Coding space within but not between objects: evidence from Balint's syndrome.
The ability to make spatial judgements was examined in a patient demonstrating poor perception of multiple objects following bilateral parietal lesions, under conditions in which the presence of the stimuli to which judgements were made could be detected. The tasks required judgements of spatial length or the position of coloured parts of stimuli. We manipulated the degree to which two uprights in a display could be encoded into a single perceptual object using either stored knowledge or bottom-up cues based on 2D or 3D image relations. Performance was dependent on the presence of both bottom-up grouping and familiarity. However, connectedness in the image was not sufficient to benefit performance, when stimuli were separate objects in 3D space. This deficit in spatial judgements, arising following detection of the relevant stimulus elements, is attributed to an impairment in coding the spatial relations between separate perceptual objects. This deficit could be overcome if stimuli could be grouped in 3D, using bottom-up cues and top-down knowledge.


Management of congenital ichthyoses: European guidelines of care, part two.
These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.


Efficient Transduction of LEDGF/p75 Mutant Cells by Gain-of-Function HIV-1 Integrase Mutant Viruses.
Controlling the specificity of retroviral DNA integration could improve the safety of gene therapy vectors, and fusions of heterologous chromatin binding modules to the integrase-binding domain from the lentiviral integration host cofactor LEDGF/p75 are a promising retargeting strategy. We previously proposed the utility of integrase mutant lentiviral vectors that are selectively activated by complementary LEDGF/p75 variants, and our initial modifications in HIV-1 integrase and LEDGF/p75 supported about 13% of wild-type vector transduction activity. Here we describe the selection and characterization of the K42E gain-of-function mutation in HIV-1 integrase, which greatly improves the efficiency of this system. Both K42E and initial reverse-charge mutations in integrase negatively impacted reverse transcription and integration, yet when combined together boosted viral transduction efficiency to ~75% of the wild-type vector in a manner dependent on a complementary LEDGF/p75 variant. Although the K42E mutation conferred functional gains to integrase mutant viral reverse transcription and integration, only the integration boost depended on the engineered LEDGF/p75 mutant. We conclude that the specificity of lentiviral retargeting strategies based on heterologous LEDGF/p75 fusion proteins will benefit from our optimized system that utilizes the unique complementation properties of reverse-charge integrase mutant viral and LEDGF/p75 host proteins.


Coronary artery bypass grafting: Part 2--optimizing outcomes and future prospects.
Since first introduced in the mid-1960s, coronary artery bypass grafting (CABG) has become the standard of care for patients with coronary artery disease. Surprisingly, the fundamental surgical technique itself did not change much over time. Nevertheless, outcomes after CABG have dramatically improved over the first 50 years. Randomized trials comparing percutaneous coronary intervention (PCI) to CABG have shown converging outcomes for select patient populations, providing more evidence for wider use of PCI. It is increasingly important to focus on the optimization of the short- and long-term outcomes of CABG and to reduce the level of invasiveness of this procedure. This review provides an overview on how new techniques and widespread consideration of evolving strategies have the potential to optimize outcomes after CABG. Such developments include off-pump CABG, clampless/anaortic CABG, minimally invasive CABG with or without extending to hybrid procedures, arterial revascularization, endoscopic vein harvesting, intraprocedural epiaortic scanning, graft flow assessment, and improved secondary prevention measures. In addition, this review represents a framework for future studies by summarizing the areas that need more rigorous clinical (randomized) evaluation.


The intestinal barrier and its regulation by neuroimmune factors.
The ability to control uptake across the mucosa and protect from damage of harmful substances from the lumen is defined as intestinal barrier function. A disturbed barrier dysfunction has been described in many human diseases and animal models, for example, inflammatory bowel disease, irritable bowel syndrome, and intestinal hypersensitivity. In most diseases and models, alterations are seen both of the paracellular pathway, via the tight junctions, and of the transcellular routes, via different types of endocytosis. Recent studies of pathogenic mechanisms have demonstrated the important role of neuroimmune interaction with the epithelial cells in the regulation of barrier function. Neural impulses from extrinsic vagal and/or sympathetic efferent fibers or intrinsic enteric nerves influence mucosal barrier function via direct effects on epithelial cells or via interaction with immune cells. For example, by nerve-mediated activation by corticotropin-releasing hormone or cholinergic pathways, mucosal mast cells release a range of mediators with effects on transcellular, and/or paracellular permeability (for example, tryptase, TNF-alpha, nerve growth factor, and interleukins). In this review, we discuss current physiological and pathophysiological aspects of the intestinal barrier and, in particular, its regulation by neuroimmune factors.


Orthogonal enzymatic reactions for rapid crosslinking and dynamic tuning of PEG-peptide hydrogels.
Stiffening of the extracellular matrix is a hallmark in cancer progression, embryonic development, and wound healing. To mimic this dynamic process, our work explored orthogonal enzymatic reactions capable of modulating the properties of poly(ethylene glycol) (PEG)-peptide hydrogels. A hepta-mutant bacterial transpeptidase sortase A (SrtA7M) was used to ligate two PEG-peptide macromers (i.e., PEG-YLPRTG and NH2-GGGG-PEG) into a primary hydrogel network. The hydrogels were dynamically stiffened using mushroom tyrosinase (MT), which oxidized tyrosine residues into di-tyrosine and led to increased matrix stiffness. After confirming the expression and enhanced catalytic activity of SrtA7M, we investigated the cytocompatibility of the enzymatic reaction with a mouse insulinoma cell line, MIN6. In addition, we altered peptide substrate concentrations and evaluated their influence on primary hydrogel network properties and MT-triggered stiffening. Using a pancreatic cancer cell line, COLO-357, the effect of MT-triggered stiffening on spheroid formation was investigated. We found that cell spheroids formed in hydrogels that were exposed to MT were significantly smaller than spheroids formed without MT incubation, suggesting that matrix stiffening played a crucial role in the sizes of cancer cell spheroids. Through utilizing highly specific and orthogonal enzymatic reactions, this hydrogel platform permits rapid and mild in situ cell encapsulation, as well as dynamic control of matrix stiffness for investigating the role of matrix stiffening on cell fate processes.


Kinetic-Spectrophotometric Determination of Thiocyanate in Human Saliva Based on Landolt Effect in Presence of Astrafloxine FF.
In the present study a kinetic-spectrophotometric method for thiocyanate determination is described. The suggested method for the determination of thiocyanate is based on its "Landolt effect" on the reaction of bromate with hydrobromic acid, which leads to the formation of only one halogen bromine. The reaction was monitored spectrophotometrically at the maximum wavelength of astrafloxine FF light absorption at 535 nm. The absorbance of reactants mixture decreased with an increase of the reaction time. The calibration curve for thiocyanate determination was obtained in the concentration range of 0.03-2.0 μg mLμ1 under the optimal conditions (pH 1.5; CBrO3 - = 7.6 × 10-4 mol L-1; Castrafloxine FF = 1 × 10-5 mol L-1). The limit of detection was 0.01 μg mLμ1. The method was successfully applied to the determination of thiocyanate in human saliva samples with satisfactory results.


Label-retaining cells in the adult murine salivary glands possess characteristics of adult progenitor cells.
Radiotherapy is the primary treatment for patients with head and neck cancer, which account for roughly 500,000 annual cases worldwide. Dysfunction of the salivary glands and associated conditions like xerostomia and dysphagia are often developed by these patients, greatly diminishing their life quality. Current preventative and palliative care fail to deliver an improvement in the quality of life, thus accentuating the need for regenerative therapies. In this study, a model of label retaining cells (LRCs) in murine salivary glands was developed, in which LRCs demonstrated proliferative potential and possessed markers of putative salivary progenitors. Mice were labeled with 5-Ethynyl-2'-deoxyuridine (EdU) at postnatal day 10 and chased for 8 weeks. Tissue sections from salivary glands obtained at the end of chase demonstrated co-localization between LRCs and the salivary progenitor markers keratin 5 and keratin 14, as well as kit mRNA, indicating that LRCs encompass a heterogeneous population of salivary progenitors. Proliferative potential of LRCs was demonstrated by a sphere assay, in which LRCs were found in primary and secondary spheres and they co-localized with the proliferation marker Ki67 throughout sphere formation. Surprisingly, LRCs were shown to be radio-resistant and evade apoptosis following radiation treatment. The clinical significance of these findings lie in the potential of this model to study the mechanisms that prevent salivary progenitors from maintaining homeostasis upon exposure to radiation, which will in turn facilitate the development of regenerative therapies for salivary gland dysfunction.


Elastin biosynthesis: The missing link in tissue-engineered blood vessels.
Nearly 20 years have passed since Weinberg and Bell attempted to make the first tissue-engineered blood vessels. Following this early attempt, vascular tissue engineering has emerged as one of the most promising approaches to fabricate orderly and mechanically competent vascular substitutes. In elastic and muscular arteries, elastin is a critical structural and regulatory matrix protein and plays an important and dominant role by conferring elasticity to the vessel wall. Elastin also regulates vascular smooth muscle cells activity and phenotype. Despite the great promise that tissue-engineered blood vessels have to offer, little research in the last two decades has addressed the importance of elastin incorporation into these vessels. Although cardiovascular tissue engineering has been reviewed in the past, very little attention has been given to elastin. Thus, this review focuses on the recent advances made towards elastogenesis and the challenges we face in the quest for appropriate functional vascular substitutes.


