the PCR-positive samples analysed. Effective cleaning can reduce the risk of fomite (contact) transmission, but some surface types may facilitate the survival, persistence and/or dispersal of SARS-CoV-2. The presence of low or undetectable concentrations of viral RNA in the air supports current guidance on the use of specific personal protective equipment for aerosol-generating and non-aerosol-generating procedures.


Delivery styles and formats for different stroke information topics: patient and carer preferences.
To identify the preferences of patients with stroke and their carers for format and delivery style, of different categories of stroke information, and whether these preferences changed over time. A semi-structured questionnaire, designed to explore preferences for four topic categories was administered to 34 acute stroke unit patients and 18 carers prior to discharge and again, 3 months after discharge to 27 of these patients and 16 of these carers. Overall format preferences were a combination of face-to-face, written and telephone for both patients and carers prior to discharge. This combination continued for carers following discharge, while patients preferred face-to-face, written and alternative formats of online and audiovisual at this time. Patients and carers most frequently preferred delivery styles appeared to be a mix of active and passive delivery styles, across all topics. Access to a telephone hotline was a popular delivery style. Patient and carer preferences varied, supporting the need to offer a variety of formats and delivery styles at each point of contact. By focusing on specific formats and delivery styles for different topics, health professionals may maximise the access to, and relevance of, stroke information for patients and their carers.


Identification and Characterization of a Carlavirus Causing Veinal Necrosis of Coleus.
A filamentous virus identified in coleus (Coleus × hybrida) in Minnesota and New York was found to cause veinal necrosis in coleus, although this symptom was observed only under certain conditions. The virus was transmitted readily by mechanical inoculation to coleus and Nicotiana spp. and was not transmitted by Myzus persicae. The particles of the coleus virus had a modal length of 640 nm and a single capsid protein with an estimated molecular mass of 34 kDa. The amino acid sequence of the coat protein region of the coleus virus genome had significant similarities only to the corresponding domain of carlaviruses. Based on virion morphology, capsid protein size, genome size and organization, amino acid sequence, and phylogenetic analyses, the coleus virus, which was named provisionally Coleus vein necrosis virus (CVNV), was concluded to be a new definitive member of the genus Carlavirus. A 2-kb fragment of the 3' terminus of the CVNV genome sequence is accessible under accession number DQ915963 in GenBank.


Systems Glycobiology: Integrating Glycogenomics, Glycoproteomics, Glycomics, and Other 'Omics Data Sets to Characterize Cellular Glycosylation Processes.
The number of proteins encoded in the human genome has been estimated at between 20,000 and 25,000, despite estimates that the entire proteome contains more than a million proteins. One reason for this difference is due to many post-translational modifications of protein that contribute to proteome complexity. Among these, glycosylation is of particular relevance because it serves to modify a large number of cellular proteins. Glycogenomics, glycoproteomics, glycomics, and glycoinformatics are helping to accelerate our understanding of the cellular events involved in generating the glycoproteome, the variety of glycan structures possible, and the importance of roles that glycans play in therapeutics and disease. Indeed, interest in glycosylation has expanded rapidly over the past decade, as large amounts of experimental 'omics data relevant to glycosylation processing have accumulated. Furthermore, new and more sophisticated glycoinformatics tools and databases are now available for glycan and glycosylation pathway analysis. Here, we summarize some of the recent advances in both experimental profiling and analytical methods involving N- and O-linked glycosylation processing for biotechnological and medically relevant cells together with the unique opportunities and challenges associated with interrogating and assimilating multiple, disparate high-throughput glycosylation data sets. This emerging era of advanced glycomics will lead to the discovery of key glycan biomarkers linked to diseases and help establish a better understanding of physiology and improved control of glycosylation processing in diverse cells and tissues important to disease and production of recombinant therapeutics. Furthermore, methodologies that facilitate the integration of glycomics measurements together with other 'omics data sets will lead to a deeper understanding and greater insights into the nature of glycosylation as a complex cellular process.


Optical spectra in the condensed phase: Capturing anharmonic and vibronic features using dynamic and static approaches.
Simulating optical spectra in the condensed phase remains a challenge for theory due to the need to capture spectral signatures arising from anharmonicity and dynamical effects, such as vibronic progressions and asymmetry. As such, numerous simulation methods have been developed that invoke different approximations and vary in their ability to capture different physical regimes. Here, we use several models of chromophores in the condensed phase and ab initio molecular dynamics simulations to rigorously assess the applicability of methods to simulate optical absorption spectra. Specifically, we focus on the ensemble scheme, which can address anharmonic potential energy surfaces but relies on the applicability of extreme nuclear-electronic time scale separation; the Franck-Condon method, which includes dynamical effects but generally only at the harmonic level; and the recently introduced ensemble zero-temperature Franck-Condon approach, which straddles these limits. We also devote particular attention to the performance of methods derived from a cumulant expansion of the energy gap fluctuations and test the ability to approximate the requisite time correlation functions using classical dynamics with quantum correction factors. These results provide insights as to when these methods are applicable and able to capture the features of condensed phase spectra qualitatively and, in some cases, quantitatively across a range of regimes.


The use of 3D face shape modelling in dysmorphology.
Facial appearance can be a significant clue in the initial identification of genetic conditions, but their low incidence limits exposure during training and inhibits the development of skills in recognising the facial "gestalt" characteristic of many dysmorphic syndromes. Here we describe the potential of computer-based models of three-dimensional (3D) facial morphology to assist in dysmorphology training, in clinical diagnosis and in multidisciplinary studies of phenotype-genotype correlations.


Self-aggregation of gel forming PEG-PLA star block copolymers in water.
The aggregation behavior and dynamics of poly(ethylene glycol) (PEG) and poly(lactide) (PLA) chains in a homologous series of eight-armed PEG-PLA star block copolymers ((PEG(65)-NHCO-PLA(n))(8) with n = 11, 13, and 15) in water at different concentrations and temperatures were studied by means of (1)H and (13)C NMR spectroscopy and (1)H longitudinal relaxation time analysis. The state of water in these systems was also investigated through the combined use of (1)H and (2)H longitudinal relaxation time measurement. On the basis of the NMR experimental findings and of dynamic light scattering measurements, (PEG(65)-NHCO-PLA(n))(8) in water can be described as self-aggregated systems with quite rigid hydrophobic domains made of PLA chains and aqueous domains where both PEG chains and water molecules undergo fast dynamics. A smaller number of rigid domains was found for (PEG(65)-NHCO-PLA(11))(8) with respect to the homologous copolymers with longer PLA chains. At low concentrations, the PLA domains are mainly formed by chains belonging to the same molecule, thus giving rise to unimolecular micelles. At intermediate concentrations, that is, above the critical association concentration (CAC) but below the critical gel concentration (CGC), nanogels are formed by interconnection of several PLA domains through shared unimers. Above the CGC, the network is extended to the entire system, giving rise to macroscopic gels. In all cases, a fraction of PLA chains remains quite mobile and exposed to water due to topological constraints of the star architecture.


Copper-based redox shuttles supported by preorganized tetradentate ligands for dye-sensitized solar cells.
Three copper redox shuttles ([Cu(1)]2+/1+, [Cu(2)]2+/1+, and [Cu(3)]2+/1+) featuring tetradentate ligands were synthesized and evaluated computationally, electrochemically, and in dye-sensitized solar cell (DSC) devices using a benchmark organic dye, Y123. Neutral polyaromatic ligands with limited flexibility were targeted as a strategy to improve solar-to-electrical energy conversion by reducing voltage losses associated with redox shuttle electron transfer events. Inner-sphere electron transfer reorganization energies (λ) were computed quantum chemically and compared to the commonly used [Co(bpy)3]3+/2+ redox shuttle which has a reported λ value of 0.61 eV. The geometrically constrained biphenyl-based Cu redox shuttles investigated here have lower reorganization energies (0.34-0.53 eV) and thus can potentially operate with lower driving forces for dye regeneration (ΔGreg) in DSC devices when compared to [Co(bpy)3]3+/2+-based devices. The rigid tetradentate ligand design promotes more efficient electron transfer reactions leading to an improved JSC (14.1 mA cm-2), higher stability due to the chelate effect, and a decrease in VlossOC for one of the copper redox shuttle-based devices.


