Climate policy to defeat the green paradox.
Carbon dioxide emissions have accelerated since the signing of the Kyoto Protocol. This discouraging development may partly be blamed on accelerating world growth and on lags in policy instruments. However, it also raises serious question concerning whether policies to reduce CO2 emissions are as effective as generally assumed. In recent years, a considerable number of studies have identified various feedback mechanisms of climate policies that often erode, and occasionally reinforce, their effectiveness. These studies generally focus on a few feedback mechanisms at a time, without capturing the entire effect. Partial accounting of policy feedbacks is common in many climate scenarios. The IPCC, for example, only accounts for direct leakage and rebound effects. This article attempts to map the aggregate effects of different types of climate policy feedback mechanisms in a cohesive framework. Controlling feedback effects is essential if the policy measures are to make any difference on a global level. A general conclusion is that aggregate policy feedback mechanisms tend to make current climate policies much less effective than is generally assumed. In fact, various policy measures involve a definite risk of 'backfiring' and actually increasing CO2 emissions. This risk is particularly pronounced once effects of climate policies on the pace of innovation in climate technology are considered. To stand any chance of controlling carbon emissions, it is imperative that feedback mechanisms are integrated into emission scenarios, targets for emission reduction and implementation of climate policy. In many cases, this will reduce the scope for subsidies to renewable energy sources, but increase the scope for other measures such as schemes to return carbon dioxide to the ground and to mitigate emissions of greenhouse gases from wetlands and oceans. A framework that incorporates policy feedback effects necessitates rethinking the design of the national and regional emission targets. This leads us to a new way of formulating emission targets that include feedback effects, the global impact target. Once the full climate policy feedback mechanisms are accounted for, there are probably only three main routes in climate policy that stand a chance of mitigating global warming: (a) returning carbon to the ground, (b) technological leaps in zero-emission energy technology that make it profitable to leave much carbon in the ground even in Annex II countries and (c) international agreements that make it more profitable to leave carbon in the ground or in forests.


Silver nanoparticles induced oxidative and endoplasmic reticulum stresses in mouse tissues: implications for the development of acute toxicity after intravenous administration.
Concerns have arisen about the health and environmental impacts of the increasing commercial use of silver nanoparticles (AgNPs). However, the toxic mechanisms and target tissues of AgNPs have not been fully defined. In this paper, we investigated the tissue toxicity of mice after intravenous administration of AgNPs at a single-dose of 0.2, 2 or 5 mg per kg (body weight), respectively. Biodistribution, endoplasmic reticulum stress, and oxidative stress were examined in mouse organs at eight hours after exposure. Stress markers, e.g. HSP70, BIP, p-IRE1, p-PERK, chop and xbp-1s proteins/genes, were significantly upregulated in a dose-dependent manner. In the liver, spleen, lung and kidney, high stress accompanied by apoptosis occurred. Low stress levels were observed in the heart and brain. Thus, it is proposed that the liver, spleen, lung and kidney are dominant target tissues of AgNP exposure. The lower stress and toxicity in the heart and brain were in agreement with lower AgNP accumulation. The present results demonstrated that AgNP exposure eventually resulted in permanent toxic damage by gradually imposing stress impacts on target organs. These findings highlight the potent applications of stress markers in future risk evaluation of silver nanoparticle toxicity.


MetaMapp: mapping and visualizing metabolomic data by integrating information from biochemical pathways and chemical and mass spectral similarity.
Exposure to environmental tobacco smoke (ETS) leads to higher rates of pulmonary diseases and infections in children. To study the biochemical changes that may precede lung diseases, metabolomic effects on fetal and maternal lungs and plasma from rats exposed to ETS were compared to filtered air control animals. Genome- reconstructed metabolic pathways may be used to map and interpret dysregulation in metabolic networks. However, mass spectrometry-based non-targeted metabolomics datasets often comprise many metabolites for which links to enzymatic reactions have not yet been reported. Hence, network visualizations that rely on current biochemical databases are incomplete and also fail to visualize novel, structurally unidentified metabolites. We present a novel approach to integrate biochemical pathway and chemical relationships to map all detected metabolites in network graphs (MetaMapp) using KEGG reactant pair database, Tanimoto chemical and NIST mass spectral similarity scores. In fetal and maternal lungs, and in maternal blood plasma from pregnant rats exposed to environmental tobacco smoke (ETS), 459 unique metabolites comprising 179 structurally identified compounds were detected by gas chromatography time of flight mass spectrometry (GC-TOF MS) and BinBase data processing. MetaMapp graphs in Cytoscape showed much clearer metabolic modularity and complete content visualization compared to conventional biochemical mapping approaches. Cytoscape visualization of differential statistics results using these graphs showed that overall, fetal lung metabolism was more impaired than lungs and blood metabolism in dams. Fetuses from ETS-exposed dams expressed lower lipid and nucleotide levels and higher amounts of energy metabolism intermediates than control animals, indicating lower biosynthetic rates of metabolites for cell division, structural proteins and lipids that are critical for in lung development. MetaMapp graphs efficiently visualizes mass spectrometry based metabolomics datasets as network graphs in Cytoscape, and highlights metabolic alterations that can be associated with higher rate of pulmonary diseases and infections in children prenatally exposed to ETS. The MetaMapp scripts can be accessed at http://metamapp.fiehnlab.ucdavis.edu.


Quercetin-3-oleoyl derivatives as new GPR40 agonists: Molecular docking studies and functional evaluation.
The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1, was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2, was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes.


Tackling the climate targets set by the Paris Agreement (COP 21): Green leadership empowers public hospitals to overcome obstacles and challenges in a resource-constrained environment.
The healthcare sector itself contributes to climate change, the creation of hazardous waste, use of toxic metals such as mercury, and water and air pollution. To mitigate the effect of healthcare provision on the deteriorating environment and avoid creating further challenges for already burdened health systems, Global Green Hospitals was formed as a global network. Groote Schuur Hospital (GSH), as the leading academic hospital in Africa, joined the network in 2014. Since then, several projects have been initiated to reduce the amount of general waste, energy consumption and food waste, and create an environmentally friendlier and more sustainable hospital in a resource-constrained public healthcare setting. We outline the various efforts made to reduce the carbon footprint of GSH and reduce waste and hazardous substances such as mercury and polystyrene, and elaborate how obstacles and resistance to change were overcome. The hospital was able to halve the amount of coal and water used, increase recycling by 50% over 6 months, replace polystyrene cups and packaging with Forest Stewardship Council recyclable paper-based products, reduce the effect of food wastage by making use of local farmers, and implement measures to reduce the amount of expired pharmaceutical drugs. To improve commitment from all involved roleplayers, political leadership, supportive government policies and financial funding is mandatory, or public hospitals will be unable to tackle the exponentially increasing costs related to climate change and its effects on healthcare.


A chimera of the cytoplasmic tail of the mannose 6-phosphate/IGF-II receptor and lysozyme localizes to the TGN rather than prelysosomes where the bulk of the endogenous receptor is found.
We fused the cytoplasmic and transmembrane domains of the bovine mannose 6-phosphate/IGF-II receptor (MPR) to lysozyme, a monomeric secretory protein thought to be devoid of sorting information. When the resulting chimera (lys/MPR) was transiently expressed in COS cells or stably expressed in CV1 cells, it had a predominantly intracellular distribution in the trans-Golgi region, with less than 10% present on the surface. In contrast, a similar chimera containing the transmembrane and cytoplasmic domains of the low density lipoprotein receptor (lys/LDLR) was localized to the plasma membrane, even though it endocytoses efficiently. Exchanging domains between the lys/MPR and lys/LDLR chimeras indicated that the MPR cytoplasmic domain contains the information necessary to specify the intracellular localization of the chimeric molecule. This signal must be located in the membrane-proximal third of the tail, as deletion of the last 120 residues of the 163 residue tail has no obvious effect on the distribution of lys/MPR. However, the recycling of the lys/MPR does not completely mimic that of the intact endogenous MPR, as immunofluorescence labelling shows that they are predominantly in different locations, indicating a role for the lumenal domain of the MPR in determining the steady-state distribution of the MPR itself.


Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells.
Arrest of cell division is a prerequisite for cells to enter a program of terminal differentiation. Mitogenesis and cytostasis of neuronal cell precursors can be induced by the same or by different growth or trophic factors. Response of PC12 cells to nerve growth factor (NGF) involves a proliferative phase that is followed by growth arrest and differentiation. Here we present evidence that the cytostatic effect of NGF is mediated by nitric oxide (NO), a second messenger molecule with both para- and autocrine properties that can diffuse freely and act within a restricted volume. We show that NGF induces different forms of nitric oxide synthase (NOS) in neuronal cells, that nitric oxide (NO) acts as a cytostatic agent in these cells, that inhibition of NOS leads to reversal of NGF-induced cytostasis and thereby prevents full differentiation, and that capacity of a mutant cell line to differentiate can be rescued by exogenous NO. We suggest that induction of NOS is an important step in the commitment of neuronal precursors and that NOS serves as a growth arrest gene, initiating the switch to cytostasis during differentiation.