Birth practices: Maternal-neonate separation as a source of toxic stress.
Maternal-neonate separation for human newborns has been the standard of care since the last century; low birth weight and preterm infants are still routinely separated from their mothers. With advanced technology, survival is good, but long-term developmental outcomes are very poor for these especially vulnerable newborns. The poor outcomes are similar to those described for adversity in childhood, ascribed to toxic stress. Toxic stress is defined as the absence of the buffering protection of adult support. Parental absence has been strictly enforced in neonatal care units for many reasons and could lead to toxic stress. The understanding of toxic stress comes from discoveries about our genome and epigenetics, the microbiome, developmental neuroscience and the brain connectome, and life history theory. The common factor is the early environment that gives (a) signals to epigenes, (b) sensory inputs to neural circuits, and (c) experiences for reproductive fitness. For human newborns that environment is direct skin-to-skin contact from birth. Highly conserved neuroendocrine behaviors determined by environment are described in this review. The scientific rationale underlying skin-to-skin contact is presented: autonomic development and regulation of the physiology leads to emotional connection and achieving resilience. Maternal-neonate separation prevents these critical neural processes from taking place, but also channel development into an alternative developmental strategy. This enables better coping in a stressful environment in the short term, but with permanently elevated stress systems that negatively impact mental and physical health in the long term. This may explain the increasing incidence of developmental problems in childhood, and also Developmental Origins of Health and Disease. Arguments are presented that maternal-neonate separation is indeed a source of toxic stress, and some suggestions are offered toward a "zero separation" paradigm.


Quantum-dot-based white lighting planar source through downconversion by blue electroluminescence.
We report the unprecedented fabrication of a planar white lighting quantum dot light-emitting diode (QD-LED) through integrating a CdZnS QD-based blue electroluminescence (EL) device with a free-standing polymethyl methacrylate (PMMA) composite film embedded with orange-emitting Cu-In-S (CIS) green-greenish yellow-emitting Cu-In-Ga-S (CIGS) QDs. The hybrid device successfully generates bicolored white emission that comprises blue EL and downconverted QD photoluminescence. The hybrid QD-LEDs loaded with the composite film embedded with one type of QDs exhibit a limited white spectral coverage, consequently producing low values (<65) in color rendering index (CRI). Thus, the QD-PMMA film consisting of a blend of green CIGS and orange CIS QD downconverters is applied for obtaining a higher-CRI white light through the spectral extension, resulting in a much improved CRI of 75-77. Various EL performances of the hybrid planar white device versus the reference blue QD-LED are also characterized in details.


High incidence of false-positive PET scans in patients with aggressive non-Hodgkin's lymphoma treated with rituximab-containing regimens.
Positron emission tomography (PET) is a powerful predictor of relapse and survival in non-Hodgkin's lymphomas (NHLs) based on studies carried out in the prerituximab era. Little is known about the predictive power of PET in rituximab-treated patients. Patients with aggressive B-cell NHL with baseline and follow-up PET studies were included. Clinical characteristics, PET and computed tomography scans, biopsy results, and outcomes were reviewed. PET was defined as positive if higher than mediastinal or background activity was observed. In all, 51 patients (diffuse large B cell-38; mantle cell lymphoma-13) treated with rituximab-containing regimens were included. For 13 of 40 patients (32.5%), mid-therapy PET studies were positive and 9 of 48 patients (18.7%) had positive posttherapy PET. The positive predictive value (PPV), negative predictive value (NPV), sensitivity (Se), and specificity (Sp) of the mid-therapy PET for predicting relapse were 33% [95% confidence interval (CI) 19% to 49%], 68% (95% CI 51% to 81%), 33% (95% CI 6% to 76%), and 68% (95% CI 49% to 82%), respectively. For posttherapy PET, the relapse PPV, NPV, Se and Sp were 19% (95% CI 9% to 33%), 81% (95% CI 67% to 91%), 13% (95% CI 0.6% to 53%), and 80%(95% CI 64% to 90%), respectively. Compared with previous reports in prerituximab era, addition of rituximab resulted in reduced PPV and sensitivity of mid- and posttherapy PET in patients with aggressive B-cell NHL.


Identifying density-dependent interactions in collective cell behaviour.
Scratch assays are routinely used to study collective cell behaviour in vitro. Typical experimental protocols do not vary the initial density of cells, and typical mathematical modelling approaches describe cell motility and proliferation based on assumptions of linear diffusion and logistic growth. Jin et al. (Jin et al. 2016 J. Theor. Biol.390, 136-145 (doi:10.1016/j.jtbi.2015.10.040)) find that the behaviour of cells in scratch assays is density-dependent, and show that standard modelling approaches cannot simultaneously describe data initiated across a range of initial densities. To address this limitation, we calibrate an individual-based model to scratch assay data across a large range of initial densities. Our model allows proliferation, motility, and a direction bias to depend on interactions between neighbouring cells. By considering a hierarchy of models where we systematically and sequentially remove interactions, we perform model selection analysis to identify the minimum interactions required for the model to simultaneously describe data across all initial densities. The calibrated model is able to match the experimental data across all densities using a single parameter distribution, and captures details about the spatial structure of cells. Our results provide strong evidence to suggest that motility is density-dependent in these experiments. On the other hand, we do not see the effect of crowding on proliferation in these experiments. These results are significant as they are precisely the opposite of the assumptions in standard continuum models, such as the Fisher-Kolmogorov equation and its generalizations.


Putative partial agonist 1-aminocyclopropanecarboxylic acid acts concurrently as a glycine-site agonist and a glutamate-site antagonist at N-methyl-D-aspartate receptors.
1-Aminocyclopropanecarboxylic acid (ACPC) has been shown to protect against neuronal cell death after ischemic insult in vivo. Such results can be correlated with in vitro assays in which ACPC protected neurons against glutamate-induced neurotoxicity by reducing the activity of N-methyl-D-aspartate (NMDA) channel activation. Electrophysiological studies have determined that ACPC inhibits NMDA receptor activity by acting as a glycine-binding site partial agonist. In this study, rapid drug perfusion combined with whole-cell voltage-clamp was used to elicit and measure the effects of ACPC on NMDA receptor-mediated responses from cultured hippocampal neurons and cerebellar granule cells. The ACPC steady-state dose-response curve had both stimulatory and inhibitory phases. Half-maximal activation by ACPC as a glycine-site agonist was 0.7 to 0.9 microM. Half-maximal inhibition by ACPC was dependent on NMDA concentration. Peak responses to a >100 microM ACPC pulse in the presence of 1 microM glutamate were similar to those of glycine but decayed to a steady-state amplitude below that of glycine. The removal of ACPC initially caused an increase in inward current followed by a subsequent decrease to baseline levels. This suggests that relief of low-affinity antagonism occurs before high-affinity agonist dissociation. Simulations of ACPC action by a two glutamate-binding site/two glycine-binding site model for NMDA channel activation in conjunction with the concurrent role of ACPC as a glycine-site full agonist and glutamate-site competitive antagonist were able to successfully approximate experimental results.


Globally homochiral assembly of two-dimensional molecular networks triggered by co-absorbers.
Understanding the chirality induction and amplification processes, and the construction of globally homochiral surfaces, represent essential challenges in surface chirality studies. Here we report the induction of global homochirality in two-dimensional enantiomorphous networks of achiral molecules via co-assembly with chiral co-absorbers. The scanning tunnelling microscopy investigations and molecular mechanics simulations demonstrate that the point chirality of the co-absorbers transfers to organizational chirality of the assembly units via enantioselective supramolecular interactions, and is then hierarchically amplified to the global homochirality of two-dimensional networks. The global homochirality of the network assembly shows nonlinear dependence on the enantiomeric excess of chiral co-absorber in the solution phase, demonstrating, for the first time, the validation of the 'majority rules' for the homochirality control of achiral molecules at the liquid/solid interface. Such an induction and nonlinear chirality amplification effect promises a new approach towards two-dimensional homochirality control and may reveal important insights into asymmetric heterogeneous catalysis, chiral separation and chiral crystallization.


Hierarchical assembly of the siliceous skeletal lattice of the hexactinellid sponge Euplectella aspergillum.
Despite its inherent mechanical fragility, silica is widely used as a skeletal material in a great diversity of organisms ranging from diatoms and radiolaria to sponges and higher plants. In addition to their micro- and nanoscale structural regularity, many of these hard tissues form complex hierarchically ordered composites. One such example is found in the siliceous skeletal system of the Western Pacific hexactinellid sponge, Euplectella aspergillum. In this species, the skeleton comprises an elaborate cylindrical lattice-like structure with at least six hierarchical levels spanning the length scale from nanometers to centimeters. The basic building blocks are laminated skeletal elements (spicules) that consist of a central proteinaceous axial filament surrounded by alternating concentric domains of consolidated silica nanoparticles and organic interlayers. Two intersecting grids of non-planar cruciform spicules define a locally quadrate, globally cylindrical skeletal lattice that provides the framework onto which other skeletal constituents are deposited. The grids are supported by bundles of spicules that form vertical, horizontal and diagonally ordered struts. The overall cylindrical lattice is capped at its upper end by a terminal sieve plate and rooted into the sea floor at its base by a flexible cluster of barbed fibrillar anchor spicules. External diagonally oriented spiral ridges that extend perpendicular to the surface further strengthen the lattice. A secondarily deposited laminated silica matrix that cements the structure together additionally reinforces the resulting skeletal mass. The mechanical consequences of each of these various levels of structural complexity are discussed.


The role of ethics in shale gas policies.
The United States has experienced a boom in natural gas production due to recent technological innovations that have enabled natural gas to be produced from unconventional sources, such as shale. There has been much discussion about the costs and benefits of developing shale gas among scientists, policy makers, and the general public. The debate has typically revolved around potential gains in economics, employment, energy independence, and national security as well as potential harms to the environment, the climate, and public health. In the face of scientific uncertainty, national and international governments must make decisions on how to proceed. So far, the results have been varied, with some governments banning the process, others enacting moratoria until it is better understood, and others explicitly sanctioning shale gas development. These policies reflect legislature's preferences to avoid false negative errors or false positive ones. Here we argue that policy makers have a prima facie duty to minimize false negatives based on three considerations: (1) protection from serious harm generally takes precedence over the enhancement of welfare; (2) minimizing false negatives in this case is more respectful to people's autonomy; and (3) alternative solutions exist that may provide many of the same benefits while minimizing many of the harms.