Hospitalization Fatality Risk of Influenza A(H1N1)pdm09: A Systematic Review and Meta-Analysis.
During the 2009 influenza pandemic, uncertainty surrounding the severity of human infections with the influenza A(H1N1)pdm09 virus hindered the calibration of the early public health response. The case fatality risk was widely used to assess severity, but another underexplored and potentially more immediate measure is the hospitalization fatality risk (HFR), defined as the probability of death among H1N1pdm09 cases who required hospitalization for medical reasons. In this review, we searched for relevant studies published in MEDLINE (PubMed) and EMBASE between April 1, 2009, and January 9, 2014. Crude estimates of the HFR ranged from 0% to 52%, with higher estimates from tertiary-care referral hospitals in countries with a lower gross domestic product, but in wealthy countries the estimate was 1%-3% in all settings. Point estimates increased substantially with age and with lower gross domestic product. Early in the next pandemic, estimation of a standardized HFR may provide a picture of the severity of infection, particularly if it is presented in comparison with a similarly standardized HFR for seasonal influenza in the same setting.


The future endocrine patient. Reflections on the future of clinical endocrinology.
In recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular interventions. In this manuscript we describe 'the endocrine patient' of the past, the present, and the future. Complete therapeutic breakthroughs resulting in 'cure' are compared with 'halfway technologies' which help in creating the (life-long) chronic endocrine patient. The potential use of molecular diagnostics in optimalizing hormone replacement therapy is discussed. Clinical endocrinology is at risk of developing into a subspecialty where life-style drugs created for new diseases or conditions are offered, but also actively pursued by otherwise healthy individuals (e.g. in normal short stature, regulation of appetite, body composition, sexuality, reproduction and aging). The potential opportunities and risks for clinical endocrinology in creating 'the endocrine patient' of the future are discussed.


Are school meals a viable and sustainable tool to improve the healthiness and sustainability of children´s diet and food consumption? A cross-national comparative perspective.
There is little agreement among governments, institutions, scientists and food activists as to how to best tackle the challenging issues of health and sustainability in the food sector. This essay discusses the potential of school meals as a platform to promote healthy and sustainable food behavior. School meal programs are of particular interest for improving public diet because they reach children at a population scale across socio-economic classes and for over a decade of their lives, and because food habits of children are more malleable than those of adults. Current research on the history and health implications of school meal programs is reviewed in a cross-national comparative framework, and arguments explored that speak for the need of a new developmental phase of school meals as an integrative learning platform for healthy and sustainable food behavior. Nutritional, social, practical, educational, economical, political, and cultural perspectives and challenges linked to the implementation of healthy and sustainable school meals are discussed. Finally, the need for long-term interventions and evaluations is highlighted and new research directions are proposed.


Estimation of an optimal chemotherapy utilization rate for malignant pleural mesothelioma: an evidence-based benchmark for cancer care.
Chemotherapy with cisplatin and pemetrexed has been shown to provide a survival benefit and improvement in quality of life in patients with malignant pleural mesothelioma (MPM). The reported chemotherapy utilization rates range from 18% to 61%. This study aimed to estimate the proportion of MPM patients that should receive chemotherapy based on best available evidence. An optimal chemotherapy utilization model for MPM was constructed using indications for chemotherapy identified from evidence-based MPM treatment guidelines. Epidemiological data on the proportion of patients and their tumor-related attributes were combined with the chemotherapy indications to estimate the optimal chemotherapy utilization rate using decision analysis software (TreeAge Pro 2007). Sensitivity analyses were performed to assess the impact of major variations in the epidemiological data on the optimal chemotherapy utilization rate. The optimal rate was compared with the actual rate reported in the literature. Chemotherapy is recommended at least once during the disease trajectory in 65% of MPM patients. Sensitivity analyses indicate an optimal utilization rate ranging from 50% to 65%. This optimal rate is relatively comparable to the rates mentioned in contemporary reports from Canada (61% between 2003 and 2005) and Australia (54% between 2007 and 2009) and high when compared with data from the Netherlands (36% during 2005-2006). An evidence-based model provided an optimal chemotherapy utilization rate of 65% for patients with MPM. Chemotherapy for MPM may be underutilized and barriers are likely multifactorial.


Multiple pathways are involved in the anoxia response of SKIP3 including HuR-regulated RNA stability, NF-kappaB and ATF4.
Under anoxia a coordinated, cytoprotective program is induced, called the unfolded protein response (UPR). Activating transcription factor 4 (ATF4) is a mediator of the UPR and activates a gene expression program, promoting tumour growth and survival under anoxia. A key gene induced by ATF4 under normoxic conditions is SKIP3. We characterized the induction of SKIP3 during anoxic exposure to determine whether UPR alone was sufficient or there was a more complex regulatory response to anoxia. There was temporal separation of acute hypoxia-inducible factor (HIF)-1alpha- and chronic ATF4-dependent gene expression programs. SKIP3 was regulated by chronic (48 h) rather than acute anoxia (<24 h) by a complex set of pathways and mechanisms, besides ATF4 induced by the classical UPR, there was transcriptional regulation by nuclear factor-kappa B (NF-kappaB) and RNA stabilization by HuR. Temporal activation of the NF-kappaB pathway under anoxia protected cells from negative consequences of the oxygen stress and involved the canonical signalling pathways that promote IkappaBA phosphorylation and degradation, and reduced mRNA level of the inhibitory protein IkappaBA followed by the translational repression of IkappaBA. We also show that SKIP3 acts as an inhibitor of NF-kappaB and ATF4-dependent transcription under anoxia and provides a regulatory feedback loop. Repression of the survival pathway NF-kappaB by SKIP3 sensitized cells to metabolic consequences of the anoxic stress. Thus, the response to anoxia is mediated by three pathways independently of HIF, suggesting that combined therapeutic approaches would be needed to maximize effects against this pathway.


Thirty-years of screening for cystic fibrosis in East Anglia.
Newborn screening for cystic fibrosis (CF) relies on the measurement of immunoreactive trypsinogen (IRT) originating from the pancreas. The Norfolk, Suffolk and Cambridgeshire screening programme initially exploited the persistent increase in IRT seen in CF (IRT-IRT protocol) and later changed to include mutation analysis as a second tier test (IRT-DNA-IRT protocol). During a 30 year period 582 966 babies have been screened by IRT-IRT and 147 764 by IRT-DNA-IRT (total 730730), resulting in 296 screen positive cases of CF and 29 false negatives (including 10 false negatives with meconium ileus). Ten missed CF cases were pancreatic insufficient, however all were diagnosed before their first birthday, suggesting that a false negative result did not forestall appropriate clinical investigation. The IRT-DNA-IRT protocol had a much improved positive predictive value (PPV) of 85.9% compared to 67.3% for IRT-IRT, excluding CF babies with meconium ileus. The PPVs increased to 82.2% and 98.2% respectively if only well, term babies were considered. The main factor to account for this improvement in PPV has probably been the incorporation of DNA analysis in the second tier testing. The diagnosis of screen-positive babies proved difficult in a minority of cases with the classification of some patients changing with evolving phenotype. Our results illustrate the importance of collecting outcome data over a long time period for accurate assessment of the screening programme. This study provides evidence that newborn screening for CF is a valid undertaking that detects 95% of unsuspected CF cases presenting before 3 years of age.