Risk factors for inflammatory bowel disease: A prospective multi-center study.
Environmental risk factors have been associated with inflammatory bowel disease (IBD). With rising incidence, it is important to know risk factors associated with IBD in our population. This study was aimed to evaluate risk factors for IBD from western India. This was prospective, multi-center case-control study which included 1054 patients with IBD of which 765 (72.5%) were ulcerative colitis (UC) and 289 (27.4%) Crohn's disease (CD). Asymptomatic individuals without a history of any major illness served as controls. The questionnaire containing risk factors for IBD was given to patients and control group. Odds ratio and 95% confidence interval were calculated for each variable. Significant numbers of patients with CD were from rural area. Rural environment (OR 1.071, 0.82-1.38 and OR 1.441, 1.02-2.02), higher education (OR 1.830, 1.52-2.19 and OR 1.519, 1.16-1.97), professional by occupation (OR 1.754, 1.46-2.09 and OR 1.293, 0.99-1.67), annual family income >100,000 Indian national rupees (OR 2.185, 1.52-3.13 and OR 4.648, 3.10-6.95), history of appendectomy (OR 3.158, 1.71-5.80 and OR 3.158, 1.71-5.80), and family history of IBD (OR 4.510, 2.19-9.25 and OR 3.972, 1.58-9.96) were the risk factors for UC and CD, respectively. Vegetarian diet was protective factor for UC (OR 0.29, 0.27-0.39) and risk for CD (OR 1.179, 0.88-1.57). Smoking and chronic alcoholism were not found to be the risk factors. This study highlights association between socioeconomic, dietary factors, appendectomy, and family history as risk factors for IBD.


Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice.
Amyotrophic lateral sclerosis (ALS) is the most common adult onset motoneuron disease. The etiology and precise pathogenic mechanisms of the disease remain unknown, and there is no effective treatment. Vascular endothelial growth factor (VEGF) has recently been shown to exert direct neurotrophic and neuroprotective effects in animal models of ALS. Here we show that intrathecal transplantation of immortalized human neural stem cells (NSCs) overexpressing human VEGF gene (HB1.F3.VEGF) significantly delayed disease onset and prolonged the survival of the SOD1G93A mouse model of ALS. At 4 weeks, post-transplantation grafted cells were found within the gray matter of the spinal cord. Furthermore, transplanted F3.VEGF cells that express neuronal phenotype (MAP2+) were found in the anterior horn of the spinal cord gray matter indicating that the transplanted human NSCs migrated into the gray matter, took the correct structural position, integrated into the spinal cord anterior horn and differentiated into motoneurons. Intrathecal transplantation of F3.VEGF cells provides a neuroprotective effect in the diseased spinal cord by concomitant downregulation of proapoptotic proteins and upregulation of antiapoptotic proteins. Our results suggest that this treatment modality of intrathecal transplantation of human NSCs genetically modified to overexpress neurotrophic factor(s) might be of value in the treatment of ALS patients without significant adverse effects.


Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution.
Lysergic acid diethylamide (LSD) is a non-selective serotonin-receptor agonist that was first synthesized in 1938 and identified as (potently) psychoactive in 1943. Psychedelics have been used by indigenous cultures for millennia [1]; however, because of LSD's unique potency and the timing of its discovery (coinciding with a period of major discovery in psychopharmacology), it is generally regarded as the quintessential contemporary psychedelic [2]. LSD has profound modulatory effects on consciousness and was used extensively in psychological research and psychiatric practice in the 1950s and 1960s [3]. In spite of this, however, there have been no modern human imaging studies of its acute effects on the brain. Here we studied the effects of LSD on intrinsic functional connectivity within the human brain using fMRI. High-level association cortices (partially overlapping with the default-mode, salience, and frontoparietal attention networks) and the thalamus showed increased global connectivity under the drug. The cortical areas showing increased global connectivity overlapped significantly with a map of serotonin 2A (5-HT2A) receptor densities (the key site of action of psychedelic drugs [4]). LSD also increased global integration by inflating the level of communication between normally distinct brain networks. The increase in global connectivity observed under LSD correlated with subjective reports of "ego dissolution." The present results provide the first evidence that LSD selectively expands global connectivity in the brain, compromising the brain's modular and "rich-club" organization and, simultaneously, the perceptual boundaries between the self and the environment.


Therapeutic synthetic polymers: a game of Russian roulette?
Synthetic polymer-based drug-delivery systems have been applied in drug delivery for the past 50 years. So why are there so few examples of these macromolecules being used successfully in the clinic? It is our view that many products are failing because of a neglect of the fundamental science surrounding the architectural control of the molecules present, their behaviour following in vivo administration and host response. Adverse events following parenteral administration of approved synthetic polymer-based systems have resulted in unpredictable and fatal responses in a significant number of individuals. Acceptance of the importance of immunotoxicological factors in response to the presence of these macromolecules must be addressed if emergent technologies, such as polymer-based gene-delivery systems, are going to succeed.


Hyperoxia enhances self-paced exercise performance to a greater extent in cool than hot conditions.
What is the central question of this study? Hyperoxia enhances endurance performance by increasing O2 availability to locomotor muscles. We investigated whether hyperoxia can also improve prolonged self-paced exercise in conditions of elevated thermal and cardiovascular strain. What is the main finding and its importance? Hyperoxia improved self-paced exercise performance in hot and cool conditions. However, the extent of the improvement (increased work rate relative to normoxia) was greater in cool conditions. This suggests that the development of thermal and cardiovascular strain during prolonged self-paced exercise under heat stress might attenuate the hyperoxia-mediated increase in O2 delivery to locomotor muscles. The aim of this study was to determine whether breathing hyperoxic gas when self-paced exercise performance is impaired under heat stress enhances power output. Nine well-trained male cyclists performed four 40 min cycling time trials: two at 18°C (COOL) and two at 35°C (HOT). For the first 30 min, participants breathed ambient air, and for the remaining 10 min normoxic (fraction of inspired O2 0.21; NOR) or hyperoxic (fraction of inspired O2 0.45; HYPER) air. During the first 30 min of the time trials, power output was lower in the HOT (∼250 W) compared with COOL (∼273 W) conditions (P < 0.05). In the final 10 min, power output was higher in HOT-HYPER (264 ± 25 W) than in HOT-NOR (244 ± 31 W; P = 0.008) and in COOL-HYPER (315 ± 28 W) than in COOL-NOR (284 ± 25 W; P < 0.001). The increase in absolute power output in COOL-HYPER was greater than in HOT-HYPER (∼12 W; P = 0.057), as was normalized power output (∼30%; P < 0.001). The peripheral capillary percentage oxygen saturation increased in HOT-HYPER and COOL-HYPER (P < 0.05), with COOL-HYPER being higher than HOT-HYPER (P < 0.01). Heart rate was higher during the HOT compared with COOL trials (P < 0.01), as were mean skin temperature (P < 0.001) and peak rectal temperature (HOT, ∼39.5°C and COOL, ∼38.9°C; P < 0.01). Thermal discomfort was also higher in the HOT compared with COOL (P < 0.01), whereas ratings of perceived exertion were similar (P > 0.05). Hyperoxia enhanced performance during the final 25% of a 40 min time trial in both HOT and COOL conditions compared with normoxia. However, the attenuated increase in absolute and normalized power output noted in the HOT condition suggests that heat stress might mitigate the influence of hyperoxia.


Traumatic adult respiratory distress syndrome.
ARDS is the pulmonary manifestation of both direct and indirect insults to the lung. Trauma patients are at particular risk for ARDS from the direct effects of their injuries, as well as from complications that may occur during their hospital courses. ARDS prevention can be enhanced through diverse areas of medical focus. Public health issues addressing trauma prevention, improved understanding and treatment of trauma-related pathophysiology, as well as a better understanding of basic pathophysiology of this disease process will allow refinement and improvement of our management practices. Newer modes of mechanical ventilation may help us to avoid ventilator-induced exacerbation of lung injury. As we define the role of nonconventional therapies, such as anti-inflammatory and anticytokine therapies, our ability to actively interrupt and reverse the progression of the inflammatory cascade will be enhanced. As yet, ARDS continues to be a challenging disease process to both fully understand and successfully treat in our critically ill patients.


Active droplet generation in microfluidics.
The reliable generation of micron-sized droplets is an important process for various applications in droplet-based microfluidics. The generated droplets work as a self-contained reaction platform in droplet-based lab-on-a-chip systems. With the maturity of this platform technology, sophisticated and delicate control of the droplet generation process is needed to address increasingly complex applications. This review presents the state of the art of active droplet generation concepts, which are categorized according to the nature of the induced energy. At the liquid/liquid interface, an energy imbalance leads to instability and droplet breakup.


Building postgraduate capacity in medical and public health research in Vietnam: an in-service training model.
In Vietnam, needs to update medical and public health research capacity, but advanced training in research methodology in universities is still very limited. The first university-certified research training course aimed at physicians was conducted in Ho Chi Minh City in 2000. This paper describes the processes, outcomes and lessons learned from the project, to enable the training course to be repeated to increase research capacity among health professionals in Vietnam and other developing countries. Based on needs assessment, the 9-month, part-time course offered advanced training in practical research skills, including epidemiology, biostatistics and qualitative research methods. Thirty-seven trainees (teaching staff, interns and clinicians) completed the course, which included four group research projects. With active support from university management, the course was rigorous and participation was excellent. Trainees's knowledge of research methodologies increased, and their self-evaluation of achievement of the training objectives was high. The total score of the epidemiology and biostatistics test improved from 56% (median) in the pre-course test to 83% in the post-course test. The group research project results were disseminated through a conference and publication in peer-reviewed journals. The course has since been repeated twice as a 1-month intensive course to accommodate trainees from distant regions. This type of rigorous in-service research training at universities and teaching hospitals in developing countries appears to be an effective, sustainable approach. It also holds promise for producing research data that are responsive to a country's own needs and which are likely to be applied in health policy and practice. Further evaluation of the impact and cost of such models is indicated.


