Microtransplantation of cellular membranes from squid stellate ganglion reveals ionotropic GABA receptors.
The squid has been the most studied cephalopod, and it has served as a very useful model for investigating the events associated with nerve impulse generation and synaptic transmission. While the physiology of squid giant axons has been extensively studied, very little is known about the distribution and function of the neurotransmitters and receptors that mediate inhibitory transmission at the synapses. In this study we investigated whether γ-aminobutyric acid (GABA) activates neurotransmitter receptors in stellate ganglia membranes. To overcome the low abundance of GABA-like mRNAs in invertebrates and the low expression of GABA in cephalopods, we used a two-electrode voltage clamp technique to determine if Xenopus laevis oocytes injected with cell membranes from squid stellate ganglia responded to GABA. Using this method, membrane patches containing proteins and ion channels from the squid's stellate ganglion were incorporated into the surface of oocytes. We demonstrated that GABA activates membrane receptors in cellular membranes isolated from squid stellate ganglia. Using the same approach, we were able to record native glutamate-evoked currents. The squid's GABA receptors showed an EC(50) of 98 μmol l(-1) to GABA and were inhibited by zinc (IC(50) = 356 μmol l(-1)). Interestingly, GABA receptors from the squid were only partially blocked by bicuculline. These results indicate that the microtransplantation of native cell membranes is useful to identify and characterize scarce membrane proteins. Moreover, our data also support the role of GABA as an ionotropic neurotransmitter in cephalopods, acting through chloride-permeable membrane receptors.


Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays.
We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23-208) per tumor. LOH and gains averaged 33 (range, 3-83) and 31 (range, 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7-57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0-11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development.


Essential role of membrane cholesterol in accelerated BCR internalization and uncoupling from NF-kappa B in B cell clonal anergy.
Divergent hypotheses exist to explain how signaling by the B cell receptor (BCR) is initiated after antigen binding and how it is qualitatively altered in anergic B cells to selectively uncouple from nuclear factor kappaB and c-Jun N-terminal kinase pathways while continuing to activate extracellular signal-regulated kinase and calcium-nuclear factor of activated T cell pathways. Here we find that BCRs on anergic cells are endocytosed at a very enhanced rate upon binding antigen, resulting in a large steady-state pool of intracellularly sequestered receptors that appear to be continuously cycling between surface and intracellular compartments. This endocytic mechanism is exquisitely sensitive to the lowering of plasma membrane cholesterol by methyl-beta-cyclodextrin, and, when blocked in this way, the sequestered BCRs return to the cell surface and RelA nuclear accumulation is stimulated. In contrast, when plasma membrane cholesterol is lowered and GM1 sphingolipid markers of membrane rafts are depleted in naive B cells, this does not diminish BCR signaling to calcium or RelA. These results provide a possible explanation for the signaling changes in clonal anergy and indicate that a chief function of membrane cholesterol in B cells is not to initiate BCR signaling, but instead to terminate a subset of signals by rapid receptor internalization.


Integrated assessment of the spatial variability of ozone impacts from emissions of nitrogen oxides.
This paper examines the ozone (O3) damages caused by nitrogen oxides (NO(x)) emissions in different locations around the Atlanta metropolitan area during a summer month. We calculate O3 impacts using a new integrated assessment model that links pollution emissions to their chemical transformation, transport, population exposures, and effects on human health. We find that increased NO(x) emissions in rural areas around Atlanta increase human exposure to ambient O3 twice as much as suburban emissions. However, increased NO(x) emissions in central city Atlanta actually reduce O3 exposures. For downtown emissions, the reduction in human exposures to O3 from titration by NO in the central city outweighs the effects from increased downwind O3. The results indicate that the marginal damage from NO(x) emissions varies greatly across a metropolitan area. The results raise concerns if cap and trade regulations cause emissions to migrate toward higher marginal damage locations.