On the origin of natural IgM in immunoglobulin transgenic mice.
Surface transgenic IgM was expressed by > 95% of small resting splenic B cells but only by 50% of CD5+ and CD5- peritoneal B cells from the mu-transgenic mouse line M54. Transgenic male M54 were crossed with female CBA/N mice carrying the Xid defect. Offspring F1 animals carrying the transgene were analysed for the presence of transgenic and endogenous IgM expressed both in the serum as well as on the surface of splenic and peritoneal B cells. We found that the levels of serum IgM coded for by the transgene were similar in both F1 male, which lack CD5 B cells, and female transgenic mice, which have CD5 B cells. Thus, the Xid defect does not influence the expression of the transgene at the level of naturally activated plasma cells, a finding substantiated by the fact that both male and female naturally activated splenic plasma cells express the transgene at the same frequency. F1 hybrid mice, like transgenic C57BI/6 M54 mice, have naturally activated splenic plasma cells that overexpress endogenous IgM coded for by the VH gene family Q52. The data indicate that normal serum IgM is not derived from CD5+ B cells and that the serum IgM coded for by the mu-transgene from M54 is produced at normal levels even in the male F1 mouse which lacks CD5+ B cells.


A Digital Repository and Execution Platform for Interactive Scholarly Publications in Neuroscience.
The CARMEN Virtual Laboratory (VL) is a cloud-based platform which allows neuroscientists to store, share, develop, execute, reproduce and publicise their work. This paper describes new functionality in the CARMEN VL: an interactive publications repository. This new facility allows users to link data and software to publications. This enables other users to examine data and software associated with the publication and execute the associated software within the VL using the same data as the authors used in the publication. The cloud-based architecture and SaaS (Software as a Service) framework allows vast data sets to be uploaded and analysed using software services. Thus, this new interactive publications facility allows others to build on research results through reuse. This aligns with recent developments by funding agencies, institutions, and publishers with a move to open access research. Open access provides reproducibility and verification of research resources and results. Publications and their associated data and software will be assured of long-term preservation and curation in the repository. Further, analysing research data and the evaluations described in publications frequently requires a number of execution stages many of which are iterative. The VL provides a scientific workflow environment to combine software services into a processing tree. These workflows can also be associated with publications and executed by users. The VL also provides a secure environment where users can decide the access rights for each resource to ensure copyright and privacy restrictions are met.


Features and prognostic factors of large node-negative non-small-cell lung cancers shifted to stage II.
During the period that randomized clinical trials were establishing the role of adjuvant therapy in tumors larger than 5 cm without lymph-node invasion, which shifted from stage IB (6th TNM) to stage II (7th TNM), we derived the rate of shifted patients in our series and analyzed the relationship between specific patient- and tumor- characteristics, and clinical outcome, to identify putative prognostic factors. We retrospectively collected data (age, sex, smoking status, type of surgery grading, and histological type) from 467 patients who underwent radical surgery for primary 6th TNM-T2N0 non-small cell lung cancer patients between 1998 and 2009 at our institute. Categorical variables were cross-tabulated by tumor staging according to the 7th TNM edition, and they were tested both for association with stage and survival. One hundred and eighteen patients shifted to stage II, mainly older patients and patients with a sarcomatoid or a poorly differentiated carcinoma. Median overall survival time was significantly different across stages. Among the factors investigated, only the tumor dimension resulted in being statistically significant in multivariate analysis. Nearly a quarter of patients shifted from stage I (6th TNM) to stage II (7th TNM), raising a major need for information on the effects of adjuvant chemotherapy in this group of patients. Our findings suggest that randomized clinical trials aimed at addressing this topic should consider only tumor dimensions as principal selection criteria.


Mutation of a gene for a Drosophila kinesin-like protein, Klp38B, leads to failure of cytokinesis.
Mutations in a gene (Klp38B) encoding a novel kinesin-like protein in Drosophila melanogaster lead to the formation of polyploid cells in the larval central nervous system and in the follicle cells of adult egg chambers. Some homozygous mutants survive to adulthood and also exhibit morphological defects indicative of abnormal cell cycle progression, including rough eyes, missing bristles, and abnormal abdominal cuticles. In larval brains, there is no accumulation of mitotic cells and the frequency of anaphase figures is comparable to wild type, suggesting that nuclear division is not affected. Such brains contain polyploid cells with metaphase and anaphase chromosomes associated with bipolar spindles. Such spindles have a number of unseparated centrosomes at their poles reflecting the degree of polyploidy of the cell. Follicle cells frequently contain two nuclei of roughly equal size. Taken together, we conclude that these Klp38B mutations lead to a failure of cytokinesis resulting in polyploidy, and discuss whether or not this is a direct effect of the mutation.


The WNKs: atypical protein kinases with pleiotropic actions.
WNKs are serine/threonine kinases that comprise a unique branch of the kinome. They are so-named owing to the unusual placement of an essential catalytic lysine. WNKs have now been identified in diverse organisms. In humans and other mammals, four genes encode WNKs. WNKs are widely expressed at the message level, although data on protein expression is more limited. Soon after the WNKs were identified, mutations in genes encoding WNK1 and -4 were determined to cause the human disease familial hyperkalemic hypertension (also known as pseudohypoaldosteronism II, or Gordon's Syndrome). For this reason, a major focus of investigation has been to dissect the role of WNK kinases in renal regulation of ion transport. More recently, a different mutation in WNK1 was identified as the cause of hereditary sensory and autonomic neuropathy type II, an early-onset autosomal disease of peripheral sensory nerves. Thus the WNKs represent an important family of potential targets for the treatment of human disease, and further elucidation of their physiological actions outside of the kidney and brain is necessary. In this review, we describe the gene structure and mechanisms regulating expression and activity of the WNKs. Subsequently, we outline substrates and targets of WNKs as well as effects of WNKs on cellular physiology, both in the kidney and elsewhere. Next, consequences of these effects on integrated physiological function are outlined. Finally, we discuss the known and putative pathophysiological relevance of the WNKs.


Cortical microinfarcts in memory clinic patients are associated with reduced cerebral perfusion.
Cerebral cortical microinfarcts (CMIs) are small ischemic lesions associated with cognitive impairment and dementia. CMIs are frequently observed in cortical watershed areas suggesting that hypoperfusion contributes to their development. We investigated if presence of CMIs was related to a decrease in cerebral perfusion, globally or specifically in cortex surrounding CMIs. In 181 memory clinic patients (mean age 72 ± 9 years, 51% male), CMI presence was rated on 3-T magnetic resonance imaging (MRI). Cerebral perfusion was assessed from cortical gray matter of the anterior circulation using pseudo-continuous arterial spin labeling parameters cerebral blood flow (CBF) (perfusion in mL blood/100 g tissue/min) and spatial coefficient of variation (CoV) (reflecting arterial transit time (ATT)). Patients with CMIs had a 12% lower CBF (beta = -.20) and 22% higher spatial CoV (beta = .20) (both p < .05) without a specific regional pattern on voxel-based CBF analysis. CBF in a 2 cm region-of-interest around the CMIs did not differ from CBF in a reference zone in the contralateral hemisphere. These findings show that CMIs in memory clinic patients are primarily related to global reductions in cerebral perfusion, thus shedding new light on the etiology of vascular brain injury in dementia.