Ultraviolet-induced effects on chloramine and cyanogen chloride formation from chlorination of amino acids.
Ultraviolet (UV)-based treatment is commonly used to augment chlorination in swimming pools. However, the effects of combined application of UV254/chlorine on disinfection byproduct (DBP) formation are incompletely defined. To examine this issue, experiments were conducted with amino acids (l-arginine, l-histidine, and glycine) that are representative of those introduced to swimming pools via human body fluids. For each precursor, stepwise experiments were conducted with chlorination and UV254 exposure, with/without post-chlorination. Net formation and decomposition of chloramines and cyanogen chloride (CNCl) were measured for a range of chlorine/precursor (Cl/P) molar ratios and UV254 doses. Substantial production of NH2Cl from l-arginine and l-histidine was observed at Cl/P = 1.0 and 2.0 when post-chlorination was applied to UV254-irradiated samples. These results suggested a mechanism of rapid N-chlorination, followed by cleavage of NH3 by UV254 irradiation. CNCl formation was observed from UV254-irradiated samples of l-arginine and l-histidine when Cl/P = 2.0 and 3.0, as well as from glycine for Cl/P ≤ 1. Structurally related precursor compounds were examined for CNCl formation potential in chlorination/UV experiments. CNCl formation was promoted by UV254 exposure of chlorinated imidazole and guanidine compounds, which suggested that these groups contributed to CNCl formation. The results have implications with respect to the application of chlorine and UV for water treatment in swimming pools and other settings, such as water reuse and advanced oxidation processes.


RNA-seq analysis identifies different transcriptomic types and developmental trajectories of primary melanomas.
Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive RNA-seq analysis of laser-microdissected melanocytic nevi (n = 23) and primary melanoma samples (n = 57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering, and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2). N1/M1 lesions are characterized by pigmentation-type and MITF gene signatures, and a high prevalence of NRAS mutations in M1 melanomas. N2/M2 lesions are characterized by inflammatory-type and AXL gene signatures with an equal distribution of wild-type and mutated BRAF and low prevalence of NRAS mutations in M2 melanomas. Interestingly, N1 nevi and M1 melanomas and N2 nevi and M2 melanomas, respectively, cluster together, but there is no clustering in a stage-dependent manner. Transcriptional signatures of M1 melanomas harbor signatures of BRAF/MEK inhibitor resistance and M2 melanomas harbor signatures of anti-PD-1 antibody treatment resistance. Pseudotime dynamics of nevus and melanoma samples are suggestive for a switch-like immune-escape mechanism in melanoma development with downregulation of immune genes paralleled by an increasing expression of a cell cycle signature in late-stage melanomas. Taken together, the transcriptome analysis identifies gene signatures and mechanisms underlying development of melanoma in early and late stages with relevance for diagnostics and therapy.


The globalisation strategies of five Asian tobacco companies: a comparative analysis and implications for global health governance.
The global tobacco industry, from the 1960s to mid 1990s, saw consolidation and eventual domination by a small number of transnational tobacco companies (TTC). This paper draws together comparative analysis of five case studies in the special issue on 'The Emergence of Asian Tobacco Companies: Implications for Global Health Governance.' The cases suggest that tobacco industry globalisation is undergoing a new phase, beginning in the late 1990s, with the adoption of global business strategies by five Asian companies. The strategies were prompted foremost by external factors, notably market liberalisation, competition from TTCs and declining domestic markets. State protection and promotion enabled the industries in Japan, South Korea and China to rationalise their operations ahead of foreign market expansion. The TTM and TTL will likely remain domestic or perhaps regional companies, JTI and KT&G have achieved TTC status, and the CNTC is poised to dwarf all existing companies. This global expansion of Asian tobacco companies will increase competition which, in turn, will intensify marketing, exert downward price pressures along the global value chain, and encourage product innovation. Global tobacco control requires fuller understanding of these emerging changes and the regulatory challenges posed by ongoing globalisation.


Evaluation of cognitive function in weanling rats: a review of methods suitable for chemical screening.
Current developmental neurotoxicity (DNT) tests that are used for environmental agents require cognitive testing around the age of weaning as well as adulthood. There are challenges associated with testing weanling rodents that are not present with testing older subjects, including rapid brain development, and the impact of food or water restriction necessary for appetitive paradigms. This review provides an overview of cognitive tests that can be used for laboratory rodents in the context of such DNT studies; as such, those requiring surgery or food/water deprivation are excluded. Potential test methods described herein include spontaneous, avoidance, conditioned, spatial, and sequential behavioral assays; although, some procedures meet scientific and regulatory requirements better than others. Scientific judgment should be exercised in the choice of cognitive measures for weanling rodents in DNT studies, and should include an assessment of the sensitivity and efficiency of the procedure, an understanding of the literature and the neuronal substrates involved, and evaluation of available information on the mode(s) of action of the test chemical.


Performance and Value of IFN-Lambda3 and IFN-Lambda4 Genotyping in Patients with Chronic Hepatitis C (CHC) Genotype 2/3 in a Real World Setting.
SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.


Inhibition of chloroplastic fructose 1,6-bisphosphatase in tomato fruits leads to decreased fruit size, but only small changes in carbohydrate metabolism.
A potato (Solanum tuberosum L.) cDNA coding for the chloroplastic isoform of fructose 1,6-bisphosphatase (cp-FBPase) was utilized to repress its activity in tomatoes (Lycopersicon esculentum Mill.) using antisense techniques. The patatin B33 promoter was used to ensure fruit specificity of the antisense effect. Transgenic plants were isolated in which fructose 1,6-bisphosphatase activity was reduced by more than 50% of the control in green fruits. Immunoblots indicated that the plastidial isoform was almost completely eliminated in the most strongly inhibited lines. Fruits of the transgenic plants were analyzed for levels of metabolites during fruit development. Glucose and fructose concentrations were increased in green fruits in the transgenic lines, but unchanged at later stages of development. The sucrose concentration was low, and was not significantly altered in the transgenic lines. There was net degradation of starch over the developmental period, but the starch content was not decreased. In green fruit the levels of hexose phosphates were unchanged, whilst the level of 3-phosphoglyceric acid was significantly increased in one line. Most importantly the deduced ratio of hexose phosphate to 3-phosphoglyceric acid decreased, consistent with an in vivo inhibition of fructose 1,6-bisphosphatase activity. One consequence of this reduction of in vivo activity of cp-FBPase was that the average weight of fully ripe fruits was significantly decreased by up to 20% in all transgenic lines in comparison with the control.


The effect of macronutrients on glycaemic control: a systematic review of dietary randomised controlled trials in overweight and obese adults with type 2 diabetes in which there was no difference in weight loss between treatment groups.
Weight loss is crucial for treating type 2 diabetes mellitus (T2DM). It remains unclear which dietary intervention is best for optimising glycaemic control, or whether weight loss itself is the main reason behind observed improvements. The objective of this study was to assess the effects of various dietary interventions on glycaemic control in overweight and obese adults with T2DM when controlling for weight loss between dietary interventions. A systematic review of randomised controlled trials (RCT) was conducted. Electronic searches of Medline, Embase, Cinahl and Web of Science databases were conducted. Inclusion criteria included RCT with minimum 6 months duration, with participants having BMI≥25·0 kg/m2, a diagnosis of T2DM using HbA1c, and no statistically significant difference in mean weight loss at the end point of intervention between dietary arms. Results showed that eleven studies met the inclusion criteria. Only four RCT indicated the benefit of a particular dietary intervention over another in improving HbA1c levels, including the Mediterranean, vegan and low glycaemic index (GI) diets. However the findings from one of the four studies showing a significant benefit are questionable because of failure to control for diabetes medications and poor adherence to the prescribed diets. In conclusion there is currently insufficient evidence to suggest that any particular diet is superior in treating overweight and obese patients with T2DM. Although the Mediterranean, vegan and low-GI diets appear to be promising, further research that controls for weight loss and the effects of diabetes medications in larger samples is needed.


Symptoms and health complaints and their association with perceived stressors among students at nine Libyan universities.
University students are exposed to many stressors. We assessed the associations between two stressors (educational related and general overall), socio-demographic characteristics (five variables), health behaviours/lifestyle factors (six variables), as well as religiosity and quality of life as independent variables, with self-reported symptoms/health complaints as dependent variables (eight health complaints). A sample of 2100 undergraduate students from nine institutions (six universities, three colleges) located in seven cities in Libya completed a general health questionnaire. The most prevalent symptoms were headaches, depressive mood, difficulties to concentrate and sleep disorder/insomnia that have been reported by 50%-60% of the students. The majority of students (62%) reported having had three or more symptoms sometimes or very often in the last 12 months. There was a positive association between perceived stressors and health symptoms, which remained significant after adjustment for gender and many other relevant factors for headache (OR 1.52; 95% CI 1.15-2.02), depressive mood (OR 2.20; 95% CI 1.64-2.94) and sleep disorder/ insomnia (OR 1.55, 95% CI 1.19-2.03). Other factors independently associated with most health symptoms were female gender and poor self-perceived health. Stress management programmes and a reduction of educational related stressors might help to prevent stress-related symptoms and health complaints in this student population.