The role of the Mre11-Rad50-Nbs1 complex in double-strand break repair-facts and myths.
Homologous recombination (HR) initiates double-strand break (DSB) repair by digesting 5'-termini at DSBs, the biochemical reaction called DSB resection, during which DSBs are processed by nucleases to generate 3' single-strand DNA. Rad51 recombinase polymerizes along resected DNA, and the resulting Rad51-DNA complex undergoes homology search. Although DSB resection by the Mre11 nuclease plays a critical role in HR in Saccharomyces cerevisiae, it remains elusive whether DSB resection by Mre11 significantly contributes to HR-dependent DSB repair in mammalian cells. Depletion of Mre11 decreases the efficiency of DSB resection only by 2- to 3-fold in mammalian cells. We show that although Mre11 is required for efficient HR-dependent repair of ionizing-radiation-induced DSBs, Mre11 is largely dispensable for DSB resection in both chicken DT40 and human TK6 B cell lines. Moreover, a 2- to 3-fold decrease in DSB resection has virtually no impact on the efficiency of HR. Thus, although a large number of researchers have reported the vital role of Mre11-mediated DSB resection in HR, the role may not explain the very severe defect in HR in Mre11-deficient cells, including their lethality. We here show experimental evidence for the additional roles of Mre11 in (i) elimination of chemical adducts from DSB ends for subsequent DSB repair, and (ii) maintaining HR intermediates for their proper resolution.


A Decision Support System Based on Degree-Days to Initiate Fungicide Spray Programs for Peach Powdery Mildew in Catalonia, Spain.
The incidence of peach powdery mildew (PPM) on fruit was monitored in commercial peach orchards to i) describe the disease progress in relation to several environmental parameters and ii) establish an operating threshold to initiate a fungicide spray program based on accumulated degree-day (ADD) data. A beta-regression model for disease incidence showed a substantial contribution of the random effects orchard and year, whereas relevant fixed effects corresponded to ADD, wetness duration, and ADD considering vapor pressure deficit and rain. When beta-regression models were fitted for each orchard and year considering only ADD, disease onset was observed at 242 ± 13 ADD and symptoms did not develop further after 484 ± 42 ADD. An operating threshold to initiate fungicide applications was established at 220 ADD, coinciding with a PPM incidence in fruit around 0.05. A validation was further conducted by comparing PPM incidence in i) a standard, calendar-based program, ii) a program with applications initiated at 220 ADD, and iii) a nontreated control. A statistically relevant reduction in disease incidence in fruit was obtained with both fungicide programs, from 0.244 recorded in the control to 0.073 with the 220-ADD alert program, and 0.049 with the standard program. The 220-ADD alert program resulted in 33% reduction in fungicide applications.


The increase in mannose receptor recycling favors arginase induction and Trypanosoma cruzi survival in macrophages.
The macrophage mannose receptor (MR) is a pattern recognition receptor of the innate immune system that binds to microbial structures bearing mannose, fucose and N-acetylglucosamine on their surface. Trypanosoma cruzi antigen cruzipain (Cz) is found in the different developmental forms of the parasite. This glycoprotein has a highly mannosylated C-terminal domain that participates in the host-antigen contact. Our group previously demonstrated that Cz-macrophage (Mo) interaction could modulate the immune response against T. cruzi through the induction of a preferential metabolic pathway. In this work, we have studied in Mo the role of MR in arginase induction and in T. cruzi survival using different MR ligands. We have showed that pre-incubation of T. cruzi infected cells with mannose-Bovine Serum Albumin (Man-BSA, MR specific ligand) biased nitric oxide (NO)/urea balance towards urea production and increased intracellular amastigotes growth. The study of intracellular signals showed that pre-incubation with Man-BSA in T. cruzi J774 infected cells induced down-regulation of JNK and p44/p42 phosphorylation and increased of p38 MAPK phosphorylation. These results are coincident with previous data showing that Cz also modifies the MAPK phosphorylation profile induced by the parasite. In addition, we have showed by confocal microscopy that Cz and Man-BSA enhance MR recycling. Furthermore, we studied MR behavior during T. cruzi infection in vivo. MR was up-regulated in F4/80+ cells from T. cruzi infected mice at 13 and 15 days post infection. Besides, we investigated the effect of MR blocking antibody in T. cruzi infected peritoneal Mo. Arginase activity and parasite growth were decreased in infected cells pre-incubated with anti-MR antibody as compared with infected cells treated with control antibody. Therefore, we postulate that during T. cruzi infection, Cz may contact with MR, increasing MR recycling which leads to arginase activity up-regulation and intracellular parasite growth.


Synergistic antifungal activity of berberine derivative B-7b and fluconazole.
Our previous study demonstrated berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. We also suggested BBR played a major antifungal role in the synergism of FLC and BBR, while FLC increased intracellular BBR concentrations. Our following systematic structural modification and reconstruction of BBR core identified the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acet-amide derivatives 7a-i, including B-7b and B-7d exhibiting remarkable synergistic antifungal activity and low cytotoxicity. Here, the study mainly investigated the synergistic activity of FLC and B-7b and the underlying mechanism. In vitro interaction of FLC and B-7b was investigated against 30 FLC-resistant clinical isolates of C. albicans and non-C. albicans species, including Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida krusei and Cryptococcus neoformans. The potent synergistic activity of B-7b in combination with FLC against FLC-resistant C. albicans was found through the checkerboard microdilution assay. The findings of agar diffusion tests and time-kill curves confirmed its better synergism with FLC. And as expected, B-7b exhibited much lower cytotoxicity than BBR to human umbilical vein endothelial cells. In contrast to BBR, we found that endogenous ROS augmentation was not involved in the synergism of FLC and B-7b. According to the results from our present comparative proteomic study, it seemed that the disruption of protein folding and processing and the weakening of cells' self-defensive ability contributed to the synergism of FLC and B-7b. Together, these results suggested novel scaffold BBR derivative B-7b could be a promising synergist in combination with FLC for the treatment of invasive fungal infections.


Measurement of the ν μ energy spectrum with IceCube-79: IceCube Collaboration.
IceCube is a neutrino observatory deployed in the glacial ice at the geographic South Pole. The ν μ energy unfolding described in this paper is based on data taken with IceCube in its 79-string configuration. A sample of muon neutrino charged-current interactions with a purity of 99.5% was selected by means of a multivariate classification process based on machine learning. The subsequent unfolding was performed using the software Truee. The resulting spectrum covers an E ν -range of more than four orders of magnitude from 125 GeV to 3.2 PeV. Compared to the Honda atmospheric neutrino flux model, the energy spectrum shows an excess of more than 1.9 σ in four adjacent bins for neutrino energies E ν ≥ 177.8 TeV . The obtained spectrum is fully compatible with previous measurements of the atmospheric neutrino flux and recent IceCube measurements of a flux of high-energy astrophysical neutrinos.


The visual size of one׳s own hand modulates pain anticipation and perception.
How to reduce pain is a fundamental clinical and experimental question. Acute pain is a complex experience which seems to emerge from the co-activation of two main processes, namely the nociceptive/discriminative analysis and the affective/cognitive evaluation of the painful stimulus. Recently it has been found that pain threshold increases following the visual magnification of the body part targeted by the painful stimulation. This finding is compatible with the well-known notion that body representation and perceptual experience relay on complex, multisensory factors. However, the level of cognitive processing and the physiological mechanisms underlying this analgesic effect are still to be investigated. In the present work we found that following the visual magnification of a body part, the Skin Conductance Responses (SCR), to an approaching painful stimulus increases before contact and decreases following the real stimulation, compared to the non-distorted view of the hand. By contrast, an unspecific SCR increase is found when the hand is visually shrunk. Moreover a reduction of subjective pain experience was found specifically for the magnified hand in explicit pain ratings. These findings suggest that the visual increase of body size enhances the cognitive, anticipatory component of pain processing; such an anticipatory reaction reduces the response to the following contact with the noxious stimulus. The present results support the idea that cognitive aspects of pain experience relay on the multisensory representation of the body, and that could be usefully exploited for inducing a significant reduction of subjective pain experience.


Histone deacetylase inhibitor romidepsin enhances anti-tumor effect of erlotinib in non-small cell lung cancer (NSCLC) cell lines.
Most epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs) are sensitive to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, but many EGFR wild type NSCLCs are resistant to TKIs. In this study, we examined the effects of the histone deacetylase inhibitor, romidepsin, in combination with erlotinib, in NSCLC cell lines and xenografts. For in vitro studies, nine NSCLC cell lines with varying mutation status and histology were treated with erlotinib and romidepsin alone or in combination. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays were performed to determine the concentration that inhibits 50% (IC50) value of each drug or the combination. For in vivo studies, NCI-H1299 xenografts were inoculated subcutaneously into athymic nude mice. Romidepsin and/or erlotinib were injected intraperitoneally after tumors developed and tumor sizes were measured. We found that romidepsin increased the sensitivity of erlotinib synergistically in all nine NSCLC cell lines including EGFR and KRAS wild type cell lines, KRAS mutant cell lines, and TKI resistant EGFR mutant cell lines. This effect was partially due to enhanced apoptosis. Furthermore, cotreatment of erlotinib and romidepsin inhibited NCI-H1299 xenograft growth in athymic nude mice. These observations support a role for the combination of a histone deacetylase inhibitor and a TKI in the treatment of NSCLCs.