The genomic distribution of L1 elements: the role of insertion bias and natural selection.
LINE-1 (L1) retrotransposons constitute the most successful family of retroelements in mammals and account for as much as 20% of mammalian DNA. L1 elements can be found in all genomic regions but they are far more abundant in AT-rich, gene-poor, and low-recombining regions of the genome. In addition, the sex chromosomes and some genes seem disproportionately enriched in L1 elements. Insertion bias and selective processes can both account for this biased distribution of L1 elements. L1 elements do not appear to insert randomly in the genome and this insertion bias can at least partially explain the genomic distribution of L1. The contrasted distribution of L1 and Alu elements suggests that postinsertional processes play a major role in shaping L1 distribution. The most likely mechanism is the loss of recently integrated L1 elements that are deleterious (negative selection) either because of disruption of gene function or their ability to mediate ectopic recombination. By comparison, the retention of L1 elements because of some positive effect is limited to a small fraction of the genome. Understanding the respective importance of insertion bias and selection will require a better knowledge of insertion mechanisms and the dynamics of L1 inserts in populations.


A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania.
Lithium is an effective prophylactic and anti-manic treatment in bipolar disorder; however, its use is declining through perceived poor tolerance and toxicity. Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe. To assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and the Altman Self-Rating Mania (ASRM) Scale and Clinical Global Impression-Severity Scale (CGI-S) among the secondary outcomes. Randomised, double-blind, placebo-controlled, parallel-group trial conducted between October 2017 and June 2019, at Oxford Health NHS Foundation Trust. Pharmacy-controlled randomisation was computer-generated, with full allocation concealment. In/outpatients (n = 68) aged 18-70, experiencing mania or hypomania, were assigned to 3 weeks ebselen (600 mg bd) (n = 33) or placebo (n = 35). Participants received usual clinical care and psychotropic medication. Ebselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, - 1.71 (- 5.34 to 1.91), p = 0.35) and ASRM (- 1.36 (- 3.75 to 1.17), p = 0.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, - 0.58 (- 1.14 to - 0.03), p = 0.04). A post hoc analysis excluding patients taking concomitant valproate treatment magnified the difference between ebselen and placebo on the YMRS. Adverse events were comparable between groups, and mild. Ebselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen's superior tolerance and safety could make it a useful alternative to lithium. Trial Registry: www.clinicaltrials.gov , Identifier: NCT03013400.


Nutraceutical potential of Asparagopsis taxiformis (Delile) Trevisan extracts and assessment of a downstream purification strategy.
The main goal of the present work was to determine the nutraceutical potential of Asparagopsis taxiformis D. extracts from Madeira Archipelago south coast. Extraction methodologies consisted either/or in 72 hours stirring, at room temperature (M1), or 6 cycles of Soxhlet extraction (M2), both with re-extraction. Solvents used were distilled water, ethanol, methanol and ethyl acetate. M1 allowed to obtain the highest values for extraction yield (31.65 g.100g-1 dw) using water, whereas iodine content (3.37 g.100g-1 dw), TPC (1.71 g GAE.100g-1 dw) and chlorophyll a (45.96 mg.100g-1 dw) were obtained using ethanol, and TCC (36.23 mg.100g-1 dw) with methanol. Extracts that showed higher reduction activity in M1 were derived from ethanol extraction (1,908 mg AAE.100g-1 dw). Water and ethanol were the best solvents for higher DPPH scavenging activity in M2, both with same result (IC50 1.37 mg.mL-1). The lowest value of IC50 for chelating activity (1.57 mg.mL-1) was determined in M1, using ethyl acetate. The remaining residue was used to obtain other products, i.e. lipid extraction (M1, 2.05 g.100g-1 dw), carrageenans (M2, 21.18 g.100g-1 dw) and cellulose (M1, 23.81 g.100g-1 dw) with subsequent FTIR ATR analysis. Our results show that A. taxiformis is a valuable source of bioactive compounds. The M1 extraction methodology using ethanol is the most effective solvent to produce an iodine rich bioactive extract with potential of being used as a nutraceutical supplement. Also, we have demonstrated a possible downstream strategy that could be implemented for multiple compound extraction from A. taxiformis residue. This has a vital importance for future feasibility, when using this biomass as an industrial feedstock for multiple products production. Statistical analysis, using SPSS 24.0, was also performed and important correlations were found between assays and methods.


Depression in cancer: The many biobehavioral pathways driving tumor progression.
Major Depressive Disorder (MDD) is common among cancer patients, with prevalence rates up to four-times higher than the general population. Depression confers worse outcomes, including non-adherence to treatment and increased mortality in the oncology setting. Advances in the understanding of neurobiological underpinnings of depression have revealed shared biobehavioral mechanisms may contribute to cancer progression. Moreover, psychosocial stressors in cancer promote: (1) inflammation and oxidative/nitrosative stress; (2) a decreased immunosurveillance; and (3) a dysfunctional activation of the autonomic nervous system and of the hypothalamic-pituitaryadrenal axis. Consequently, the prompt recognition of depression among patients with cancer who may benefit of treatment strategies targeting depressive symptoms, cognitive dysfunction, fatigue and sleep disturbances, is a public health priority. Moreover, behavioral strategies aiming at reducing psychological distress and depressive symptoms, including addressing unhealthy diet and life-style choices, as well as physical inactivity and sleep dysfunction, may represent important strategies not only to treat depression, but also to improve wider cancer-related outcomes. Herein, we provide a comprehensive review of the intertwined biobehavioral pathways linking depression to cancer progression. In addition, the clinical implications of these findings are critically reviewed.


Human cytomegalovirus (CMV) in Africa: a neglected but important pathogen.
In Africa, human cytomegalovirus (CMV) is an important pathogen in a diverse range of patient groups. Congenital CMV infection is common, and most children undergo primary infection during the first year of life. Preliminary studies suggest that these early primary CMV infections could have population-wide effects on growth and development. In most studies of adults, CMV seroprevalence is close to 100%, but some studies have found that significant minorities of adults are seronegative. CMV is a common cause of pneumonia and meningitis in hospitalised immunosuppressed patient groups, and CMV DNAemia may be an important marker of rapid progression and poor outcomes of HIV infection, despite roll-out of antiretroviral therapy (ART). Diagnosis and treatment of CMV-related disease is broadly neglected in Africa, and no randomised clinical trials of anti-CMV drugs have been conducted to date. Autopsy is rarely performed in Africa, but identifies CMV as a frequent pathogen when it is carried out. Here we review the available literature on CMV in Africa, primarily in adult patients, and discuss this in the context of contemporary understanding of CMV as a human pathogen.


In vitro decidualisation of canine uterine stromal cells.
The uterine response to the presence of embryos is poorly understood in the domestic dog (Canis familiaris). The intimate embryo-maternal cross-talk, which begins following the hatching of blastocysts and embryo attachment leads to strong structural and functional remodelling of the uterus. A part of this process is decidualisation, comprising morphological and biochemical changes that result in formation of maternal stroma-derived decidual cells. These are an integral part of the canine placenta materna, which together with the maternal vascular endothelium are the only cells of the canine endotheliochorial placenta able to resist trophoblast invasion. These cells are also the only ones within the canine placenta expressing the progesterone receptor (PGR). Understanding the decidualisation process thus appears essential for understanding canine reproductive physiology. Here, we investigated the capability of canine uterine stromal cells to decidualise in vitro, thereby serving as a canine model of decidualisation. A dbcAMP-mediated approach was chosen during a time course of 24 - 72 h. Tissue material from six (n = 6) healthy, dioestric bitches was used (approximately 2 weeks after ovulation). Cells were characterized by differential staining, nearly 100 % of which were vimentin-positive. Scanning and transmission electron microscope analyses were applied, and morphological changes were recorded with a live cell imaging microscope. Expression of several decidualisation markers was investigated. The in vitro cultured stromal cells acquired characteristics of decidual cells when incubated with 0.5 mM dbcAMP for 72 h. Their shape changed from elongated to rounded, while ultrastructural analysis revealed higher numbers of mitochondria and secretory follicles, and an increased proliferation rate. Elevated expression levels of IGF1, IGF2, PRLR and ERα were observed in decidualised cells; PRL and ERβ remained mostly below the detection limit, while PGR remained unaffected. The expression of smooth muscle α actin (αSMA), another decidualisation marker, was strongly induced. Among prostaglandin system members, levels of COX2 (PTGS2) and of PGE2-synthase (PTGES) were upregulated. Expression of the PGE2 receptors, PTGER2 and PTGER4, was clearly detectable. An in vitro decidualisation model with canine uterine stromal cells was successfully established, allowing future, more detailed studies to be undertaken on the underlying molecular and endocrine mechanisms of canine decidualisation.


Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: a potential role?
Recently, there has been interest in lysergic acid diethylamide (LSD) and psilocybin for depression, anxiety and fear of death in terminal illness. The aim of this review is to discuss the potential use of LSD and psilocybin for patients with persistent pain. LSD and psilocybin are 5-hydroxytryptamine receptor agonists and may interact with nociceptive and antinociceptive processing. Tentative evidence from a systematic review suggests that LSD (7 studies, 323 participants) and psilocybin (3 studies, 92 participants) may be beneficial for depression and anxiety associated with distress in life-threatening diseases. LSD and psilocybin are generally safe if administered by a healthcare professional, although further investigations are needed to assess their utility for patients with persistent pain, especially associated with terminal illness.


"Bouba" and "Kiki" in Namibia? A remote culture make similar shape-sound matches, but different shape-taste matches to Westerners.
Western participants consistently match certain shapes with particular speech sounds, tastes, and flavours. Here we demonstrate that the "Bouba-Kiki effect", a well-known shape-sound symbolism effect commonly observed in Western participants, is also observable in the Himba of Northern Namibia, a remote population with little exposure to Western cultural and environmental influences, and who do not use a written language. However, in contrast to Westerners, the Himba did not map carbonation (in a sample of sparkling water) onto an angular (as opposed to a rounded) shape. Furthermore, they also tended to match less bitter (i.e., milk) chocolate samples to angular rather than rounded shapes; the opposite mapping to that shown by Westerners. Together, these results show that cultural-environmental as well as phylogenetic factors play a central role in shaping our repertoire of crossmodal correspondences.


Use of an innovative T-tube maze assay and the proboscis extension response assay to assess sublethal effects of GM products and pesticides on learning capacity of the honey bee Apis mellifera L.
Transgenic Cry1Ac+CpTI cotton (CCRI41) is a promising cotton cultivar throughout China but side effects and especially sublethal effects of this transgenic cultivar on beneficial insects remain poorly studied. More specifically potential sublethal effects on behavioural traits of the honey bee Apis mellifera L. have not been formally assessed despite the importance of honey bees for pollination. The goal of our study was to assess potential effects of CCRI41 cotton pollen on visual and olfactory learning by honey bees. After a 7-day oral chronic exposure to honey mixed with either CCRI41 pollen, imidacloprid-treated conventional pollen (used as positive sublethal control) or conventional pollen (control), learning performance was evaluated by the classical proboscis extension reflex (PER) procedure as well as a T-tube maze test. The latter assay was designed as a new device to assess potential side effects of pesticides on visual associative learning of honey bees. These two procedures were complementary because the former focused on olfactory learning while the latter was involved in visual learning based on visual orientation ability. Oral exposure to CCRI41 pollen did not affect learning capacities of honey bees in both the T-tube maze and PER tests. However, exposure to imidacloprid resulted in reduced visual learning capacities in T-tube maze evaluation and decreased olfactory learning performances measured with PER. The implications of these results are discussed in terms of risks of transgenic CCRI41 cotton crops for honey bees.


Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
Imerslund-Gräsbeck syndrome (IGS) or selective vitamin B(12) (cobalamin) malabsorption with proteinuria is a rare autosomal recessive disorder characterized by vitamin B(12) deficiency commonly resulting in megaloblastic anemia, which is responsive to parenteral vitamin B(12) therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Mild proteinuria (with no signs of kidney disease) is present in about half of the patients. Anatomical anomalies in the urinary tract were observed in some Norwegian patients. Vitamin B(12) absorption tests show low absorption, not corrected by administration of intrinsic factor. The symptoms appear from 4 months (not immediately after birth as in transcobalamin deficiency) up to several years after birth. The syndrome was first described in Finland and Norway where the prevalence is about 1:200,000. The cause is a defect in the receptor of the vitamin B(12)-intrinsic factor complex of the ileal enterocyte. In most cases, the molecular basis of the selective malabsorption and proteinuria involves a mutation in one of two genes, cubilin (CUBN) on chromosome 10 or amnionless (AMN) on chromosome 14. Both proteins are components of the intestinal receptor for the vitamin B(12)-intrinsic factor complex and the receptor mediating the tubular reabsorption of protein from the primary urine. Management includes life-long vitamin B(12) injections, and with this regimen, the patients stay healthy for decades. However, the proteinuria persists. In diagnosing this disease, it is important to be aware that cobalamin deficiency affects enterocyte function; therefore, all tests suggesting general and cobalamin malabsorption should be repeated after abolishment of the deficiency.


A quantitative quasispecies theory-based model of virus escape mutation under immune selection.
Viral infections involve a complex interplay of the immune response and escape mutation of the virus quasispecies inside a single host. Although fundamental aspects of such a balance of mutation and selection pressure have been established by the quasispecies theory decades ago, its implications have largely remained qualitative. Here, we present a quantitative approach to model the virus evolution under cytotoxic T-lymphocyte immune response. The virus quasispecies dynamics are explicitly represented by mutations in the combined sequence space of a set of epitopes within the viral genome. We stochastically simulated the growth of a viral population originating from a single wild-type founder virus and its recognition and clearance by the immune response, as well as the expansion of its genetic diversity. Applied to the immune escape of a simian immunodeficiency virus epitope, model predictions were quantitatively comparable to the experimental data. Within the model parameter space, we found two qualitatively different regimes of infectious disease pathogenesis, each representing alternative fates of the immune response: It can clear the infection in finite time or eventually be overwhelmed by viral growth and escape mutation. The latter regime exhibits the characteristic disease progression pattern of human immunodeficiency virus, while the former is bounded by maximum mutation rates that can be suppressed by the immune response. Our results demonstrate that, by explicitly representing epitope mutations and thus providing a genotype-phenotype map, the quasispecies theory can form the basis of a detailed sequence-specific model of real-world viral pathogens evolving under immune selection.


Electromagnetic spatial coherence wavelets.
The recently introduced concept of spatial coherence wavelets is generalized to describe the propagation of electromagnetic fields in the free space. For this aim, the spatial coherence wavelet tensor is introduced as an elementary amount, in terms of which the formerly known quantities for this domain can be expressed. It allows for the analysis of the relationship between the spatial coherence properties and the polarization state of the electromagnetic wave. This approach is completely consistent with the recently introduced unified theory of coherence and polarization for random electromagnetic beams, but it provides further insight about the causal relationship between the polarization states at different planes along the propagation path.