New insights into plant development in New England.
This year, the biannually organized FASEB meeting 'Mechanisms in Plant Development' took place in August in Vermont, USA, organized by Martin Hulskamp (University of Koln, Koln, Germany) and John Schiefelbein (University of Michigan, Ann Arbor, MI, USA). The meeting covered numerous topics, ranging from patterning and differentiation to the evolution of developmental mechanisms. Despite apparent distinctions between the sessions, many of the talks were broad ranging and most highlighted unifying developmental concepts.


Personality modulates the effects of emotional arousal and valence on brain activation.
The influence of personality on the neural correlates of emotional processing is still not well characterized. We investigated the relationship between extraversion and neuroticism and emotional perception using functional magnetic resonance imaging (fMRI) in a group of 23 young, healthy women. Using a parametric modulation approach, we examined how the blood oxygenation level dependent (BOLD) signal varied with the participants' ratings of arousal and valence, and whether levels of extraversion and neuroticism were related to these modulations. In particular, we wished to test Eysenck's biological theory of personality, which links high extraversion to lower levels of reticulothalamic-cortical arousal, and neuroticism to increased reactivity of the limbic system and stronger reactions to emotional arousal. Individuals high in neuroticism demonstrated reduced sustained activation in the orbitofrontal cortex (OFC) and attenuated valence processing in the right temporal lobe while viewing emotional images, but an increased BOLD response to emotional arousal in the right medial prefrontal cortex (mPFC). These results support Eysenck's theory, as well as our hypothesis that high levels of neuroticism are associated with attenuated reward processing. Extraversion was inversely related to arousal processing in the right cerebellum, but positively associated with arousal processing in the right insula, indicating that the relationship between extraversion and arousal is not as simple as that proposed by Eysenck.


Structure-activity relationship of caffeoylquinic acids on the accelerating activity on ATP production.
Caffeoylquinic acid (CQA) is one of the phenylpropanoids which have various bioactivities such as antioxidant, antibacterial, anticancer, antihistamic, and other biological effects. We previously reported that 3,5-di-O-caffeoylquinic acid inhibited amyloid β(1-42)-induced cellular toxicity on human neuroblastoma SH-SY5Y cells and increased the mRNA expression level of glycolytic enzymes and the intracellular ATP level. To investigate structure-activity relationship on the accelerating activity on ATP production, we synthesized 1,4,5-tri-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, 3,4,5-tri-O-caffeoylquinic acid, and other derivatives. Additionally, we evaluated intracellular ATP level in SH-SY5Y treated with each CQA derivative. As a result, 3,4,5-tri-O-caffeoylquinic acid showed the highest accelerating activity on ATP production among tested compounds. It was suggested that caffeoyl groups bound to quinic acid are important for activity and the more caffeoyl groups are bound to quinic acid, the higher accelerating activity on ATP production exhibits.


High-Tempo and Stinky: High Arousal Sound-Odor Congruence Affects Product Memory.
The tendency to match different sensory modalities together can be beneficial for marketing. Here we assessed the effect of sound-odor congruence on people's attitude and memory for products of a familiar and unfamiliar brand. Participants smelled high- and low-arousal odors and then saw an advertisement for a product of a familiar or unfamiliar brand, paired with a high- or low-arousal jingle. Participants' attitude towards the advertisement, the advertised product, and the product's brand was measured, as well as memory for the product. In general, no sound-odor congruence effect was found on attitude, irrespective of brand familiarity. However, congruence was found to affect recognition: when a high-arousal odor and a high-arousal sound were combined, participants recognized products faster than in the other conditions. In addition, familiar brands were recognized faster than unfamiliar brands, but only when sound or odor arousal was high. This study provides insight into the possible applications of sound-odor congruence for marketing by demonstrating its potential to influence product memory.


A significant but rather mild contribution of T286 autophosphorylation to Ca2+/CaM-stimulated CaMKII activity.
Autophosphorylation of the Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) at T286 generates partially Ca(2+)/CaM-independent "autonomous" activity, which is thought to be required for long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning and memory. A requirement for T286 autophosphorylation also for efficient Ca(2+)/CaM-stimulated CaMKII activity has been described, but remains controversial. In order to determine the contribution of T286 autophosphorylation to Ca(2+)/CaM-stimulated CaMKII activity, the activity of CaMKII wild type and its phosphorylation-incompetent T286A mutant was compared. As the absolute activity can vary between individual kinase preparations, the activity was measured in six different extracts for each kinase (expressed in HEK-293 cells). Consistent with measurements on purified kinase (from a baculovirus/Sf9 cell expression system), CaMKII T286A showed a mildly but significantly reduced rate of Ca(2+)/CaM-stimulated phosphorylation for two different peptide substrates (to ~75-84% of wild type). Additional slower CaMKII autophosphorylation at T305/306 inhibits stimulation by Ca(2+)/CaM, but occurs only minimally for CaMKII wild type during CaM-stimulated activity assays. Thus, we tested if the T286A mutant may show more extensive inhibitory autophosphorylation, which could explain its reduced stimulated activity. By contrast, inhibitory autophosphorylation was instead found to be even further reduced for the T286A mutant under our assay conditions. On a side note, the phospho-T305 antibody showed some basal background immuno-reactivity also with non-phosphorylated CaMKII, as indicated by T305/306A mutants. These results indicate that Ca(2+)/CaM-stimulated CaMKII activity is mildly (~1.2-1.3fold) further increased by additional T286 autophosphorylation, but that this autophosphorylation is not required for the major part of the stimulated activity. This indicates that the phenotype of CaMKII T286A mutant mice is indeed due to the lack of autonomous activity, as the T286A mutant showed no dramatic reduction in stimulated activity.


Colorectal cancer screening: are stool and blood based tests good enough?
Colorectal cancer (CRC) is the third commonest cancer worldwide. As many CRC patients were identified at advanced stages, screening asymptomatic individuals has substantial clinical benefit. Most CRC arises through recognizable early stage. With the improved understanding of the biology of CRC and precancerous lesion, testing molecular aberrations in stool and blood promises novel screening approaches that are noninvasive, sensitive, and more affordable compared with traditional structural examinations.


Paclitaxel-based high-dose chemotherapy with autologous stem cell rescue for relapsed germ cell cancer.
We evaluated the antitumor activity of tandem cycles of high-dose chemotherapy with autologous peripheral stem cell transplantation (aPSCT) in relapsed germ cell tumors by using high-dose paclitaxel, carboplatin, etoposide, and ifosfamide. Thirty-three patients were entered, and 31 underwent protocol therapy. Paclitaxel 350 mg/m2 (5 patients) or 425 mg/m2 (26 patients) by 24-hour continuous intravenous infusion was followed by 3 daily doses of carboplatin and either etoposide (cycle 1) or ifosfamide/mesna (cycle 2). The carboplatin dose had a calculated area under the curve of 7 mg-min/mL, and the daily dose of etoposide was 20 mg/kg (cycle 1). Ifosfamide 3 g/m2/d for 3 days (with mesna uroprotection) was substituted for etoposide in cycle 2. Each cycle was supported by granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. Thirty-one patients were evaluable for response, toxicity, and long-term disease control. Two patients did not undergo aPSCT because of rapid disease progression. Nineteen patients received both cycles of aPSCT, 8 progressed after cycle 1, 3 refused the second cycle, and 1 died of fungal infection during cycle 1. Twelve patients remain relapse free at a median of 67 months from the initiation of therapy. Whereas the International Germ Cell Cancer Collaborative Group category at the time of initial diagnosis did not seem to predict outcome, the patient's probability of achieving durable remission was significantly associated with the Beyer prognostic score at the time of protocol entry. Regimens containing the most active agents in relapsed nonseminomatous germ cell tumors, including high-dose paclitaxel, are well tolerated and have promising activity even in patients with poor-risk features who do not achieve durable remissions with standard therapy. The Beyer prognostic system is a valuable predictor for patients undergoing aPSCT.


Predicted protein-protein interaction sites from local sequence information.
Protein-protein interactions are facilitated by a myriad of residue-residue contacts on the interacting proteins. Identifying the site of interaction in the protein is a key for deciphering its functional mechanisms, and is crucial for drug development. Many studies indicate that the compositions of contacting residues are unique. Here, we describe a neural network that identifies protein-protein interfaces from sequence. For the most strongly predicted sites (in 34 of 333 proteins), 94% of the predictions were confirmed experimentally. When 70% of our predictions were right, we correctly predicted at least one interaction site in 20% of the complexes (66/333). These results indicate that the prediction of some interaction sites from sequence alone is possible. Incorporating evolutionary and predicted structural information may improve our method. However, even at this early stage, our tool might already assist wet-lab biology.


Auditory brain stem response to complex sounds: a tutorial.
This tutorial provides a comprehensive overview of the methodological approach to collecting and analyzing auditory brain stem responses to complex sounds (cABRs). cABRs provide a window into how behaviorally relevant sounds such as speech and music are processed in the brain. Because temporal and spectral characteristics of sounds are preserved in this subcortical response, cABRs can be used to assess specific impairments and enhancements in auditory processing. Notably, subcortical auditory function is neither passive nor hardwired but dynamically interacts with higher-level cognitive processes to refine how sounds are transcribed into neural code. This experience-dependent plasticity, which can occur on a number of time scales (e.g., life-long experience with speech or music, short-term auditory training, on-line auditory processing), helps shape sensory perception. Thus, by being an objective and noninvasive means for examining cognitive function and experience-dependent processes in sensory activity, cABRs have considerable utility in the study of populations where auditory function is of interest (e.g., auditory experts such as musicians, and persons with hearing loss, auditory processing, and language disorders). This tutorial is intended for clinicians and researchers seeking to integrate cABRs into their clinical or research programs.