Development of an Enzyme-Linked Immunosorbent Assay To Detect Antibodies Targeting Recombinant Envelope Protein 2 of Mayaro Virus.
Mayaro virus (MAYV) is a neglected arthropod-borne virus (arbovirus) antigenically clustered into the Semliki Forest complex group of Alphavirus genus (Togaviridae family), maintained in an unclear zoonotic cycle involving mosquitoes from Haemagogus genus as the main vector. The genome is composed of a positive single-stranded RNA of 11.5 kb in length, which contains two genes that encode four nonstructural (nsP1 to nsP4) and five structural (C, E3, E2, 6K, and E1) proteins. In the present study, we have developed an enzyme-linked immunosorbent assay (ELISA) using as antigen the recombinant envelope protein 2 of MAYV produced in an Escherichia coli system (rE2-MAYV ELISAs). A panel of 68 human serum samples from suspected arboviral cases was analyzed and titrated for anti-MAYV IgM and IgG antibody detection. The rE2-MAYV ELISA detected 33.8% (23/68) IgG-positive samples, demonstrating 100% sensitivity and 78.95% specificity compared to the MAYV-specific 50% plaque reduction neutralization assay. In addition, the positive MAYV-neutralizing samples showed high titers of detection by rE2-MAYV ELISA, suggesting a highly sensitive test. The rE2-MAYV ELISA also detected 42.5% (29/68) IgM-positive samples, of which 13.8% (4/29) presented high-avidity interactions with rE2-MAYV. Cross-reactivity was observed with Chikungunya virus (CHIKV)-specific murine antibody sample but not with CHIKV-specific human and other Alphavirus murine antibodies. In short, we have developed a rapid, simple, specific, and sensitive MAYV rE2-ELISA, and our preliminary results show its potential applicability to diagnosis of MAYV infections.


Carotenoid bioaccessibility in pulp and fresh juice from carotenoid-rich sweet oranges and mandarins.
Citrus fruits are a good source of carotenoids for the human diet; however, comparative studies of carotenoids in different citrus food matrices are scarce. In this work the concentration and bioaccessibility of carotenoids in sweet oranges and mandarins with marked differences in carotenoid composition were evaluated in pulp and compared to those in fresh juice. The pulp and juice of the red-fleshed Cara Cara sweet orange variety was highly rich in carotenes (mainly lycopene and phytoene) compared to standard Navel orange, while β-cryptoxanthin and phytoene predominated in mandarins. Total carotenoid content in the pulp of the ordinary Navel orange and in the red-fleshed Cara Cara orange, as well as in the Clementine mandarin were higher than in the corresponding juices, although individual carotenoids were differentially affected by juice preparation. Bioaccessibility of the bioactive carotenoids (the ones described to be absorbed by humans) was greater in both pulp and juice of the carotenoid-rich Cara Cara orange compared to the Navel orange while increasing levels of β-cryptoxanthin were detected in the bioaccessible fractions of pulp and juice of mandarins postharvest stored at 12 °C compared to freshly-harvested fruits. Overall, results indicated that higher soluble bioactive carotenoids from citrus fruits and, consequently, potential nutritional and health benefits are obtained by the consumption of pulp with respect to fresh juice.


The metabolic interface between Pseudomonas syringae and plant cells.
The bacterial plant pathogen Pseudomonas syringae causes economically important diseases of a wide variety of plant species and is used as a model organism to understand the molecular basis of plant disease. Much existing research into P. syringae-plant interactions has focused on the molecular basis of plant disease resistance and the role of secreted effector proteins in the suppression of plant defences. However, researchers have speculated that the diverse array of effectors, toxins and hormones produced by this pathogen also play an important role in manipulating plant metabolism to promote infection. Recent advances in metabolomics, genomics, transcriptomics and metabolic modelling offer new opportunities to address this question and generate a system-level understanding of metabolic interactions at the host-pathogen interface.


Beyond sensory images: Object-based representation in the human ventral pathway.
We investigated whether the topographically organized, category-related patterns of neural response in the ventral visual pathway are a representation of sensory images or a more abstract representation of object form that is not dependent on sensory modality. We used functional MRI to measure patterns of response evoked during visual and tactile recognition of faces and manmade objects in sighted subjects and during tactile recognition in blind subjects. Results showed that visual and tactile recognition evoked category-related patterns of response in a ventral extrastriate visual area in the inferior temporal gyrus that were correlated across modality for manmade objects. Blind subjects also demonstrated category-related patterns of response in this "visual" area, and in more ventral cortical regions in the fusiform gyrus, indicating that these patterns are not due to visual imagery and, furthermore, that visual experience is not necessary for category-related representations to develop in these cortices. These results demonstrate that the representation of objects in the ventral visual pathway is not simply a representation of visual images but, rather, is a representation of more abstract features of object form.


Sports and games for post-traumatic stress disorder (PTSD).
Traumatic experiences evoke emotions such as fear, anxiety and distress and may encourage avoidance of similar situations in the future. For a proportion of those exposed to a traumatic event, this emotional reaction becomes uncontrollable and can develop into Post Traumatic Stress Disorder (PTSD) (Breslau 2001). Most of those diagnosed with PTSD fully recover while a small proportion develop a chronic PTSD a year after the event (First 2004). Sports and games may be able to alleviate symptoms of PTSD. 1. To assess the effectiveness of sports, and games in alleviating and/or diminishing the symptoms of PTSD when compared to usual care or other interventions. 2. To assess the effectiveness of different types of sports and games in alleviating and/or diminishing symptoms of PTSD. The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDAN-CTR) were searched up to June 2008.The following databases were searched up to June 2008: the Cochrane Central registry of Controlled Trials; MEDLINE; EMBASE; CINAHL; PsycINFO. Reference lists of relevant papers were searched and experts in the field were contacted to determine if other studies were available. To be included, participants had to be diagnosed with PTSD using criteria outlined in the Diagnostic and Statistical Manual for Mental Disorders (DSM IV) and/or ICD criteria. Randomised controlled trials (RCTs) that considered one or more well-specified sports or games for alleviating and/or diminishing symptoms of PTSD were included.Sports, and games were defined as any organized physical activity done alone or with a group and non-physical activities such as computer games and card games done alone or with a group. Psychological interventions such as music therapy, art therapy and play therapy and behavioural therapy were excluded. Two reviewers (SL and MD) separately checked the titles and abstracts of the search results to determine which studies met the pre-determined inclusion criteria. A flow chart was used to guide the selection process. No studies met the inclusion criteria. The search strategy identified five papers but none of the studies met inclusion criteria. No studies met the inclusion criteria. More research is therefore required before a fair assessment can be made of the effectiveness of sports and games in alleviating symptoms of PTSD.


Neural stem cells: brain building blocks and beyond.
Neural stem cells are the origins of neurons and glia and generate all the differentiated neural cells of the mammalian central nervous system via the formation of intermediate precursors. Although less frequent, neural stem cells persevere in the postnatal brain where they generate neurons and glia. Adult neurogenesis occurs throughout life in a few limited brain regions. Regulation of neural stem cell number during central nervous system development and in adult life is associated with rigorous control. Failure in this regulation may lead to e.g. brain malformation, impaired learning and memory, or tumor development. Signaling pathways that are perturbed in glioma are the same that are important for neural stem cell self-renewal, differentiation, survival, and migration. The heterogeneity of human gliomas has impeded efficient treatment, but detailed molecular characterization together with novel stem cell-like glioma cell models that reflect the original tumor gives opportunities for research into new therapies. The observation that neural stem cells can be isolated and expanded in vitro has opened new avenues for medical research, with the hope that they could be used to compensate the loss of cells that features in several severe neurological diseases. Multipotent neural stem cells can be isolated from the embryonic and adult brain and maintained in culture in a defined medium. In addition, neural stem cells can be derived from embryonic stem cells and induced pluripotent stem cells by in vitro differentiation, thus adding to available models to study stem cells in health and disease.


How different is cancer control across Canada? Comparing performance indicators for prevention, screening, diagnosis, and treatment.
Meaningful performance measures are an important part of the toolkit for health system improvement. The Canadian Partnership Against Cancer has been reporting on pan-Canadian cancer system performance indicators since 2009-work that has led to the availability of standardized measures that can help to shed light on the extent of variation and opportunities for quality improvement across the country. Those measures include a core set of system indicators ranging from prevention and screening, through diagnosis and treatment, to survivorship and end-of-life care. Key indicators were calculated and graphed, showing the range from worst to best result for the provinces and territories included in the data. There were often significant differences in cancer system performance between provinces and territories. For example, smoking prevalence rates ranged from 14% to 62%. The 90th percentile wait times from an abnormal breast screen to resolution (without biopsy) ranged from 4 weeks to 8 weeks. The percentage of breast cancer resections that used breast-conserving surgery rather than mastectomy ranged from 38% to 75%. Clinical trial participation rates for adults ranged from 0.2% to 6.6%. Variations in performance indicators between Canadian jurisdictions suggest potential differences in the planning and delivery of cancer control services and in clinical practice patterns and patient outcomes. Understanding sources of variation can help to identify opportunities for improvements in the quality and outcomes of cancer control service delivery in each province and territory.


Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase.
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.


UV-B radiation arising from stratospheric ozone depletion influences the pigmentation of the Antarctic moss Andreaea regularis.
Changes to the radiative environment arising from stratospheric ozone (O(3)) depletion and subsequent associations between these changes and the pigmentation of the moss Andreaea regularis were measured in late austral spring and early summer 1998 at Rothera Point on the western Antarctic Peninsula (67 degrees S, 68 degrees W). A strong relationship between O(3) column depth and the ratio of UV-B to PAR irradiance ( F(uv-b)/ F(par)) was recorded at ground level ( r(2)=92%, P<0.001). Weaker, but significant, associations between O(3) column depth and ground level unweighted and biologically effective UV-B radiation (UV-B(be)) were also found. Regression analyses indicated that F(uv-b)/ F(par) was the best predictor for concentrations of UV-B screening pigments and total carotenoids extracted from plant tissues. Concentrations of these pigments were loosely ( r(2)= ca. 30%) but significantly ( P<0.01) positively associated with F(uv-b)/ F(par). Concentrations of UV-B screening pigments were also positively associated with irradiances and daily doses of unweighted UV-B and UV-B(be) radiation. The concentrations of chlorophylls a and b were apparently unaffected by O(3) depletion. The data derived from this study suggest that changes to the radiative environment associated with stratospheric O(3) depletion influence the pigmentation of A. regularis. As a corollary, flavonoids are shown to be present in tissues of A. regularis.


Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors.
Mitochondrial DNA (mtDNA) mutations scattered through coding and noncoding regions have been reported in cancer. The mechanisms that generate such mutations and the importance of mtDNA mutations in tumor development are still not clear. Here we present the identification of a specific and highly polymorphic homopolymeric C stretch (D310), located within the displacement (D) loop, as a mutational hotspot in primary tumors. Twenty-two % of the 247 primary tumors analyzed harbored somatic deletions/insertions at this mononucleotide repeat. Moreover, these alterations were also present in head and neck preneoplastic lesions. We further characterized the D310 variants that appeared in the lung and head and neck tumors. Most of the somatic alterations found in tumors showed deletion/insertions of 1- or 2-bp generating D310 variants identical to constitutive polymorphisms described previously. Sequencing analysis of individual clones from lymphocytes revealed that patients with D310 mutations in the tumors had statistically significant higher levels of D310 heteroplasmy (more than one length variant) in the lymphocyte mtDNA as compared with the patients without D310 mutations in the tumor mtDNA. On the basis of our observations, we propose a model in which D310 alterations are already present in normal cells and achieve homoplasmy in the tumor through a restriction/amplification event attributable to random genetic drift and clonal expansion.


Closed subarachnoid drainage for management of cerebrospinal fluid leakage after an operation on the spine.
A retrospective review was conducted to assess the effectiveness and safety of a temporary subarachnoid shunt to treat patients who have a leak of cerebrospinal fluid after a spinal operation. The shunt is percutaneously inserted in the lumbar spine and is removed after four days. This technique was used in nineteen patients over a ten-year period. Of the seventeen patients who had the shunt in place for the full four days, fourteen had resolution of the drainage of cerebrospinal fluid from the wound. One of two patients whose shunt was removed early also had a successful result. Eleven of the fifteen patients who were successfully treated were available for follow-up, and none had any adverse effects related to the original cerebrospinal-fluid leak or its treatment. The four patients who had a persistent leak were successfully treated with reoperation and direct repair of the dura. Eleven (58 per cent) of the nineteen patients had transient complaints of nausea and vomiting while being treated with subarachnoid drainage. Two of the nineteen patients had evidence of an intradural infection after placement of the catheter; the infection resolved in both patients after removal of the catheter and treatment with appropriate antibiotics. Closed subarachnoid drainage, when properly performed and monitored, is a reasonably effective and safe method for treating dural-cutaneous cerebrospinal-fluid leaks after a spinal operation. It may be considered as a non-operative alternative to the standard procedure of reoperation and direct repair of the dura. A good result is still possible in patients in whom this technique fails and who eventually need surgical management.


Interaction between GATA and the C/EBP family of transcription factors is critical in GATA-mediated suppression of adipocyte differentiation.
We have previously demonstrated that GATA-2 and GATA-3 are expressed in adipocyte precursors and control the preadipocyte-to-adipocyte transition. Constitutive expression of both GATA-2 and GATA-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (PPARgamma) promoter and suppression of its basal activity. In the present study, we demonstrate that both GATA-2 and GATA-3 form protein complexes with CCAAT/enhancer binding protein alpha (C/EBPalpha) and C/EBPbeta, members of a family of transcription factors that are integral to adipogenesis. We mapped this interaction to the basic leucine zipper domain of C/EBPalpha and a region adjacent to the carboxyl zinc finger of GATA-2. The interaction between GATA and C/EBP factors is critical for the ability of GATA to suppress adipocyte differentiation. Thus, these results show that in addition to its previously recognized function in suppressing PPARgamma transcriptional activity, interaction of GATA factors with C/EBP is necessary for their ability to negatively regulate adipogenesis.


Paraxial and nonparaxial polynomial beams and the analytic approach to propagation.
We construct solutions of the paraxial and Helmholtz equations that are polynomials in their spatial variables. These are derived explicitly by using the angular spectrum method and generating functions. Paraxial polynomials have the form of homogeneous Hermite and Laguerre polynomials in Cartesian and cylindrical coordinates, respectively, analogous to heat polynomials for the diffusion equation. Nonparaxial polynomials are found by substituting monomials in the propagation variable z with reverse Bessel polynomials. These explicit analytic forms give insight into the mathematical structure of paraxially and nonparaxially propagating beams, especially in regard to the divergence of nonparaxial analogs to familiar paraxial beams.


Experimental analysis of sperm competition mechanisms in a wild bird population.
Recent work on wild birds has revealed the importance of sperm competition as a source of sexual selection, but behavioral and paternity studies have previously provided only indirect evidence for mechanisms of sperm competition in wild birds. In a field study of collared flycatchers Ficedula albicollis we used a previously uncharacterized method to determine the frequency and timing of extra-pair inseminations. By counting the number of sperm trapped on the perivitelline layer of eggs, we determined the timing of inseminations and estimated, on a day-to-day basis, the amount of sperm females stored. Our results showed that female collared flycatchers preferentially engaged in extra-pair copulations when mated to an unattractive male with a small white forehead patch. These copulations were timed for the middle part of their fertile period, at least 2 days after the last within-pair insemination. Although the mean number of extra-pair insemination events was only 1.33 per cuckolding female, the ratio between the number of sperm from extra-pair and pair inseminations was at least 5 to 1. Thus a single, well timed extra-pair insemination caused by female behavior could greatly bias fertilization probability in favor of an attractive extra-pair male. Our results suggest a possible behavioral mechanism for female control of sperm competition.


Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.
Interferon lambda 1 (IFN-lambda1) is a type III IFN that produces intracellular responses similar to those of IFN-alpha but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-lambda) at 1.5 or 3.0 microg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-alpha-based treatment. Part 2 evaluated weekly doses of PEG-IFN-lambda ranging from 0.5 to 2.25 microg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-lambda at 1.5 microg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-lambda dose levels (from 0.5 to 3.0 microg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-lambda. Most DLT occurred in patients with high PEG-IFN-lambda exposure. Weekly PEG-IFN-lambda with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV.


Acute exercise activates AMPK and eNOS in the mouse aorta.
Exercise can prevent endothelial cell (EC) dysfunction and atherosclerosis even in the absence of improvements in plasma lipids. However, the mechanisms responsible for these effects are incompletely understood. In this study we examined in mice whether an acute bout of exercise activates enzymes that could prevent EC dysfunction, such as AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). We also examined whether exercise alters known regulators of these enzymes. C57BL/6 mice underwent a single bout of exhaustive treadmill exercise after which their aortas were analyzed for activation of AMPK, AMPK regulatory proteins, eNOS, and various enzymes that, like AMPK, activate eNOS. We found that such exercise acutely activates both AMPK and eNOS in the whole aorta and that the magnitude of these effects correlated with both the distance run and activation of the AMPK regulatory proteins silent information regulator-1 (SIRT1)-LKB1 and CaMKKβ. In contrast, Akt, PKA, PKG, and Src, other kinases known to activate eNOS, were unaffected. Immunohistochemical analysis revealed that AMPK and eNOS were both activated in the ECs of the aorta. This study provides the first evidence that an acute bout of exercise activates AMPK and eNOS in the endothelium of the aorta. The results also suggest that AMPK likely is the principal activator of eNOS in this setting and that its own activation may be mediated by both SIRT1-LKB1 and CaMKKβ.


Effect of self-triage on waiting times at a walk-in sexual health clinic.
Lengthy waiting times can be a major problem in walk-in sexual health clinics. They are stressful for both patients and staff and may lead to clients with significant health issues leaving the department before being seen by a clinician. A self-triage system may help reduce waiting times and duplication of work, improve patient pathways and decrease wasted visits. This paper describes implementation of a self-triage system in two busy sexual and reproductive health clinics. Patients were asked to complete a self-assessment form on registration to determine the reason for attendance. This then enabled patients to be directed to the most appropriate specialist or clinical service. The benefits of this approach were determined by measuring patient waiting times, reduction in unnecessary specialist review together with patient acceptability as tested by a patient satisfaction survey. The ease of comprehension of the triage form was also assessed by an independent readers' panel. A total of 193 patients were recruited over a 4-month period from November 2004 to February 2005. Patients from the November and December clinics were assigned to the 'traditional treatment' arm, with patients at subsequent clinics being assigned to the 'self-triage' system. Waiting times were collected by the receptionist and clinic staff. Ninety six patients followed the traditional route, 97 the new self-triage system. Sixty-nine (35.8%) patients completed the satisfaction survey. The self-triage system significantly reduced waiting time from 40 (22, 60) to 23 (10, 40) minutes [results expressed as median (interquartile range)]. There was a non-significant reduction in the proportion of patients seeing two clinicians from 21% to 13% (p = 0.17). Satisfaction levels were not significantly altered (95% compared to 97% satisfied, p = 0.64). The readers' panel found the triage form both easy to understand and to complete. Self-triage can effectively reduce clinic waiting times and allow better organisation of resources. Urgent cases can be prioritised. This process appears to be acceptable to and understandable by patients.