The role of the G20 economies in global health.
The Meetings of Health Ministers of the Group of Twenty (G20) that started at the G20 Summit in Berlin, Germany in 2017 have provided a platform for the discussion of global health matters such as antimicrobial resistance (AMR), public health emergencies, and universal health coverage. Similar issues are also discussed at meetings of the G7 and the World Health Assembly (WHA). This article will examine recent data to explore the characteristics of the G20 and its potential for improving health outcomes. G20 countries have a leading role to play in helping other countries improve global health outcomes because member countries have already faced many issues associated with aging society and increased prevalence of non-communicable diseases (NCDs). Indeed, 71% of the world's elderly population lives in the G20 countries and most of these countries have a high proportional mortality from NCDs of more than 70%. G20 countries are also responsible for a disproportionate share of global impacts. For instance, 72% of CO2 emissions are produced by G20 countries. Migration dynamics and its consequences also need to be considered from the perspective of optimizing health outcomes. Moreover, 78% of the world's top 50 pharmaceutical companies are located in the G20 countries. There is ample room for G20 countries to pursue collaborative and cooperative approaches that can complement the roles of the G7 and WHA in similar health issues. The G20 could, for example, share experiences on dealing with aging and NCDs, reduce their CO2 emissions, prohibit the production of low-quality medicines, and use standardized health check-up formats for migrants and refugees to transfer their own health information. As a group, the G20 countries have the potential to solve global health problems and other issues. The convening of high-level health meetings at G20 summits has the potential to facilitate such endeavors.


Observation of a cascaded process in intracavity terahertz optical parametric oscillators based on lithium niobate.
Cascaded difference frequency generation has been observed in intracavity optical parametric oscillators based on bulk lithium niobate and producing nanosecond pulses of terahertz radiation. Two idler waves are generated, namely: the primary idler wave associated with the parametric down conversion process itself; and a secondary idler wave, due to difference frequency generation. Experimental investigations of the frequency, temporal evolution, propagation direction, intensity, phase matching and oscillation threshold of the generated down-converted waves are reported. The overall generation efficiency for the terahertz radiation is enhanced, thereby overcoming the Manley-Rowe limit. Advantages of the present approach over schemes based on periodically poled lithium niobate are identified.


How Chanting Relates to Cognitive Function, Altered States and Quality of Life.
Chanting is practiced in many religious and secular traditions and involves rhythmic vocalization or mental repetition of a sound or phrase. This study examined how chanting relates to cognitive function, altered states, and quality of life across a wide range of traditions. A global survey was used to assess experiences during chanting including flow states, mystical experiences, mindfulness, and mind wandering. Further, attributes of chanting were assessed to determine their association with altered states and cognitive benefits, and whether psychological correlates of chanting are associated with quality of life. Responses were analyzed from 456 English speaking participants who regularly chant across 32 countries and various chanting traditions. Results revealed that different aspects of chanting were associated with distinctive experiential outcomes. Stronger intentionality (devotion, intention, sound) and higher chanting engagement (experience, practice duration, regularity) were associated with altered states and cognitive benefits. Participants whose main practice was call and response chanting reported higher scores of mystical experiences. Participants whose main practice was repetitive prayer reported lower mind wandering. Lastly, intentionality and engagement were associated with quality of life indirectly through altered states and cognitive benefits. This research sheds new light on the phenomenology and psychological consequences of chanting across a range of practices and traditions.


Prefrontal cortex activation supports the emergence of early stone age toolmaking skill.
Trends toward encephalization and technological complexity ∼1.8 million years ago may signify cognitive development in the genus Homo. Using functional near-infrared spectroscopy, we measured relative brain activity of 33 human subjects at three different points as they learned to make replicative Oldowan and Acheulian Early Stone Age tools. Here we show that the more complex early Acheulian industry recruits left dorsolateral prefrontal cortex when skills related to this task are first being learned. Individuals with increased activity in this area are the most proficient at the Acheulian task. The Oldowan task, on the other hand, transitions to automatic processing in less than 4 h of training. Individuals with increased sensorimotor activity demonstrate the most skill at this task. We argue that enhanced working memory abilities received positive selection in response to technological needs during the early Pleistocene, setting Homo on the path to becoming human.


Molecular phylogenetics and phylogeography of all the Saimiri taxa (Cebidae, Primates) inferred from mt COI and COII gene sequences.
Some previous genetic studies have been performed to resolve the molecular phylogenetics of the squirrel monkeys (Saimiri). However, these studies did not show consensus in how many taxa are within this genus and what the relationships among them are. For this reason, we sequenced 2,237 base pairs of the mt COI and COII genes in 218 Saimiri individuals. All, less 12 S. sciureus sciureus from French Guyana, were sampled in the wild. These samples represented all the living Saimiri taxa recognized. There were four main findings of this study. (1) Our analysis detected 17 different Saimiri groups: albigena, cassiquiarensis, five polyphyletic macrodon groups, three polyphyletic ustus groups, sciureus, collinsi, boliviensis, peruviensis, vanzolinii, oerstedii and citrinellus. Four different phylogenetic trees showed the Central American squirrel monkey (S. oerstedii) as the most differentiated taxon. In contrast, albigena was indicated to be the most recent taxon. (2) There was extensive hybridization and/or historical introgression among albigena, different macrodon groups, peruviensis, sciureus and collinsi. (3) Different tests showed that our maximum likelihood tree was consistent with two species of Saimiri: S. oerstedii and S. sciureus. If no cases of hybridization were detected implicating S. vanzolinii, this could be a third recognized species. (4) We also estimated that the first temporal splits within this genus occurred around 1.4-1.6 million years ago, which indicates that the temporal split events within Saimiri were correlated with Pleistocene climatic changes. If the biological species concept is applied because, in this case, it is operative due to observed hybridization in the wild, the number of species within this genus is probably more limited than recently proposed by other authors. The Pleistocene was the fundamental epoch when the mitochondrial Saimiri diversification process occurred.


Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance.
Genetic susceptibility may be responsible for high prevalence of insulin resistance in Asian Indians. This study was carried out in samples of local Asian Indians and Caucasians to determine whether plasma cell membrane glycoprotein (PC)-1 K121Q and insulin receptor substrate-1 (IRS-1) G972A polymorphisms contribute significantly to susceptibility to insulin resistance in Asian Indians. The frequency of carrying at least one copy of the PC-1 121Q variant in Asian Indians was significantly higher than that in Caucasians (P = 0.01), but the frequency was similar for IRS-1 972A (6% and 7%). A significantly higher insulin area under the curve during oral glucose tolerance testing (P < 0.0001) and lower insulin sensitivity during hyperinsulinemic-euglycemic clamps (P = 0.04) were found in Asian Indians with PC-1 121Q variant compared with Asian Indians with wild-type PC-1 and with Caucasians with or without the polymorphism. IRS-1 972A was not associated with any change in insulin sensitivity. We conclude that the PC-1 K121Q polymorphism associates with primary insulin resistance in migrant Asian Indians. A relatively high frequency of this polymorphism thus may be one factor contributing to insulin resistance susceptibility in Asian Indians. This finding indicates the need for expanded studies on the association between PC-1 K121Q and insulin resistance in a representative sample of the Asian Indian population.


Inhibition of the infectivity of influenza virus by tea polyphenols.
(-)Epigallocatechin gallate (EGCg) and theaflavin digallate (TF3) (1-10 microM) inhibited the infectivity of both influenza A virus and influenza B virus in Madin-Darby canine kidney (MDCK) cells in vitro. Study by electron microscope revealed that EGCg and TF3 (1 mM) agglutinated influenza viruses as well as did antibody, and that they prevented the viruses from adsorbing to MDCK cells. EGCg and TF3 more weakly inhibited adsorption of the viruses to MDCK cells. EGCg and TF3 (1-16 microM) also inhibited haemagglutination by influenza viruses. These findings suggest that tea polyphenols bind to the haemagglutinin of influenza virus, inhibit its adsorption to MDCK cells, and thus block its infectivity.


3D nanostructures fabricated by advanced stencil lithography.
This letter reports on a novel fabrication method for 3D metal nanostructures using high-throughput nanostencil lithography. Aperture clogging, which occurs on the stencil membranes during physical vapor deposition, is leveraged to create complex topographies on the nanoscale. The precision of the 3D nanofabrication method is studied in terms of geometric parameters and material types. The versatility of the technique is demonstrated by various symmetric and chiral patterns made of Al and Au.