Breastfeeding Self-efficacy: A Critical Review of Available Instruments.
Increasing breastfeeding rates in the United States is a national priority. Yet, initiation and duration of breastfeeding remains below national targets. Breastfeeding self-efficacy has been shown to be a strong predictor of both breastfeeding initiation and duration and is therefore an important characteristic to be able to measure. However, there is currently a myriad of instruments for measuring breastfeeding self-efficacy, which makes selection of an appropriate instrument difficult. Thus, our aim was to identify, compare, and critically review available breastfeeding self-efficacy instruments. In a systematic review, 6 breastfeeding self-efficacy instruments were identified. The instruments' purposes, theoretical framework, final scale development, and application in 5 most recent settings were analyzed. The 6 breastfeeding self-efficacy instruments apply a number of theoretical and conceptual frameworks in their development, with Bandura's social cognitive theory being most common. Content, construct, and predictive validity were strong for most scales. Some, but not all, have been successfully adapted to novel settings. In sum, there are several measurements of breastfeeding self-efficacy that can and should be employed to better understand reasons for suboptimal breastfeeding rates and the effects of interventions on breastfeeding self-efficacy. Instrument selection should be based on domains of primary interest, time available, peripartum timing, and assessment of previous adaptations. Failure to apply appropriate measures in research may garner results that are inconclusive, inaccurate, or nonrepresentative of true study effects.


Grasping naturally versus grasping with a reacher in people without disability: motor control and muscle activation differences.
We investigated motor control and muscle activation when reaching for and grasping objects with a reacher compared with the unaided hand. In a repeated-measures counterbalanced design, 41 healthy participants with no previous experience using a reacher were randomly assigned to a sequence of four conditions. Movements of the wrist and fingers were recorded using a three-dimensional Qualisys camera system for assessing reach and grasp. Muscle activations from finger and arm flexors and extensors were recorded by surface electromyography. Participants exhibited a smaller grasp aperture, longer reaching time, and more muscle activity when they used a reacher. Efficient motor control, which requires both time and practice, is needed to successfully use a reacher. Clients presented with reachers without sufficient time to develop motor skills unique to reacher use may be more likely to abandon this assistive device and fail to benefit from its function.


Depression, Compulsive Sexual Behavior, and Sexual Risk-Taking Among Urban Young Gay and Bisexual Men: The P18 Cohort Study.
Young gay, bisexual, and other men who have sex with men (YMSM) are at increased likelihood of experiencing depression and engaging in condomless sexual behaviors. The goal of the current investigation was to examine the relationship between negative mood and compulsive sexual behavior (CSB) and to assess for their individual and combined influence on sexual risk-taking behavior among a diverse sample of YMSM in New York City (the P18 Cohort Study). We first analyzed sociodemographic, depressive symptoms, CSB, and sexual risk-taking from the cross-sectional data of 509, 18- or 19-year-old YMSM recruited using non-probability sampling. We found a significant positive correlation between CSB and depression and between CSB and frequency of condomless anal sex acts reported over the last 30 days. Multivariate results found that the presence of both depression and CSB contributed to elevated sexual risk-taking among these urban YMSM. Clinical implications include the importance of assessing for CSB when depression is present and vice versa in order to improve HIV prevention. Informed by minority stress theory and syndemic theory, our results suggest that interventions focused on the health of YMSM recognize that mental health and social context all interact to increase physical health vulnerability vis-a-vis sexual behaviors, depression, and CSB. Thus, HIV prevention and intervention programs need to incorporate mental health components and services that address these needs.


Yoga and Aerobic Dance for Pain Management in Juvenile Idiopathic Arthritis: Protocol for a Pilot Randomized Controlled Trial.
Juvenile idiopathic arthritis (JIA) is one of the most common types of arthritis among children. According to JIA guidelines for physical activity (PA), structured PA interventions led to improved health outcomes. However, many PA programs, such as yoga and aerobic dance, have not been studied in this population despite being popular among youth. Web-based PA programs could provide patients with accessible and affordable interventions. The primary aims of the proposed pilot randomized controlled trial (RCT) are to examine (1) the feasibility of conducting a full-scale RCT to evaluate the effectiveness of two popular types of PA: a yoga training program and an aerobic dance training program, in female adolescents (aged 13-18 years) with JIA compared with an electronic pamphlet control group; and (2) the acceptability of these interventions. A three-arm prospective randomized open-label study with a parallel group design will be used. A total of 25 female adolescents with JIA who have pain will be randomized in a ratio of 2:2:1 to one of the 3 groups: (1) online yoga training program (group A: n=10); (2) online aerobic dance training program (group B: n=10); and (3) electronic pamphlet control group (group C: n=5). Participants in groups A and B will complete 3 individual 1-hour sessions per week using online exercise videos, as well as a 1-hour virtual group session per week using a videoconferencing platform for 12 weeks. Participants from all groups will have access to an electronic educational pamphlet on PA for arthritis developed by the Arthritis Society. All participants will also take part in weekly online consultations with a research coordinator and discussions on Facebook with participants from their own group. Feasibility (ie, recruitment rate, self-reported adherence to the interventions, dropout rates, and percentage of missing data), acceptability, and usability of Facebook and the videoconferencing platform will be assessed at the end of the program. Pain intensity, participation in general PA, morning stiffness, functional status, fatigue, self-efficacy, patient global assessment, disease activity, and adverse events will be assessed using self-administered electronic surveys at baseline and then weekly until the end of the 12-week program. This pilot RCT has been funded by the Arthritis Health Professions Association. This protocol was approved by the Children's Hospital of Eastern Ontario Research Ethics Board (#17/08X). As of May 11, 2020, recruitment and data collection have not started. To our knowledge, this is the first study to evaluate the effectiveness of yoga and aerobic dance as pain management interventions for female adolescents with JIA. The use of online programs to disseminate these 2 PA interventions may facilitate access to alternative methods of pain management. This study can lead to a full-scale RCT. PRR1-10.2196/12823.


The membrane chamber: a new type of in vitro recording chamber.
In vitro brain slice electrophysiology is a powerful and highly successful technique where a thin slice is cut from the brain and kept alive artificially in a recording chamber. The design of this recording chamber is pivotal to the success and the quality of such experiments. Most often one of two types of chambers is used today, the interface chamber or the submerged chamber. These chambers, however, have the disadvantage that they are limited in either their experimental or their physiological properties respectively. Here we present a new working principle for an in vitro chamber design which aims at combining the advantages of the classical designs whilst overcoming their disadvantages. This is achieved by using a semipermeable membrane on which the slice is placed. The membrane allows for a fast flow of artificial cerebrospinal fluid of up to at least 17 ml/min. Due to a Bernoulli effect, this high speed flow also causes a 64% increase in flow of solution across the membrane on which the slice rests. The fact that the membrane is transparent introduces the possibility of wide field inverted optical imaging to brain slice electrophysiology. The utility of this setup was demonstrated in the recording of local field potential, single cell and voltage sensitive dye imaging data simultaneously from an area smaller then 1/8mm(2). The combination of all these features in the membrane chamber make it a versatile and promising device for many current and future in vitro applications, especially in the regard to optical imaging.


Abnormal intra-aural pressure waves associated with death in African children with acute nontraumatic coma.
We explored the relationship between tympanic membrane displacement (TMD) measurements, a tool to monitor intracranial pressure noninvasively, and clinical features and death in children with acute coma in Kilifi, Kenya. Between November 2007 and September 2009, we made serial TMD measurements and clinical observations on children with acute coma (Blantyre coma score (BCS) ≤ 2) on the pediatric high dependency unit of Kilifi District Hospital, and on well children presenting to the hospital's outpatient department for routine follow-up. We examined middle ear function using tympanometry and measured cardiac pulse (CPA) and respiratory pulse pressure amplitudes (RPA) using the TMD analyzer. We recruited 75 children (32 (43%) females; median age 3.3 (IQR: 2.0, 4.3) years). Twenty-one (28%) children died. Higher TMD measurements predicted death. Adjusting for diagnosis, every 50 nl rise in both semirecumbent and recumbent CPA was associated with increased odds of death associated with intracranial herniation (OR: 1.61, 95% confidence interval (CI): 1.07, 2.41; P = 0.02 and OR: 1.35, 95% CI: 1.10, 1.66; P ≤ 0.01 respectively). Raised TMD pulse pressure measurements are associated with death and may be useful in detecting and monitoring risk of intracranial herniation and intracranial pressure in childhood coma.


Current perspectives on the use of statins in the treatment of dyslipidaemic patients: focus on pitavastatin.
A meeting entitled 'Current Perspective on the Use of Statins in the Treatment of Dyslipidemic Patients' was held in Stresa, Italy, on 27-28th June 2019. The presentations covered the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines on dyslipidaemia, with discussion about the importance of controlling low-density lipoprotein cholesterol (LDL-C) and the pharmacological opportunities to reach the novel lipid goals. The roles of statins to manage dyslipidaemia in patients with different cardiovascular risks were also discussed. In particular, the efficacy and safety of pitavastatin for the treatment of dyslipidaemia were reviewed, highlighting its further advantages beyond LDL-C reduction. Therefore, the impact of statins on the glycaemic profile was discussed in view of the null/lower effect of pitavastatin as compared with other statins, as well as the interaction profile with other drugs commonly used. This meeting report summarizes the main messages of the discussion with a special focus on pitavastatin, whose main features in different settings are described.