Protein profiling reveals inter-individual protein homogeneity of arachnoid cyst fluid and high qualitative similarity to cerebrospinal fluid.
The mechanisms behind formation and filling of intracranial arachnoid cysts (AC) are poorly understood. The aim of this study was to evaluate AC fluid by proteomics to gain further knowledge about ACs. Two goals were set: 1) Comparison of AC fluid from individual patients to determine whether or not temporal AC is a homogenous condition; and 2) Evaluate the protein content of a pool of AC fluid from several patients and qualitatively compare this with published protein lists of cerebrospinal fluid (CSF) and plasma. AC fluid from 15 patients with temporal AC was included in this study. In the AC protein comparison experiment, AC fluid from 14 patients was digested, analyzed by LC-MS/MS using a semi-quantitative label-free approach and the data were compared by principal component analysis (PCA) to gain knowledge of protein homogeneity of AC. In the AC proteome evaluation experiment, AC fluid from 11 patients was pooled, digested, and fractionated by SCX chromatography prior to analysis by LC-MS/MS. Proteins identified were compared to published databases of proteins identified from CSF and plasma. AC fluid proteins not found in these two databases were experimentally searched for in lumbar CSF taken from neurologically-normal patients, by a targeted protein identification approach called MIDAS (Multiple Reaction Monitoring (MRM) initiated detection and sequence analysis). We did not identify systematic trends or grouping of data in the AC protein comparison experiment, implying low variability between individual proteomic profiles of AC.In the AC proteome evaluation experiment, we identified 199 proteins. When compared to previously published lists of proteins identified from CSF and plasma, 15 of the AC proteins had not been reported in either of these datasets. By a targeted protein identification approach, we identified 11 of these 15 proteins in pooled CSF from neurologically-normal patients, demonstrating that the majority of abundant proteins in AC fluid also can be found in CSF. Compared to plasma, as many as 104 proteins in AC were not found in the list of 3017 plasma proteins. Based on the protein content of AC fluid, our data indicate that temporal AC is a homogenous condition, pointing towards a similar AC filling mechanism for the 14 patients examined. Most of the proteins identified in AC fluid have been identified in CSF, indicating high similarity in the qualitative protein content of AC to CSF, whereas this was not the case between AC and plasma. This indicates that AC is filled with a liquid similar to CSF. As far as we know, this is the first proteomics study that explores the AC fluid proteome.


Genetic Architecture of Flowering-Time Variation in Brachypodium distachyon.
The transition to reproductive development is a crucial step in the plant life cycle, and the timing of this transition is an important factor in crop yields. Here, we report new insights into the genetic control of natural variation in flowering time in Brachypodium distachyon, a nondomesticated pooid grass closely related to cereals such as wheat (Triticum spp.) and barley (Hordeum vulgare L.). A recombinant inbred line population derived from a cross between the rapid-flowering accession Bd21 and the delayed-flowering accession Bd1-1 were grown in a variety of environmental conditions to enable exploration of the genetic architecture of flowering time. A genotyping-by-sequencing approach was used to develop SNP markers for genetic map construction, and quantitative trait loci (QTLs) that control differences in flowering time were identified. Many of the flowering-time QTLs are detected across a range of photoperiod and vernalization conditions, suggesting that the genetic control of flowering within this population is robust. The two major QTLs identified in undomesticated B. distachyon colocalize with VERNALIZATION1/PHYTOCHROME C and VERNALIZATION2, loci identified as flowering regulators in the domesticated crops wheat and barley. This suggests that variation in flowering time is controlled in part by a set of genes broadly conserved within pooid grasses.


Extremely nondegenerate two-photon absorption in direct-gap semiconductors [Invited].
Two-photon absorption (2PA) spectra with pairs of extremely nondegenerate photons are measured in several direct-gap semiconductors (GaAs, CdTe, ZnO, ZnS and ZnSe) using picosecond or femtosecond pulses. In ZnSe, using photons with a ratio of energies of ~12, we obtain a 270-fold enhancement of 2PA when comparing to the corresponding degenerate 2PA coefficient at the average photon energy (ηω1 + ηω2)/2. This corresponds to a pump photon energy of 8% of the bandgap. 2PA coefficients as large as 1 cm/MW are measured. Thus, by using two widely different wavelengths we are able to access the large 2PA observed previously only in narrow gap semiconductors. We also calculate the corresponding enhancement of nonlinear refraction, consisting of two-photon, AC-Stark and Raman contributions. The net effect is a smaller enhancement, but exhibits very large dispersion within the 2PA regime.


Direct evidence of milk consumption from ancient human dental calculus.
Milk is a major food of global economic importance, and its consumption is regarded as a classic example of gene-culture evolution. Humans have exploited animal milk as a food resource for at least 8500 years, but the origins, spread, and scale of dairying remain poorly understood. Indirect lines of evidence, such as lipid isotopic ratios of pottery residues, faunal mortality profiles, and lactase persistence allele frequencies, provide a partial picture of this process; however, in order to understand how, where, and when humans consumed milk products, it is necessary to link evidence of consumption directly to individuals and their dairy livestock. Here we report the first direct evidence of milk consumption, the whey protein β-lactoglobulin (BLG), preserved in human dental calculus from the Bronze Age (ca. 3000 BCE) to the present day. Using protein tandem mass spectrometry, we demonstrate that BLG is a species-specific biomarker of dairy consumption, and we identify individuals consuming cattle, sheep, and goat milk products in the archaeological record. We then apply this method to human dental calculus from Greenland's medieval Norse colonies, and report a decline of this biomarker leading up to the abandonment of the Norse Greenland colonies in the 15(th) century CE.


Admixture facilitates genetic adaptations to high altitude in Tibet.
Admixture is recognized as a widespread feature of human populations, renewing interest in the possibility that genetic exchange can facilitate adaptations to new environments. Studies of Tibetans revealed candidates for high-altitude adaptations in the EGLN1 and EPAS1 genes, associated with lower haemoglobin concentration. However, the history of these variants or that of Tibetans remains poorly understood. Here we analyse genotype data for the Nepalese Sherpa, and find that Tibetans are a mixture of ancestral populations related to the Sherpa and Han Chinese. EGLN1 and EPAS1 genes show a striking enrichment of high-altitude ancestry in the Tibetan genome, indicating that migrants from low altitude acquired adaptive alleles from the highlanders. Accordingly, the Sherpa and Tibetans share adaptive haemoglobin traits. This admixture-mediated adaptation shares important features with adaptive introgression. Therefore, we identify a novel mechanism, beyond selection on new mutations or on standing variation, through which populations can adapt to local environments.


Patterns of selection in anti-malarial immune genes in malaria vectors: evidence for adaptive evolution in LRIM1 in Anopheles arabiensis.
Co-evolution between Plasmodium species and its vectors may result in adaptive changes in genes that are crucial components of the vector's defense against the pathogen. By analyzing which genes show evidence of positive selection in malaria vectors, but not in closely related non-vectors, we can identify genes that are crucial for the mosquito's resistance against Plasmodium. We investigated genetic variation of three anti-malarial genes; CEC1, GNBP-B1 and LRIM1, in both vector and non-vector species of the Anopheles gambiae complex. Whereas little protein differentiation was observed between species in CEC1 and GNBP-B1, McDonald-Kreitman and maximum likelihood tests of positive selection show that LRIM1 underwent adaptive evolution in a primary malaria vector; An. arabiensis. In particular, two adjacent codons show clear signs of adaptation by having accumulated three out of four replacement substitutions. Furthermore, our data indicate that this LRIM1 allele has introgressed from An. arabiensis into the other main malaria vector An. gambiae. Although no evidence exists to link the adaptation of LRIM1 to P. falciparum infection, an adaptive response of a known anti-malarial gene in a primary malaria vector is intriguing, and may suggest that this gene could play a role in Plasmodium resistance in An. arabiensis. If so, our data also predicts that LRIM1 alleles in An. gambiae vary in their level of resistance against P. falciparum.


High-power wavelength converters with feedback.
We have shown theoretically and experimentally that very high conversion efficiencies can be obtained in high-peak-power wavelength converters utilizing small amounts of feedback, at fluences similar to the no-feedback case. Maximum efficiencies are obtained with radially varying reflectivity profiles. We have demonstrated the concept, using second-harmonic generation in a deuterated potassium dihydrogen phosphate crystal in which 70% energy conversion was obtained, in agreement with simulation results. Energy conversion efficiencies of 56% were also obtained in a beta-barium borate optical parametric oscillator.


Occurrence and risk assessment of an azo dye - The case of Disperse Red 1.
Water quality criteria to protect aquatic life are not available for most disperse dyes which are often used as commercial mixtures in textile coloration. In this study, the acute and chronic toxicity of the commercial dye Disperse Red 1 (DR1) to eight aquatic organisms from four trophic levels was evaluated. A safety threshold, i.e. Predicted No-Effect Concentration (PNEC), was derived based on the toxicity information of the commercial product and the purified dye. This approach was possible because the toxicity of DR1 was accounting for most of the toxicity of the commercial mixture. A long-term PNEC of 60 ng L(-1) was proposed, based on the most sensitive chronic endpoint for Daphnia similis. A short-term PNEC of 1800 ng L(-1) was proposed based on the most sensitive acute endpoint also for Daphnia similis. Both key studies have been evaluated with the new "Criteria for Reporting and Evaluating ecotoxicity Data" (CRED) methodology, applying more objective criteria to assess the quality of toxicity tests, resulting in two reliable and relevant endpoints with only minor restrictions. HPLC-MS/MS was used to quantify the occurrence of DR1 in river waters of three sites, influenced by textile industry discharges, resulting in a concentration range of 50-500 ng L(-1). The risk quotients for DR1 obtained in this work suggest that this dye can pose a potential risk to freshwater biota. To reduce uncertainty of the derived PNEC, a fish partial or full lifecycle study should be performed.