A Roadmap for Foundational Research on Artificial Intelligence in Medical Imaging: From the 2018 NIH/RSNA/ACR/The Academy Workshop.
Imaging research laboratories are rapidly creating machine learning systems that achieve expert human performance using open-source methods and tools. These artificial intelligence systems are being developed to improve medical image reconstruction, noise reduction, quality assurance, triage, segmentation, computer-aided detection, computer-aided classification, and radiogenomics. In August 2018, a meeting was held in Bethesda, Maryland, at the National Institutes of Health to discuss the current state of the art and knowledge gaps and to develop a roadmap for future research initiatives. Key research priorities include: 1, new image reconstruction methods that efficiently produce images suitable for human interpretation from source data; 2, automated image labeling and annotation methods, including information extraction from the imaging report, electronic phenotyping, and prospective structured image reporting; 3, new machine learning methods for clinical imaging data, such as tailored, pretrained model architectures, and federated machine learning methods; 4, machine learning methods that can explain the advice they provide to human users (so-called explainable artificial intelligence); and 5, validated methods for image de-identification and data sharing to facilitate wide availability of clinical imaging data sets. This research roadmap is intended to identify and prioritize these needs for academic research laboratories, funding agencies, professional societies, and industry.


Extensive parallelism in protein evolution.
Independently evolving lineages mostly accumulate different changes, which leads to their gradual divergence. However, parallel accumulation of identical changes is also common, especially in traits with only a small number of possible states. We characterize parallelism in evolution of coding sequences in three four-species sets of genomes of mammals, Drosophila, and yeasts. Each such set contains two independent evolutionary paths, which we call paths I and II. An amino acid replacement which occurred along path I also occurs along path II with the probability 50-80% of that expected under selective neutrality. Thus, the per site rate of parallel evolution of proteins is several times higher than their average rate of evolution, but still lower than the rate of evolution of neutral sequences. This deficit may be caused by changes in the fitness landscape, leading to a replacement being possible along path I but not along path II. However, constant, weak selection assumed by the nearly neutral model of evolution appears to be a more likely explanation. Then, the average coefficient of selection associated with an amino acid replacement, in the units of the effective population size, must exceed approximately 0.4, and the fraction of effectively neutral replacements must be below approximately 30%. At a majority of evolvable amino acid sites, only a relatively small number of different amino acids is permitted. High, but below-neutral, rates of parallel amino acid replacements suggest that a majority of amino acid replacements that occur in evolution are subject to weak, but non-trivial, selection, as predicted by Ohta's nearly-neutral theory.


Low CA1 spine synapse density is further reduced by castration in male non-human primates.
The hippocampus plays a major role in learning and memory and its morphology and function are readily affected by gonadal hormones in female non-human primates. We sought to determine whether the gonads also affect pyramidal cell spine synapse density in the CA1 hippocampal area of male primates. Unbiased electron microscopic stereological calculations were performed to determine the volumetric density of pyramidal cell spine synapses and semiquantitative analyses on the surface density of glial fibrillary acidic protein-containing glia processes and the diameter of pyramidal cell apical dendrites in the CA1 area of intact and orchidectomized (1 month) St Kitts vervet monkeys (Chlorocebus aethiops sabaeus). The volumetric density (number of spine synapse/ micro m(3)) of spine synapses was significantly lower (40%) in the gonadectomized animals than in control monkeys; conversely, the density of glia processes was significantly higher (15%) and the diameter of dendritic shafts located in this area was also larger (30%) in the orchidectomized animals than in the controls. Strikingly, when compared to female values, intact male primates had lower spine synapse densities than either intact or ovariectomized females. Since the primate hippocampus is very similar to that of a human's, the present observations suggest that physiological levels of circulating androgen hormones are necessary to support normal spine synapse density in the CA1 stratum radiatum of human male hippocampus.