Thromboxane prostanoid receptor activation amplifies airway stretch-activated contractions assessed in perfused intact bovine bronchial segments.
A deep inspiration (DI) produces bronchodilation in healthy individuals. Conversely, in asthmatics, DIs are less effective in producing bronchodilation and can cause more rapid airway renarrowing and even bronchoconstriction in moderate to severe asthmatics. It is noteworthy that the manner by which a DI is able to cause bronchoconstriction via a stretch-activated contraction (R(stretch)) is thought to correlate positively with airway inflammation. Asthmatic airway inflammation is associated with increased production of thromboxane A(2) (TxA(2)) and subsequent thromboxane prostanoid (TP) receptor activation, causing the heightened contractility of airway smooth muscle. In this study, we sought to investigate the effect of TxA(2) on airway R(stretch) by using bovine bronchial segments. In brief, these intact bronchial segments (2 mm in diameter) were dissected, side branches were ligated, and the tissues were mounted horizontally in an organ bath. R(stretch) was elicited by varying the transmural pressure under isovolumic conditions. Using a pharmacological approach, we showed a reduced R(stretch) response in tissues pretreated with indomethacin, a cyclooxygenase inhibitor, a result mimicked by pretreatment with the TP-selective receptor antagonist 4-(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid (ICI 192605) and the selective p42/p44 mitogen-activated protein kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD 95089) and by airway epithelial denudation. 9,11-Dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619), a TP receptor agonist, elicited enhanced R(stretch) responses in a dose-dependent manner. Pretreatment with 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809), a prostaglandin E (EP) receptor 1/prostaglandin D2 (DP)-selective receptor antagonist, and 9α,15R-dihydroxy-11.β-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z,13E-dien-1-oic acid (AL 8810), a prostaglandin F (FP)-selective receptor antagonist, had no effect, suggesting EP, DP, and FP receptor activation is not involved in amplifying airway smooth muscle R(stretch). These data suggest a role for TP receptor activation and epithelial release of TxA(2) in amplifying airway R(stretch), thus providing novel insights into mechanisms regulating the DI-induced bronchoconstriction seen in asthmatics.


A CONTRIBUTION TO OUR KNOWLEDGE OF THE ACTION OF SAPONIN ON THE BLOOD CORPUSCLES AND PUS CORPUSCLES.
1. The increase of conductivity produced by saponin in formaldehyde-hardened blood is due to an increase in the conductivity of the corpuscles (increased permeability of the corpuscles to ions) and not, mainly at any rate, to the liberation of electrolytes from the corpuscles and a consequent increase in the conductivity of the serum. The increase in the permeability of the corpuscles is probably caused by a "corrosive," dissolving, or emulsifying action of the saponin on some non-proteid constituent of the envelope or stroma. 2. In the first stage of the action of saponin on blood (not fixed by formaldehyde) there seems also to be an increase in the permeability of the corpuscles for ions, even before any haemoglobin has been liberated. The liberation of the haemoglobin may be secondary to this, owing to the entrance, of water consequent on the disturbance of osmotic equilibrium. 3. Heating the blood to 40 degrees to 45 degrees C. intensifies the laking action of saponin, so that a dose insufficient to cause laking at ordinary temperature may do so when the blood is heated to the temperature mentioned. 4. Pus corpuscles, like red blood corpuscles, are worse conductors than the serum in which they are suspended. Unlike blood corpuscles, they show no preference for NH(4)Cl as compared with NaCl. On the other hand, the conductivity of pus is increased by the action of saponin, just as is the case with blood, and apparently very much in the same way, that is to say, by an action on the corpuscles and not on the serum. The fixing of the pus corpuscles by formaldehyde does not hinder this action of saponin.


Acetylcholine receptors in singly and multiply innervated skeletal muscle fibres of the chicken during development.
1. The properties of acetylcholine (ACh) receptors of the singly innervated posterior latissimus dorsi (PLD) and the multiply innervated anterior latissimus dorsi (ALD) muscles of the chicken were investigated. Studies were made on chicks from 17 days in ovo to 14 weeks after hatching. Focal extracellular recordings and intracellular recordings in voltage clamped fibres were made. 2. Peak amplitudes of miniature end-plate currents (m.e.p.c.s) of the two muscles were not significantly different. The time constants of decay (tau D) were similar in both muscles, although tau D in the PLD was generally smaller than in the ALD (usually by less than 25%). M.e.p.c. decays in both muscles were well described by a single exponential. 3. The conductance (gamma) and average lifetime (tau N) of end-plate channels activated by ionophoretically applied ACh were calculated from records of current fluctuations. Noise spectra were well fitted by a single Lorentzian function. Values obtained in PLD did not differ significantly from those obtained in the ALD. There was not difference in the ACh null potential. 4. The voltage and temperature sensitivities of the ACh-activated channels in both muscle types were very similar. 5. With age there was a slight decrease in tau D: from about 6 to 5 msec in the PLD and from about 7 to 5 msec in the ALD (at -40 mV). The change in tau N with age was even less marked. However, during development, gamma almost doubled in both muscles, increasing from about 20 to 35 pS. 6. The results provide no evidence for the hypothesis that the different pattern of innervation causes marked differences in the ACh-activated channels of singly and multiply innervated muscles.


The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3'-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition.
Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis thymidylate kinase (TMPK(Mtub)) catalyzes the ATP-dependent phosphorylation of deoxythymidine 5'-monophosphate (dTMP). Essential to DNA replication, this enzyme represents a promising target for developing new drugs against TB, because the configuration of its active site is unique within the TMPK family. Indeed, it has been proposed that, as opposed to other TMPKs, catalysis by TMPK(Mtub) necessitates the transient binding of a magnesium ion coordinating the phosphate acceptor. Moreover, 3'-azidodeoxythymidine monophosphate (AZTMP) is a competitive inhibitor of TMPK(Mtub), whereas it is a substrate for human and other TMPKs. Here, the crystal structures of TMPK(Mtub) in complex with deoxythymidine (dT) and AZTMP were determined to 2.1 and 2.0 A resolution, respectively, and suggest a mechanism for inhibition. The azido group of AZTMP perturbs the induced-fit mechanism normally adopted by the enzyme. Magnesium is prevented from binding, and the resulting electrostatic environment precludes phosphoryl transfer from occurring. Our data provide a model for drug development against tuberculosis.


Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts.
Animal models have been used to show that there are critical molecular mechanisms that can be activated to induce myocardial repair at specific times in development. For example, specific miRNAs are critical for regulating the response to myocardial infarction (MI) and improving the response to injury. Manipulating these miRNAs in small animal models provides beneficial effects post-MI; however it is not known if these miRNAs are regulated similarly in large mammals. Studying a large animal where the timing of heart development in relation to birth is similar to humans may provide insights to better understand the capacity to repair a developing mammalian heart and its application to the adult heart. We used a sheep model of MI that included permanent ligation of the left anterior descending (LAD) coronary artery. Surgery was performed on fetuses (at 105 days gestation when all cardiomyocytes are mononucleated and proliferative) and adolescent sheep (at 6 months of age when all cardiomyocytes contribute to heart growth by hypertrophy). A microarray was utilized to determine the expression of known miRNAs within the damaged and undamaged tissue regions in fetal and adolescent hearts after MI. 73 miRNAs were up-regulated and 58 miRNAs were down-regulated significantly within the fetal infarct compared to remote cardiac samples. From adolescent hearts 69 non-redundant miRNAs were up-regulated and 63 miRNAs were down-regulated significantly in the infarct area compared to remote samples. Opposite differential expression profiles of 10 miRNAs within tissue regions (Infarct area, Border zone and Remote area of the left ventricle) occurred between the fetuses and adolescent sheep. These included miR-558 and miR-1538, which when suppressed using LNA anti-miRNAs in cell culture, increased cardiomyoblast proliferation. There were significant differences in miRNA responses in fetal and adolescent sheep hearts following a MI, suggesting that the modulation of novel miRNA expression may have therapeutic potential, by promoting proliferation or repair in a damaged heart.


Sleep disturbances in adults with arthritis: prevalence, mediators, and subgroups at greatest risk. Data from the 2007 National Health Interview Survey.
To examine the prevalence of sleep disturbances in adults with arthritis in a nationally representative sample, mediators of sleep difficulties, and subgroups of individuals with arthritis at greatest risk. Using data on US adults ages≥18 years participating in the 2007 National Health Interview Survey, we computed the prevalence of 3 measures of sleep disturbance (insomnia, excessive daytime sleepiness, and sleep duration<6 hours) among persons with arthritis. We used logistic regression analysis to examine if the association of arthritis and sleep disturbances was independent of sociodemographic characteristics and comorbidities, and to identify potential mediators. We used classification trees to identify subgroups at higher risk. The adjusted prevalence of insomnia was higher among adults with arthritis than those without arthritis (23.1% versus 16.4%; P<0.0001), but was similar to those with other chronic diseases. Adults with arthritis were more likely than those without arthritis to report insomnia (unadjusted odds ratio 2.92, 95% confidence interval 2.68-3.17), but adjustment for sociodemographic characteristics and comorbidities attenuated this association. Joint pain and limitation due to pain mediated the association between arthritis and insomnia. Among adults with arthritis, those with depression and anxiety were at highest risk for sleep disturbance. Results for excessive daytime sleepiness and sleep duration<6 hours were similar. Sleep disturbance affects up to 10.2 million US adults with arthritis, and is mediated by joint pain and limitation due to pain. Among individuals with arthritis, those with depression and anxiety are at greatest risk.


TOR and RAS pathways regulate desiccation tolerance in Saccharomyces cerevisiae.
Tolerance to desiccation in cultures of Saccharomyces cerevisiae is inducible; only one in a million cells from an exponential culture survive desiccation compared with one in five cells in stationary phase. Here we exploit the desiccation sensitivity of exponentially dividing cells to understand the stresses imposed by desiccation and their stress response pathways. We found that induction of desiccation tolerance is cell autonomous and that there is an inverse correlation between desiccation tolerance and growth rate in glucose-, ammonia-, or phosphate-limited continuous cultures. A transient heat shock induces a 5000-fold increase in desiccation tolerance, whereas hyper-ionic, -reductive, -oxidative, or -osmotic stress induced much less. Furthermore, we provide evidence that the Sch9p-regulated branch of the TOR and Ras-cAMP pathway inhibits desiccation tolerance by inhibiting the stress response transcription factors Gis1p, Msn2p, and Msn4p and by activating Sfp1p, a ribosome biogenesis transcription factor. Among 41 mutants defective in ribosome biogenesis, a subset defective in 60S showed a dramatic increase in desiccation tolerance independent of growth rate. We suggest that reduction of a specific intermediate in 60S biogenesis, resulting from conditions such as heat shock and nutrient deprivation, increases desiccation tolerance.