Molecular Approaches for High Throughput Detection and Quantification of Genetically Modified Crops: A Review.
As long as the genetically modified crops are gaining attention globally, their proper approval and commercialization need accurate and reliable diagnostic methods for the transgenic content. These diagnostic techniques are mainly divided into two major groups, i.e., identification of transgenic (1) DNA and (2) proteins from GMOs and their products. Conventional methods such as PCR (polymerase chain reaction) and enzyme-linked immunosorbent assay (ELISA) were routinely employed for DNA and protein based quantification respectively. Although, these Techniques (PCR and ELISA) are considered as significantly convenient and productive, but there is need for more advance technologies that allow for high throughput detection and the quantification of GM event as the production of more complex GMO is increasing day by day. Therefore, recent approaches like microarray, capillary gel electrophoresis, digital PCR and next generation sequencing are more promising due to their accuracy and precise detection of transgenic contents. The present article is a brief comparative study of all such detection techniques on the basis of their advent, feasibility, accuracy, and cost effectiveness. However, these emerging technologies have a lot to do with detection of a specific event, contamination of different events and determination of fusion as well as stacked gene protein are the critical issues to be addressed in future.


Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part II: Effect on bone mineral density of the femur.
Ukrain, an acid alkaloid derivative of Chelidonium majus L., was administered intraperitoneally to ovariectomized and control sexually mature female rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by 10-day break. This procedure was repeated five times. At the end of the Ukrain treatment (24 h after the last dose of the drug) the right femora of the rats were harvested and the bone densitometric parameters of the whole bone and distal metaphysial and intertrochanteric subregions were assessed using the dual energy x-ray absorptiometry densitometric method. The results showed no apparent decrease in bone mineral density in groups of rats studied. A nearly significant (p = 0.08) decrease of bone mineral content was observed in ovariectomized rats treated with 14 mg/kg of Ukrain.


One-stage resection and anastomosis in the management of colovesical fistula.
Thirty-four patients with colovesical fistulas seen over a recent 10 year period were reviewed. Diverticulitis was the most common cause of colovesical fistula, accounting for 71 percent of patients in our series. The majority of patients present electively, and most have urinary tract complaints. In those patients in our study who presented with systemic infection, urinary obstruction was present in 70 percent. Although proctosigmoidoscopy and barium enema examination are essential in the preoperative assessment, cystoscopy is the most useful test in suggesting or confirming the diagnosis of colovesical fistula. Intravenous urography is not necessary in the evaluation of these patients. The surgical treatment depends on the cause of the fistula. For patients with an inflammatory cause of the fistula, one-stage operative treatment is associated with low morbidity and decreased length of stay compared with operative treatment in more than one stage. In the presence of severe inflammation or inadequate bowel preparation, two-stage operative treatment is safe and effective. Operations in three stages for colovesical fistula are not indicated. The primary objectives in the management of colovesical fistulas due to unresectable malignancy are relief of intestinal and urinary obstruction and fecal diversion. Resection of the malignancy should be performed whenever possible.


Woodchuck dendritic cells generated from peripheral blood mononuclear cells and transduced with recombinant human adenovirus serotype 5 induce antigen-specific cellular immune responses.
Woodchucks infected with the woodchuck hepatitis virus (WHV) is the best available animal model for testing the immunotherapeutic effects of dendritic cells (DCs) in the setting of a chronic infection, as woodchucks develop a persistent infection resembling that seen in humans infected with the hepatitis B virus. In the present study, DCs were generated from woodchuck peripheral blood mononuclear cells (wDCs) in the presence of human granulocyte macrophage colony-stimulating factor (hGM-CSF) and human interleukin 4 (hIL-4). After 7 days of culture, cells with morphology similar to DCs were stained positively with a cross-reactive anti-human CD86 antibody. Functional analysis showed that uptake of FITC-dextran by wDCs was very efficient and was partially inhibited after LPS-induced maturation. Furthermore, wDCs stimulated allogenic lymphocytes and induced proliferation. Moreover, wDCs were transduced efficiently with a human adenovirus serotype 5 for the expression of beta-galactosidase. Following transduction and in vivo administration of such DCs into woodchucks, an antigen-specific cellular immune response was induced. These results demonstrate that wDCs can be generated from the peripheral blood. Following transfection with a recombinant adenovirus wDCs can be used as a feasible and effective tool for eliciting WHV-specific T-cell responses indicating their potential to serve as prophylactic and therapeutic vaccines.


Sonic hedgehog multimerization: a self-organizing event driven by post-translational modifications?
Sonic hedgehog (Shh) is a morphogen active during vertebrate development and tissue homeostasis in adulthood. Dysregulation of the Shh signalling pathway is known to incite carcinogenesis. Due to the highly lipophilic nature of this protein imparted by two post-translational modifications, Shh's method of transit through the aqueous extracellular milieu has been a long-standing conundrum, prompting the proposition of numerous hypotheses to explain the manner of its displacement from the surface of the producing cell. Detection of high molecular-weight complexes of Shh in the intercellular environment has indicated that the protein achieves this by accumulating into multimeric structures prior to release from producing cells. The mechanism of assembly of the multimers, however, has hitherto remained mysterious and contentious. Here, with the aid of high-resolution optical imaging and post-translational modification mutants of Shh, we show that the C-terminal cholesterol and the N-terminal palmitate adducts contribute to the assembly of large multimers and regulate their shape. Moreover, we show that small Shh multimers are produced in the absence of any lipid modifications. Based on an assessment of the distribution of various dimensional characteristics of individual Shh clusters, in parallel with deductions about the kinetics of release of the protein from the producing cells, we conclude that multimerization is driven by self-assembly underpinned by the law of mass action. We speculate that the lipid modifications augment the size of the multimolecular complexes through prolonging their association with the exoplasmic membrane.


Spontaneous Opiate Addiction in Rhesus Monkeys.
Spontaneous drug-seeking behavior was established in 3 out of 4 rhesus monkeys that were given unrestricted access to morphine and placebo solutions. The monkeys were kept in their home cages throughout the experiment and were not subjected to conditions of stress; prior addiction was not established by the usual injection procedures. The animals became physically dependent on the drug and showed abstinence symptoms when injected intramuscularly with nalorphine (N-allyl normorphine hydrochloride). This method may be useful for studying individual differences in susceptibility to drug abuse.


Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells.
The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway. Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance. We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis. Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis. Consistent with an ER stress-induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2α (which would be expected to inhibit protein synthesis), and induced the expression of ER stress-related genes. Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis. Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo. In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis. Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance.


Signaling pathways for tumor necrosis factor-alpha and interleukin-6 expression in human macrophages exposed to titanium-alloy particulate debris in vitro.
Loosening of the implant after total joint arthroplasty remains a serious problem. The activation of macrophages by wear debris from implants, mediated by the release of cytokines that elicit bone resorption, may lead to loosening. The purpose of the present study was to elucidate the mechanisms of macrophage activation by titanium particles from the components of implants and to identify the signaling pathways involved in particle-mediated release of cytokines. Macrophages were isolated from mononuclear leukocytes obtained from healthy human donors and were exposed to titanium-alloy particles that had been obtained from periprosthetic membranes collected at revision total joint arthroplasties and then enzymatically prepared. The experimental protocols included examination of the effects of the inhibition of phagocytosis and the binding of antibodies to macrophage complement receptors on particle-induced macrophage activation. The release of the proinflammatory cytokines TNF-alpha (tumor necrosis factor-alpha) and IL-6 (interleukin-6) was used to assess macrophage activation. The signaling pathways involved in the induction of cytokine release were analyzed by identification of phosphorylated proteins with use of the Western blot technique and by translocation of the transcription factors nuclear factor-kappa B (NF-kappaB) and nuclear factor-interleukin-6 (NF-IL-6) into the nuclear protein fraction with use of electrophoretic mobility shift assays. The role of serine/threonine and tyrosine kinase pathways in the activation of nuclear factors and the release of cytokines was examined with use of selective pharmacological agents. Exposure of macrophages to titanium-alloy particles in vitro for forty-eight hours resulted in a fortyfold increase in the release of TNF-alpha and a sevenfold increase in the release of IL-6 (p<0.01). Phagocytosis of particles occurred in approximately 73 percent of the macrophages within one hour of exposure. Pretreatment of the macrophages with cytochalasin B reduced phagocytosis by 95 percent but did not reduce the release of TNF-alpha or IL-6. Thus, phagocytosis of particles was not necessary for induction of the release of TNF-alpha or IL-6 in the cultured macrophages. Ligation of the macrophage CD11b/CD18 receptors by integrin-specific antibodies also increased the release of TNF-alpha and IL-6. Antibodies to CD11b/ CD18 receptors (macrophage Mac-1 receptors) reduced phagocytosis of particles by 50 percent (p<0.05). (The CD11b/CD18 macrophage receptor is the macrophage receptor for the complement component CR3bi. The CD11b/CD18 macrophage receptor can also bind to ICAM-1 and ICAM-2. CD is the abbreviation for cluster of differentiation, and ICAM is the abbreviation for intercellular adhesion molecule.) Inhibition of phagocytosis was not accompanied by a decrease in the release of TNF-alpha and IL-6. Blocking RNA synthesis with actinomycin D or preventing protein synthesis with cycloheximide abolished or decreased particle-induced release of TNF-alpha and IL-6 from the macrophages. Macrophage release of TNF-alpha and IL-6 in response to particles coincided with increased tyrosine phosphorylation and mitogen-activated protein kinase activation. Inhibition of tyrosine and serine/threonine kinase activity decreased the particle-induced release of cytokines. Exposure of macrophages to either titanium-alloy particles or to antibodies to the receptor proteins CD11b and CD18 for thirty minutes activated the transcription factors NF-kappaB and NF-IL-6. Inhibition of particle phagocytosis did not block activation of the transcription factors. However, inhibition of tyrosine and serine/threonine kinase activity decreased the activation of NF-kappaB and NF-IL-6. These data suggest that particle induced macrophage release of TNF-alpha and IL-6 does not require phagocytosis but is dependent on tyrosine and serine/threonine kinase activity culminating in activation of