On the path to translation: Highlights from the 2010 Canadian Conference on Ovarian Cancer Research.
Ovarian cancer continues to be the most lethal of the gynaecologic malignancies due to the lack of early detection, screening strategies and ineffective therapeutics for late-stage metastatic disease, particularly in the recurrent setting. The gathering of researchers investigating fundamental pathobiology of ovarian cancer and the clinicians who treat patients with this insidious disease is paramount to meeting the challenges we face. Since 2002, the Canadian Conference on Ovarian Cancer Research, held every two years, has served this essential purpose. The objectives of this conference have been to disseminate new information arising from the most recent ovarian cancer research and identify the most pressing challenges we still face as scientists and clinicians. This is best accomplished through direct encounters and exchanges of innovative ideas among colleagues and trainees from the realms of basic science and clinical disciplines. This meeting has and continues to successfully facilitate rapid networking and establish new collaborations from across Canada. This year, more guest speakers and participants from other countries have extended the breadth of the research on ovarian cancer that was discussed at the meeting. This report summarizes the key findings presented at the fifth biennial Canadian Conference on Ovarian Cancer Research held in Toronto, Ontario, and includes the important issues and challenges we still face in the years ahead to make a significant impact on this devastating disease.


Crowdsourcing for translational research: analysis of biomarker expression using cancer microarrays.
Academic pathology suffers from an acute and growing lack of workforce resource. This especially impacts on translational elements of clinical trials, which can require detailed analysis of thousands of tissue samples. We tested whether crowdsourcing - enlisting help from the public - is a sufficiently accurate method to score such samples. We developed a novel online interface to train and test lay participants on cancer detection and immunohistochemistry scoring in tissue microarrays. Lay participants initially performed cancer detection on lung cancer images stained for CD8, and we measured how extending a basic tutorial by annotated example images and feedback-based training affected cancer detection accuracy. We then applied this tutorial to additional cancer types and immunohistochemistry markers - bladder/ki67, lung/EGFR, and oesophageal/CD8 - to establish accuracy compared with experts. Using this optimised tutorial, we then tested lay participants' accuracy on immunohistochemistry scoring of lung/EGFR and bladder/p53 samples. We observed that for cancer detection, annotated example images and feedback-based training both improved accuracy compared with a basic tutorial only. Using this optimised tutorial, we demonstrate highly accurate (>0.90 area under curve) detection of cancer in samples stained with nuclear, cytoplasmic and membrane cell markers. We also observed high Spearman correlations between lay participants and experts for immunohistochemistry scoring (0.91 (0.78, 0.96) and 0.97 (0.91, 0.99) for lung/EGFR and bladder/p53 samples, respectively). These results establish crowdsourcing as a promising method to screen large data sets for biomarkers in cancer pathology research across a range of cancers and immunohistochemical stains.


Coeliac disease in Dutch patients with Hashimoto's thyroiditis and vice versa.
To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patients. A total of 104 consecutive patients with Hashimoto's thyroiditis underwent coeliac serological tests (antigliadins, transglutaminase and endomysium antibodies) and HLA-DQ typing. Small intestinal biopsy was performed when any of coeliac serological tests was positive. On the other hand, 184 patients with coeliac disease were subjected to thyroid biochemical (thyroid stimulating hormone and free thyroxine) and thyroid serological tests (thyroglobulin and thyroid peroxidase antibodies). Of 104 patients with Hashimoto's thyroiditis, sixteen (15%) were positive for coeliac serology and five patients with documented villous atrophy were diagnosed with coeliac disease (4.8%; 95% CI 0.7-8.9). HLA-DQ2 (and/or -DQ8) was present in all the five and 53 patients with Hashimoto's thyroiditis (50%; 95% CI 43-62). Of 184 patients with coeliac disease, 39 (21%) were positive for thyroid serology. Based on thyroid biochemistry, the 39 patients were subclassified into euthyroidism in ten (5%; 95% CI 2-9), subclinical hypothyroidism in seven (3.8%; 95% CI 1.8-7.6), and overt hypothyroidism (Hashimoto's thyroiditis) in 22 (12%; 95% CI 8-16). Moreover, four patients with coeliac disease had Graves' disease (2%; 95% CI 0.8-5) and one patient had post-partum thyroiditis. The data from a Dutch population confirm the association between Hashimoto's thyroiditis and coeliac disease. Screening patients with Hashimoto's thyroiditis for coeliac disease and vice versa is recommended.


Rose-colored answers: neuropsychological deficits and patient-reported outcomes after stroke.
Patient-reported, subjective outcomes are promoted as a standard for ethical, valid studies in many neurological disorders. Such outcomes are considered potentially more sensitive and specific to important therapeutic effects, and may be more linked to disability and disease-related life losses than conventional assessments of impairment (e.g. ability to walk, performance on language tests, serological or radiological indices). Self-report is invaluable to identify social and emotional consequences of brain injury: depression, changes in intimate and family relationships, social role and community participation losses. However, common stroke-related neuropsychological deficits are likely to confound subjective stroke outcome measures. The scientific community focused on stroke-related health outcomes may arrive at {significantly underestimated} patient reports of stroke-related disability, caused by a failure to adjust for the effect on self-report of spatial neglect, deficits of magnitude estimation, pathologic alteration of self-awareness, and alteration in distributed cortical systems supporting emotional semantics and abstraction.


Probiotics to prevent the need for, and augment the use of, antibiotics.
Although humans and microbes are inseparable, our knowledge and understanding of the majority of microbes that help keep us alive and well is in desperate need of further investigation. Of the organisms that influence humans before birth and inhabit various niches from birth to old age, we know little about their identity, origin, metabolic properties, attributes and mechanisms of interactions with the host and surrounding microbes. The use of probiotics ("live microorganisms which when administered in adequate amounts confer a health benefit on the host") has re-emerged as a means to restore and boost the beneficial microbes in our bodies. The timing of resurgent interest in this ancient field coincides with the need to augment or replace antibiotics whose side effects are unwelcome and whose efficacy is diminishing due to drug resistance. Evidence that probiotic strains can act as adjuncts to antibiotic therapy by reducing adverse effects, improving antibiotic function and enhancing mucosal immunity is mounting. It is to our discredit that basic research on microbial ecology has been stalled in Canada for the past 20 years. If supported, research into indigenous and probiotic microbes will form an important part of future research that sheds light on health, disease and a basic understanding of life itself. In some cases, probiotics will be the difference between a good quality of life and a bad one, or perhaps even life over death. Improvements in clinical studies, manufacturing and regulatory standards must coincide with this progress to ensure that physicians and consumers have reliable, proven products for safe and efficacious use.


Patient satisfaction and reported long-term therapeutic efficacy associated with 1,320 nm Nd:YAG laser treatment of acne scarring and photoaging.
Nonablative laser treatments have become increasingly used for the treatment of acne scarring and photoaging. While nonablative laser treatments are more convenient and relatively safer than ablative laser resurfacing, efficacy and patient satisfaction with the level of improvement of textural abnormalities in acne scarring and rhytids associated with photoaging needs further study. DESIGN/MATERIALS AND METHODS: Structured interviews were performed with 34 patients from a referral-based academic practice who each previously received a series of 6 monthly treatments with a 1,320 nm neodymium:yttrium-aluminum-garnet (Nd:YAG) laser for treatment of acne scarring or photoaging. Topical anesthesia was applied 1 hour before each treatment. Patients were interviewed at least 3 months after cessation of treatment (range 3-12 months). Patients tolerated the treatments well. Combined results for acne scarring and photoaging patients were as follows: (a) patient satisfaction with treatment was rated at 62%, and (b) textural improvement was reported at 31% at the end of the six treatments, and 30% at the date of interview. When results were stratified by diagnosis, patient satisfaction was slightly higher for treatment of acne scarring than for photoaging. Overall degree of improvement on a 1-10 scale was 5.4 for acne scarring and 3.8 for wrinkling. Nonablative treatment with the 1,320 nm Nd:YAG laser induced significant patient-reported improvement in both acne scarring and photoaging. The majority of patients reported satisfaction with the degree of improvement.