BayesHammer: Bayesian clustering for error correction in single-cell sequencing.
Error correction of sequenced reads remains a difficult task, especially in single-cell sequencing projects with extremely non-uniform coverage. While existing error correction tools designed for standard (multi-cell) sequencing data usually come up short in single-cell sequencing projects, algorithms actually used for single-cell error correction have been so far very simplistic.We introduce several novel algorithms based on Hamming graphs and Bayesian subclustering in our new error correction tool BAYESHAMMER. While BAYESHAMMER was designed for single-cell sequencing, we demonstrate that it also improves on existing error correction tools for multi-cell sequencing data while working much faster on real-life datasets. We benchmark BAYESHAMMER on both k-mer counts and actual assembly results with the SPADES genome assembler.


Tracking and predicting COVID-19 radiological trajectory on chest X-rays using deep learning.
Radiological findings on chest X-ray (CXR) have shown to be essential for the proper management of COVID-19 patients as the maximum severity over the course of the disease is closely linked to the outcome. As such, evaluation of future severity from current CXR would be highly desirable. We trained a repurposed deep learning algorithm on the CheXnet open dataset (224,316 chest X-ray images of 65,240 unique patients) to extract features that mapped to radiological labels. We collected CXRs of COVID-19-positive patients from an open-source dataset (COVID-19 image data collection) and from a multi-institutional local ICU dataset. The data was grouped into pairs of sequential CXRs and were categorized into three categories: 'Worse', 'Stable', or 'Improved' on the basis of radiological evolution ascertained from images and reports. Classical machine-learning algorithms were trained on the deep learning extracted features to perform immediate severity evaluation and prediction of future radiological trajectory. Receiver operating characteristic analyses and Mann-Whitney tests were performed. Deep learning predictions between "Worse" and "Improved" outcome categories and for severity stratification were significantly different for three radiological signs and one diagnostic ('Consolidation', 'Lung Lesion', 'Pleural effusion' and 'Pneumonia'; all P < 0.05). Features from the first CXR of each pair could correctly predict the outcome category between 'Worse' and 'Improved' cases with a 0.81 (0.74-0.83 95% CI) AUC in the open-access dataset and with a 0.66 (0.67-0.64 95% CI) AUC in the ICU dataset. Features extracted from the CXR could predict disease severity with a 52.3% accuracy in a 4-way classification. Severity evaluation trained on the COVID-19 image data collection had good out-of-distribution generalization when testing on the local dataset, with 81.6% of intubated ICU patients being classified as critically ill, and the predicted severity was correlated with the clinical outcome with a 0.639 AUC. CXR deep learning features show promise for classifying disease severity and trajectory. Once validated in studies incorporating clinical data and with larger sample sizes, this information may be considered to inform triage decisions.


The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial.
Inflammatory markers such as interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) are elevated in dialysis patients and can predict cardiovascular events and all-cause mortality. Endotoxin is an important source and also another marker of inflammation in patients with chronic kidney disease. The aim of this study was to evaluate the impact of oral probiotics on serum levels of endotoxemia and cytokines in peritoneal dialysis (PD) patients. The decline of residual renal function, peritonitis episodes, and cardiovascular events were also recorded. From July 2011 to June 2012, a randomised, double-blind, placebo-controlled trial was conducted in PD patients. The intervention group received one capsule of probiotics containing 10(9) cfu Bifobacterium bifidum A218, 10(9) cfu Bifidobacterium catenulatum A302, 10(9) cfu Bifidobacterium longum A101, and 10(9) cfu Lactobacillus plantarum A87 daily for six months, while the placebo group received similar capsules containing maltodextrin for the same duration. Levels of serum TNF-α, interferon gamma, IL-5, IL-6, IL-10, IL-17, and endotoxin were measured before and six months after intervention. 39 patients completed the study (21 in the probiotics group and 18 in the placebo group). In patients receiving probiotics, levels of serum TNF-α, IL-5, IL-6, and endotoxin significantly decreased after six months of treatment, while levels of serum IL-10 significantly increased. In contrast, there were no significant changes in levels of serum cytokines and endotoxin in the placebo group after six months. In addition, the residual renal function was preserved in patients receiving probiotics. In conclusion, probiotics could significantly reduce the serum levels of endotoxin, pro-inflammatory cytokines (TNF-α and IL-6), IL-5, increase the serum levels of anti-inflammatory cytokine (IL-10), and preserve residual renal function in PD patients.


Human CD4+ T Cells Specific for Merkel Cell Polyomavirus Localize to Merkel Cell Carcinomas and Target a Required Oncogenic Domain.
Although CD4+ T cells likely play key roles in antitumor immune responses, most immuno-oncology studies have been limited to CD8+ T-cell responses due to multiple technical barriers and a lack of shared antigens across patients. Merkel cell carcinoma (MCC) is an aggressive skin cancer caused by Merkel cell polyomavirus (MCPyV) oncoproteins in 80% of cases. Because MCPyV oncoproteins are shared across most patients with MCC, it is unusually feasible to identify, characterize, and potentially augment tumor-specific CD4+ T cells. Here, we report the identification of CD4+ T-cell responses against six MCPyV epitopes, one of which included a conserved, essential viral oncogenic domain that binds/disables the cellular retinoblastoma (Rb) tumor suppressor. We found that this epitope (WEDLT209-228) could be presented by three population-prevalent HLA class II alleles, making it a relevant target in 64% of virus-positive MCC patients. Cellular staining with a WEDLT209-228-HLA-DRB1*0401 tetramer indicated that specific CD4+ T cells were detectable in 78% (14 of 18) of evaluable MCC patients, were 250-fold enriched within MCC tumors relative to peripheral blood, and had diverse T-cell receptor sequences. We also identified a modification of this domain that still allowed recognition by these CD4+ T cells but disabled binding to the Rb tumor suppressor, a key step in the detoxification of a possible therapeutic vaccine. The use of these new tools for deeper study of MCPyV-specific CD4+ T cells may provide broader insight into cancer-specific CD4+ T-cell responses.


Barrel-shaped ClpP Proteases Display Attenuated Cleavage Specificities.
ClpP is a self-compartmentalizing protease with crucial roles in bacterial and mitochondrial protein quality control. Although the ClpP homocomplex is composed of 14 equivalent active sites, it degrades a multitude of substrates to small peptides, demonstrating its capability to carry out diverse cleavage reactions. Here, we show that ClpP proteases from E. coli, S. aureus, and human mitochondria exhibit preferences for certain amino acids in the P1, P2, and P3 positions using a tailored fluorogenic substrate library. However, this high specificity is not retained during proteolysis of endogenous substrates as shown by mass spectrometric analysis of peptides produced in ClpXP-mediated degradation reactions. Our data suggest a mechanism that implicates the barrel-shaped architecture of ClpP not only in shielding the active sites to prevent uncontrolled proteolysis but also in providing high local substrate concentrations to enable efficient proteolytic processing. Furthermore, we introduce customized fluorogenic substrates with unnatural amino acids that greatly surpass the sensitivity of previously used tools. We used these to profile the activity of cancer-patient- and Perrault-syndrome-derived ClpP mutant proteins.


Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action.
Saffron, a spice derived from the flower of Crocus sativus, has now undergone several trials examining its antidepressant effects and, in a recent meta-analysis, was confirmed to be effective for the treatment of major depression. To provide an expanded systematic analysis of the completed clinical studies on saffron and depression, detailing dosages, extract sources, standardisations, safety profile and treatment duration; and, through a narrative review, to examine its potential antidepressant mechanisms of action. In the systematic review of clinical trials, electronic databases were searched for high-quality, randomised, double-blind studies, with placebo or antidepressant controls. A narrative review of in vivo and in vitro studies was conducted to examine its potential antidepressant mechanisms of action. In the systematic review, six studies were identified. In the placebo-comparison trials, saffron had large treatment effects and, when compared with antidepressant medications, had similar antidepressant efficacy. Saffron's antidepressant effects potentially are due to its serotonergic, antioxidant, anti-inflammatory, neuro-endocrine and neuroprotective effects. Research conducted so far provides initial support for the use of saffron for the treatment of mild-to-moderate depression. Further research is required to expand our understanding of the role and actions of saffron in major depression.


Vividness of Object and Spatial Imagery.
Vividness is one of the fundamental characteristics of visual mental imagery. The first research goal was to examine whether vividness that refer to imagery of pictorial object (color, texture, or shape) versus spatial (three dimensional structure, location, or mechanism) properties constitute separate vividness dimensions. The second goal was to develop a vividness questionnaire separately assessing dimensions of imagery vividness. In Study 1, 111 students (M age = 21.8 years, SD = 1.3) evaluated the vividness of imagery evoked by nine object and nine spatial items from the pilot version of the new Vividness of Object and Spatial Imagery (VOSI) questionnaire, completed a self-report assessment of object and spatial imagery, and rated their aptitudes in art and science. Analysis indicated that imagery vividness comprised object and spatial dimensions. Object vividness items were positively associated with the self-report measure and ratings of artistic abilities, whereas spatial vividness items were positively associated with self-report measure and ratings of science abilities. In Study 2, an independent sample of 205 students (M age = 21 years, SD = 1.7) completed the second version of the VOSI, art and science aptitude ratings, and a number of self-report and performance measures assessing object and spatial imagery. Object and spatial imagery vividness items loaded on factors with 28 retained items; this two-factor vividness model fit the data better than a unidimensional vividness model. The questionnaire had satisfactory Cronbach's α for object vividness scale (.88) and for spatial vividness scale (.85). Correlational analyses supported convergent and discriminative validity of the VOSI. While object imagery vividness and spatial imagery vividness share some underlying vividness variance, they are dissociated into separate dimensions.