A Randomized Controlled Trial of Emotion Regulation Therapy for Psychologically Distressed Caregivers of Cancer Patients.
Previous cognitive behavioral therapies for informal caregivers (ICs) have produced negligible effects. The purpose of this study was to evaluate, in a randomized controlled trial, the efficacy of Emotion Regulation Therapy adapted for caregivers (ERT-C) on psychological and inflammatory outcomes in psychologically distressed ICs and the cancer patients cared for. A total of 81 ICs with elevated psychological distress were randomly assigned to ERT-C or a waitlist condition and assessed pre-, mid-, and post-treatment. In 52 cases, the patient cared for by the IC was included. Patients did not receive ERT-C. Both the ERT-C and waitlist groups were followed 3 and 6 months post-treatment. Data were analyzed with multilevel models, and P values were two-sided. Compared with ICs in the waitlist condition, ICs in the ERT-C condition experienced medium to large statistically significant reductions in psychological distress (Hedge's g = 0.86, 95% confidence interval [CI] = 0.40 to 1.32, P < .001), worry (g = 0.96, 95% CI = 0.50 to 1.42, P < .001), and caregiver burden (g = 0.53, 95% CI = 0.10 to 1.99, P = .007) post-treatment. No statistically significant effects were found for rumination (g = 0.24, 95% CI = -0.20 to 0.68, P = .220). Results concerning caregiver burden were maintained through 6 months follow-up. Although the effects on psychological distress and worry diminished, their end-point effects remained medium to large. No statistically significant effects on systemic inflammation were detected (C-reactive protein: g = .17, 95% CI = -0.27 to 0.61, P = .570; interleukin-6: g = .35, 95% CI = -0.09 to 0.79, P = .205; tumor necrosis factor-alpha: g = .11, 95% CI = -0.33 to 0.55, P = .686). Patients whose ICs attended ERT-C experienced a large increase in quality of life post-treatment (g = 0.88, 95% CI = 0.18 to 1.58, P = .017). To our knowledge, this is the first randomized controlled trial evaluating the efficacy of ERT-C for ICs. Given the previous disappointing effects of other cognitive behavioral therapies for this population, the present findings are very encouraging. Identifying ICs with elevated psychological distress and providing them with relevant psychotherapy appears an important element of comprehensive cancer care.


Hepatic ABC transporters and triglyceride metabolism.
Elevated plasma triglyceride and reduced HDL concentrations are prominent features of metabolic syndrome and type 2 diabetes. Individuals with Tangier disease also have elevated plasma triglyceride concentrations and very low HDL, resulting from mutations in ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein that facilitates nascent HDL particle assembly. Past studies attributed the inverse relationship between plasma HDL and triglyceride to intravascular lipid exchange and catabolic events. However, recent studies also suggest that hepatic signaling and lipid mobilization and secretion may explain how HDL affects plasma triglyceride concentrations. Hepatocyte-specific ABCA1 knockout mice have markedly reduced plasma HDL and a two-fold increase in triglyceride due to failure to assemble nascent HDL particles by hepatocytes, causing increased catabolism of HDL apolipoprotein A-I and increased hepatic production of triglyceride-enriched VLDL. In-vitro studies suggest that nascent HDL particles may induce signaling to decrease triglyceride secretion. Inhibition of microRNA 33 expression in nonhuman primates augments hepatic ABCA1, genes involved in fatty acid oxidation, and decreases expression of lipogenic genes, causing increased plasma HDL and decreased triglyceride levels. New evidence suggests potential mechanisms by which hepatic ABCA1-mediated nascent HDL formation regulates VLDL-triglyceride production and contributes to the inverse relationship between plasma HDL and triglyceride.


3D self-assembly of ultrafine molybdenum carbide confined in N-doped carbon nanosheets for efficient hydrogen production.
Electrochemical water splitting has been intensively pursued as a promising approach to produce clean and sustainable hydrogen fuel. However, the lack of low-cost and high-performance electrocatalysts for the hydrogen evolution reaction (HER) hinders the large-scale application. Herein, we have rationally designed and synthesized 3D self-assembly architectures assembled from ultrafine MoC nanoparticles (0D) uniformly embedded within N-doped carbon nanosheets (2D) for the HER via a simple protocol. The well-organized 3D nanostructures are composed of very small MoC nanocrystallites (<2 nm) and free-stretching conductive carbon nanosheets with high specific surface areas and abundant mesopores, which can expose more active sites and facilitate electron/ion transport pathways. Based on the merits of the composition and configuration, the resultant hierarchical 3D self-assembly architectures exhibit remarkable electrocatalytic performance and stability for the HER.


Evolving Role of Daratumumab: From Backbencher to Frontline Agent.
Approval of daratumumab (DARA), an IgGk1 monoclonal antibody targeting CD38, for the treatment of relapsed/refractory multiple myeloma as monotherapy in November 2015 expanded the therapeutic armamentarium for multiple myeloma. Widespread tissue expression of CD38 combined with potent immunomodulatory activity provides a rationale for the expanding use of DARA and potential new marketing authorizations. Novel combinations of DARA have been built on the basis of preclinical data of synergy and overcoming DARA resistance. Newer delivery strategies have led to the administration of DARA in community settings. Despite a remarkable tolerability profile in elderly myeloma patients, DARA use increases the risk of infections, particularly virus reactivation, requiring close monitoring and/or prophylaxis. We aim to provide an in-depth review of the mechanisms of action, resistance, and synergies of DARA and to highlight its current clinical uses and potential future perspectives. Laboratory issues with the use of DARA and their mitigation strategies are also discussed.


A voxel-based analysis of cerebral perfusion in dementia and depression of old age.
Thirty-nine elderly depressed patients as well as 15 demented patients with Alzheimer's disease and 11 healthy volunteers were imaged at rest with a high resolution single-slice 12-detector head scanner (SME-Neuro 900) and the cerebral perfusion marker 99mTc-Exametazime (HM-PAO). Statistical parametric maps were computed to compare early- and late-onset depressed, Alzheimer patients and healthy volunteers and to examine associations between regional perfusion and clinical and MRI variables. Patients with late-onset depression showed reductions in temporal lobe perfusion compared with early-onset depression and controls. Alzheimer patients had the expected reduced perfusion in temporoparietal and prefontal cortex, as well as basal ganglia, compared with healthy controls. Compared with depressed patients, they showed a relative reduction in temporoparietal cortex, only. This difference was more pronounced between Alzheimer patients and early onset, compared to late-onset patients with depression. Periventricular white matter changes on MRI were associated with temporal lobe reductions of tracer uptake in depression. In the Alzheimer group, deep white matter MRI changes were associated with frontal perfusion deficits. Our results support a vulnerability hypothesis, which predicts that patients with late-onset depression will show more brain changes than patients with an early onset of their illness. Statistical parametric mapping in patients with organic psychiatric brain syndromes is feasible and promising as a clinical and research method.


Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs.
The maintenance of cellular levels of free fatty acids and acyl-CoAs, the activated form of free fatty acids, is extremely important, as imbalances in lipid metabolism have serious consequences for human health. Acyl-coenzyme A (CoA) thioesterases (ACOTs) hydrolyze acyl-CoAs to the free fatty acid and CoASH, and thereby have the potential to regulate intracellular levels of these compounds. We previously identified and characterized a mouse ACOT gene cluster comprised of six genes that apparently arose by gene duplications encoding acyl-CoA thioesterases with localizations in cytosol (ACOT1), mitochondria (ACOT2), and peroxisomes (ACOT3-6). However, the corresponding human gene cluster contains only three genes (ACOT1, ACOT2, and ACOT4) coding for full-length thioesterase proteins, of which only one is peroxisomal (ACOT4). We therefore set out to characterize the human genes, and we show here that the human ACOT4 protein catalyzes the activities of three mouse peroxisomal ACOTs (ACOT3, 4, and 5), being active on succinyl-CoA and medium to long chain acyl-CoAs, while ACOT1 and ACOT2 carry out similar functions to the corresponding mouse genes. These data strongly suggest that the human ACOT4 gene has acquired the functions of three mouse genes by a functional convergent evolution that also provides an explanation for the unexpectedly low number of human genes.


Transient IgA nephropathy with acute kidney injury in a patient with dengue fever.
Dengue virus infection can clinically manifest as dengue fever, dengue shock syndrome and dengue hemorrhagic fever. Acute kidney injury as a result of dengue virus infection can occur due to various reasons including hypotension, rhabdomyolysis, sepsis and rarely immune complex mediated glomerular injury. However, glomerulonephritis associated with IgA Nephropathy in dengue virus infection has not been reported previously. We report a case of 15-year-old boy who was admitted with dengue fever and dialysis dependant acute kidney injury. Urine examination showed microscopic glomerular hematuria and proteinuria. Kidney biopsy showed mesangial proliferation with mesangial IgA dominant immune complex deposits and acute tubular necrosis. A repeated kidney biopsy 6 weeks after clinical recovery showed reversal of glomerular changes as well as resolution of mesangial IgA deposits.