Reproducibility of retinal nerve fiber thickness measurements using the stratus OCT in normal and glaucomatous eyes.
To determine the reproducibility of Stratus Optical Coherence Tomography (OCT) retinal nerve fiber layer (RNFL) measurements around the optic nerve in normal and glaucomatous eyes. One eye was chosen at random from 88 normal subjects and 59 glaucomatous subjects distributed among mild, moderate, and severe glaucoma, determined by visual field testing. Subjects underwent six RNFL thickness measurements performed by a single operator over a 30-minute period with a brief rest between sessions. Three scans were taken with the high-density Standard RNFL protocol, and three were taken with the Fast RNFL protocol, alternating between scan protocols. Reliability, as measured by intraclass correlation coefficient (ICC), was calculated for the overall mean RNFL thickness and for each quadrant. The ICC for the mean Standard RNFL thickness (and lower 95% confidence interval [CI]) in normal and glaucomatous eyes was 0.97 (0.96 CI) and 0.98 (0.97 CI), respectively. The ICC for the mean Fast RNFL thickness in normal and glaucomatous eyes was 0.95 (0.93 CI) and 0.97 (0.95 CI), respectively. Quadrant ICCs ranged between 0.79 and 0.97, with the nasal quadrant being the least reproducible of all four quadrants, using either the Standard or Fast RNFL program. The test-retest variability ranged from 3.5 microm for the average RNFL thickness measurements in normal eyes to 13.8 microm for the nasal quadrant measurements in glaucomatous eyes, which appeared to be the most variable. Reproducibility of RNFL measurements using the Stratus OCT is excellent in normal and glaucomatous eyes. The nasal quadrant appears to be the most variable measurement. Standard RNFL and Fast RNFL scans are equally reproducible and yield comparable measurements. These findings have implications for the diagnosis of glaucoma and glaucomatous progression.


A biopsychobehavioral model of risk of severe hypoglycemia.
Severe hypoglycemia (SH) is a significant problem for many patients with type I diabetes and presents a major barrier to optimal diabetes control. A critical task facing diabetes research is to understand, predict, and reduce the risk of SH in insulin-treated patients. The purpose of this article is to propose a biopsychobehavioral model of SH risk that integrates and extends previously proposed models. Current biological and psychological models of SH risk, which focus on hormonal counterregulation and symptom awareness, are reviewed. The limitations of these models are also discussed, including their failure to recognize important psychological and behavioral processes that contribute to SH risk. Specifically, the biopsychobehavioral model includes patients' decision-making, judgment, and behavioral responses as significant predictors of SH risk. The proposed model is comprised of seven steps: 1) physiological and behavioral precursors to low blood glucose (BG), 2) low BG occurrence, 3) hormonal and neurological responses to low BG, 4) awareness of symptoms caused by hormonal and neurological changes, 5) detection of low BG, 6) decision-making and judgment, and 7) behavioral response. The model has several advantages, including the ability to mathematically calculate the transitional probabilities from each step to the next as well as the ability to describe SH risk in both hypoglycemia-aware and hypoglycemia-unaware patients. Research findings supporting the biopsychobehavioral model are presented, and its empirical and clinical implications are discussed.


Channel-mediated lactate release by K⁺-stimulated astrocytes.
Excitatory synaptic transmission is accompanied by a local surge in interstitial lactate that occurs despite adequate oxygen availability, a puzzling phenomenon termed aerobic glycolysis. In addition to its role as an energy substrate, recent studies have shown that lactate modulates neuronal excitability acting through various targets, including NMDA receptors and G-protein-coupled receptors specific for lactate, but little is known about the cellular and molecular mechanisms responsible for the increase in interstitial lactate. Using a panel of genetically encoded fluorescence nanosensors for energy metabolites, we show here that mouse astrocytes in culture, in cortical slices, and in vivo maintain a steady-state reservoir of lactate. The reservoir was released to the extracellular space immediately after exposure of astrocytes to a physiological rise in extracellular K(+) or cell depolarization. Cell-attached patch-clamp analysis of cultured astrocytes revealed a 37 pS lactate-permeable ion channel activated by cell depolarization. The channel was modulated by lactate itself, resulting in a positive feedback loop for lactate release. A rapid fall in intracellular lactate levels was also observed in cortical astrocytes of anesthetized mice in response to local field stimulation. The existence of an astrocytic lactate reservoir and its quick mobilization via an ion channel in response to a neuronal cue provides fresh support to lactate roles in neuronal fueling and in gliotransmission.


Sequential pattern formation governed by signaling gradients.
Rhythmic and sequential segmentation of the embryonic body plan is a vital developmental patterning process in all vertebrate species. However, a theoretical framework capturing the emergence of dynamic patterns of gene expression from the interplay of cell oscillations with tissue elongation and shortening and with signaling gradients, is still missing. Here we show that a set of coupled genetic oscillators in an elongating tissue that is regulated by diffusing and advected signaling molecules can account for segmentation as a self-organized patterning process. This system can form a finite number of segments and the dynamics of segmentation and the total number of segments formed depend strongly on kinetic parameters describing tissue elongation and signaling molecules. The model accounts for existing experimental perturbations to signaling gradients, and makes testable predictions about novel perturbations. The variety of different patterns formed in our model can account for the variability of segmentation between different animal species.


Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.


DS-7080a, a Selective Anti-ROBO4 Antibody, Shows Anti-Angiogenic Efficacy with Distinctly Different Profiles from Anti-VEGF Agents.
Neovascular age-related macular degeneration (nAMD) results from choroidal neovascularization (CNV) and causes severe vision loss. Intravitreal anti-vascular endothelial growth factor (VEGF) therapies have significantly improved therapeutic outcomes; however, a substantial number of patients experience disease progression. Roundabout 4 (ROBO4) has been reported to be a vascular-specific protein that stabilizes vasculature in ocular pathological angiogenesis. To explore ROBO4 targeting as a novel treatment against neovascularization, we generated a humanized anti-human ROBO4 antibody, DS-7080a, and evaluated its efficacy. ROBO4 mRNA in human whole eye cross-sections was examined by in situ hybridization. Human umbilical vein endothelial cell (HUVEC) migration was measured in the presence of VEGF, basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), or conditioned medium of primary human retinal pigment epithelial (HRPE) cells. CNV was induced in cynomolgus monkeys by laser irradiation. Vascular leakage was measured by fluorescein angiography, and pathological changes were determined by histology. ROBO4 mRNA was detected in choroidal vessels of nAMD patients. DS-7080a suppressed HGF- or bFGF-induced HUVEC migration in addition to that induced by VEGF. Further, HUVEC migration induced by HRPE-conditioned medium was inhibited by either DS-7080a or ranibizumab in a similar manner, and the combination of these showed further inhibition. In a laser-induced CNV monkey model, single intravitreous administration of 1.1 mg/eye of DS-7080a reduced the incidence of grade 4 leakage from 44.45% in control eyes to 1.85% (P < 0.05 by Dunnett's test). Anti-ROBO4 antibody DS-7080a suppressed HUVEC migration in a distinctly different fashion from anti-VEGF agents and improved laser-induced CNV in non-human primates. DS-7080a may be a novel treatment option for nAMD.