A social-media based HIV prevention intervention using peer leaders.
This study seeks to investigate qualities of peer leaders in a social media-based peer-led HIV intervention. African American and Latino men who have sex with men (MSM) peer leaders were recruited through online/offline methods. They were required to have experience with health communication and social media. Over 57% of reported using social networking for seeking sex partners within 3 months. Over 53% spent over 3 hours per week online and about 53% of peer leaders had fewer than 200 Facebook friends. Results suggest that peer leaders can be recruited for social media-based health interventions. Qualities of peer leaders are discussed.


Recreation of an antigen-driven germinal center in vitro by providing B cells with phagocytic antigen.
Successful vaccines rely on activating a functional humoral immune response through the generation of class-switched high affinity immunoglobulins (Igs). The germinal center (GC) reaction is crucial for this process, in which B cells are selected in their search for antigen and T cell help. A major hurdle to understand the mechanisms of B cell:T cell cooperation has been the lack of an antigen-specific in vitro GC system. Here we report the generation of antigen-specific, high-affinity, class-switched Igs in simple 2-cell type cultures of naive B and T cells. B cell antigen uptake by phagocytosis is key to generate these Igs. We have used the method to interrogate if T cells confer directional help to cognate B cells that present antigen and to bystander B cells. We find that bystander B cells do not generate class-switched antibodies due to a defective formation of T-B conjugates and an early conversion into memory B cells.


Effect of water/glycerol polymorphism on dynamic nuclear polarization.
A paramount feature of robust experimental methods is acquiring consistent data. However, in dynamic nuclear polarization (DNP), it has been observed that the DNP-induced NMR signal enhancement of nominally the same sample can vary between different experimental sessions. We investigated the impact of various freezing conditions on the DNP results for a standard sample, a 50/40/10 by volume d8-glycerol/D2O/H2O solution of 40 mM 4-amino TEMPO, and found that annealing the samples 10 K above the glass transition temperature (Tg) causes significant changes to the DNP profiles and enhancements compared to that in rapidly frozen samples. When varying the glycerol composition to yield a solution of 60/30/10 d8-glycerol/D2O/H2O, the DNP performance became markedly more consistent, even for samples prepared under vastly different sample freezing methods, in stark contrast with that of the 50/40/10 solution. The EPR lineshapes, Tm, and glass transition temperature, Tg, were measured under the same sample and experimental conditions as used for the DNP experiments to support the conclusion that different freezing methods change the distribution of 4-amino TEMPO radials in the 50/40/10 solution due to the formation of different polymorphs of the glass, which is mitigated in the 60/30/10 solution and is consistent with the water/glycerol vitrification literature.


MINDMAP: establishing an integrated database infrastructure for research in ageing, mental well-being, and the urban environment.
Urbanization and ageing have important implications for public mental health and well-being. Cities pose major challenges for older citizens, but also offer opportunities to develop, test, and implement policies, services, infrastructure, and interventions that promote mental well-being. The MINDMAP project aims to identify the opportunities and challenges posed by urban environmental characteristics for the promotion and management of mental well-being and cognitive function of older individuals. MINDMAP aims to achieve its research objectives by bringing together longitudinal studies from 11 countries covering over 35 cities linked to databases of area-level environmental exposures and social and urban policy indicators. The infrastructure supporting integration of this data will allow multiple MINDMAP investigators to safely and remotely co-analyse individual-level and area-level data. Individual-level data is derived from baseline and follow-up measurements of ten participating cohort studies and provides information on mental well-being outcomes, sociodemographic variables, health behaviour characteristics, social factors, measures of frailty, physical function indicators, and chronic conditions, as well as blood derived clinical biochemistry-based biomarkers and genetic biomarkers. Area-level information on physical environment characteristics (e.g. green spaces, transportation), socioeconomic and sociodemographic characteristics (e.g. neighbourhood income, residential segregation, residential density), and social environment characteristics (e.g. social cohesion, criminality) and national and urban social policies is derived from publically available sources such as geoportals and administrative databases. The linkage, harmonization, and analysis of data from different sources are being carried out using piloted tools to optimize the validity of the research results and transparency of the methodology. MINDMAP is a novel research collaboration that is combining population-based cohort data with publicly available datasets not typically used for ageing and mental well-being research. Integration of various data sources and observational units into a single platform will help to explain the differences in ageing-related mental and cognitive disorders both within as well as between cities in Europe, the US, Canada, and Russia and to assess the causal pathways and interactions between the urban environment and the individual determinants of mental well-being and cognitive ageing in older adults.


Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks.
The purpose of this study was to develop a method of classifying cancers to specific diagnostic categories based on their gene expression signatures using artificial neural networks (ANNs). We trained the ANNs using the small, round blue-cell tumors (SRBCTs) as a model. These cancers belong to four distinct diagnostic categories and often present diagnostic dilemmas in clinical practice. The ANNs correctly classified all samples and identified the genes most relevant to the classification. Expression of several of these genes has been reported in SRBCTs, but most have not been associated with these cancers. To test the ability of the trained ANN models to recognize SRBCTs, we analyzed additional blinded samples that were not previously used for the training procedure, and correctly classified them in all cases. This study demonstrates the potential applications of these methods for tumor diagnosis and the identification of candidate targets for therapy.


An optochemically organized nonlinear waveguide lattice with primitive cubic symmetry.
We describe the first example of a primitive cubic lattice assembled spontaneously from three mutually orthogonal and intersecting arrays of cylindrical, multimode waveguides. The lattice is generated in a single, room-temperature step with separate (mutually incoherent) incandescent light bulbs. To demonstrate its potential as a nonlinear photonic lattice, we generated a self-trapped lattice beam of incoherent white light. These two findings open entirely new experimental opportunities to study the behavior of spatially and temporally incoherent, polychromatic lattice solitons in 3-D Bravais lattices.


Curcumin-ER Prolonged Subcutaneous Delivery for the Treatment of Non-Small Cell Lung Cancer.
Non-small-cell lung cancer therapy is a challenge due to poor prognosis and low survival rate. There is an acute need for advanced therapies having higher drug efficacy, low immunogenicity and fewer side effects which will markedly improve patient compliance and quality of life of cancer patients. The purpose of this study was to develop a novel hybrid curcumin nanoformulation (Curcumin-ER) and evaluate the therapeutic efficacy of this formulation on a non-small cell lung cancer xenograft model. Use of curcumin, a natural anticancer agent, is majorly limited due to its poor aqueous solubility and hence it's low systemic bioavailability. In this paper, we carried out the nanoformulation of Curcumin-ER, optimized the formulation process and determined the anticancer effects of Curcumin-ER against human A549 non-small cell lung cancer using in vitro and in vivo studies. Xenograft tumors in nude mice were treated with 20 mg/kg subcutaneous injection of Curcumin-ER and liposomal curcumin (Lipocurc) twice a week for seven weeks. Results showed that tumor growth was suppressed by 52.1% by Curcumin-ER treatment and only 32.2% by Lipocurc compared to controls. Tumor sections were isolated from murine xenografts and histology and immunohistochemistry was performed. A decrease in expression of NFκB-p65 subunit and proliferation marker, Ki-67 was observed in treated tumors. In addition, a potent anti-angiogenic effect, characterized by reduced expression of annexin A2 protein, was observed in treated tumors. These results establish the effectiveness of Curcumin-ER in regressing human non-small cell lung cancer growth in the xenograft model using subcutaneous route of administration. The therapeutic efficacy of Curcumin-ER highlights the potential of this hybrid nanoformulation in treating patients with non-small cell lung cancer.


metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis.
A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness.Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies. Code is available at https://github.com/aalto-ics-kepaco email@example.com or firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Multicenter, real-life experience with checkpoint inhibitors and targeted therapy agents in advanced melanoma patients in Switzerland.
Metastatic melanoma is a highly aggressive disease. Recent progress in immunotherapy (IT) and targeted therapy (TT) has led to significant improvements in response and survival rates in metastatic melanoma patients. The current project aims to determine the benefit of the introduction of these new therapies in advanced melanoma across several regions of Switzerland. This is a retrospective multicenter analysis of 395 advanced melanoma patients treated with standard chemotherapy, checkpoint inhibitors, and kinase inhibitors from January 2008 until December 2014. The 1-year survival was 69% (n=121) in patients treated with checkpoint inhibitors (IT), 50% in patients treated with TTs (n=113), 85% in the IT+TT group (n=66), and 38% in patients treated with standard chemotherapy (n=95). The median overall survival (mOS) from first systemic treatment in the entire study cohort was 16.9 months. mOS of patients treated either with checkpoint or kinase inhibitors (n=300, 14.6 months) between 2008 and 2014 was significantly improved (P<0.0001) compared with patients treated with standard chemotherapy in 2008-2009 (n=95, 7.4 months). mOS of 61 patients with brain metastases at stage IV was 8.1 versus 12.5 months for patients without at stage IV (n=334), therefore being significantly different (P=0.00065). Furthermore, a significant reduction in hospitalization duration compared with chemotherapy was noted. Treatment with checkpoint and kinase inhibitors beyond clinical trials significantly improves the mOS in real life and the results are consistent with published prospective trial data.