Special topics--Mitigation of methane and nitrous oxide emissions from animal operations: I. A review of enteric methane mitigation options.
The goal of this review was to analyze published data related to mitigation of enteric methane (CH4) emissions from ruminant animals to document the most effective and sustainable strategies. Increasing forage digestibility and digestible forage intake was one of the major recommended CH4 mitigation practices. Although responses vary, CH4 emissions can be reduced when corn silage replaces grass silage in the diet. Feeding legume silages could also lower CH4 emissions compared to grass silage due to their lower fiber concentration. Dietary lipids can be effective in reducing CH4 emissions, but their applicability will depend on effects on feed intake, fiber digestibility, production, and milk composition. Inclusion of concentrate feeds in the diet of ruminants will likely decrease CH4 emission intensity (Ei; CH4 per unit animal product), particularly when inclusion is above 40% of dietary dry matter and rumen function is not impaired. Supplementation of diets containing medium to poor quality forages with small amounts of concentrate feed will typically decrease CH4 Ei. Nitrates show promise as CH4 mitigation agents, but more studies are needed to fully understand their impact on whole-farm greenhouse gas emissions, animal productivity, and animal health. Through their effect on feed efficiency and rumen stoichiometry, ionophores are likely to have a moderate CH4 mitigating effect in ruminants fed high-grain or mixed grain-forage diets. Tannins may also reduce CH4 emissions although in some situations intake and milk production may be compromised. Some direct-fed microbials, such as yeast-based products, might have a moderate CH4-mitigating effect through increasing animal productivity and feed efficiency, but the effect is likely to be inconsistent. Vaccines against rumen archaea may offer mitigation opportunities in the future although the extent of CH4 reduction is likely to be small and adaptation by ruminal microbes and persistence of the effect is unknown. Overall, improving forage quality and the overall efficiency of dietary nutrient use is an effective way of decreasing CH4 Ei. Several feed supplements have a potential to reduce CH4 emission from ruminants although their long-term effect has not been well established and some are toxic or may not be economically feasible.


Presidential oration: the 18 annual conference of the Indian academy of neurology, trichi, Tamil Nadu, september 24-26, 2010, epilepsy care in developing countries.
Nearly 80% of the 50 million people with epilepsy worldwide reside in developing countries that are least equipped to tackle the enormous medical, social and economic challenges posed by epilepsy. These include widespread poverty, illiteracy, inefficient and unevenly distributed health care systems, and social stigma and misconceptions associated with epilepsy. Several studies have reported that a large proportion of patients with epilepsy in developing countries never receive appropriate treatment for their condition, and many, though diagnosed and initiated on treatment, soon discontinue treatment. Unaffordable cost of treatment, unavailability of antiepileptic drugs, and superstitious and cultural beliefs contribute to high epilepsy treatment gap in resource-poor countries. A significant proportion of the current burden of epilepsy in developing countries can be minimized by educating the public about the positive aspects of life with epilepsy and the primary and secondary physicians about current trends in the management of epilepsies, scaling up routine availability of low-cost antiepileptic drugs, and developing cost-effective epilepsy surgery programs.


Natural history of brain arteriovenous malformations: a systematic review.
The authors aimed to systematically review the literature to clarify the natural history of brain arteriovenous malformations (BAVMs). The authors searched PubMed for one or more of the following terms: natural history, brain arteriovenous malformations, cerebral arteriovenous malformations, and risk of rupture. They included studies that reported annual rates of hemorrhage and that included either 100 patients or 5 years of treatment-free follow-up. The incidence of BAVMs is 1.12-1.42 cases per 100,000 person-years; 38%-68% of new cases are first-ever hemorrhage. The overall annual rates of hemorrhage for patients with untreated BAVMs range from 2.10% to 4.12%. Consistently implicated in subsequent hemorrhage are initial hemorrhagic presentation, exclusively deep venous drainage, and deep and infrantentorial brain location. The risk for rupture seems to be increased by large nidus size and concurrent arterial aneurysms, although these factors have not been studied as thoroughly. Venous stenosis has not been implicated in increased risk for rupture. For patients with BAVMs, although the overall risk for hemorrhage seems to be 2.10%-4.12% per year, calculating an accurate risk profile for decision making involves clinical attention and accounting for specific features of the malformation.


Effects of stealth liposomal daunorubicin plus tamoxifen on the breast cancer and cancer stem cells.
The cancer stem cells play an important role in the invasion, metastasis and relapse of cancers as they are resistant to regular chemotherapy. In the present study, stealth liposomal daunorubicin plus tamoxifen was developed for eradicating breast cancer cells together with cancer stem cells. Inhibitory effects were performed on the bulk human breast cancer cells (MCF-7), the sorted MCF-7 cancer stem-like cells (side population, SP), and the sorted MCF-7 cancer cells (NSP), respectively. Antitumor activity and TUNEL analysis were evaluated on the MCF-7 xenografts in nude mice. The encapsulation efficiencies of daunorubicin and tamoxifen were 95% and 90%, respectively. The mean particle size of the stealth liposomes was about 100 nm. Breast cancer stem cells were identified by the specific markers CD44+/CD24-, and isolated from bulk MCF-7 cells. When applying stealth liposomal daunorubicin plus tamoxifen, the inhibitory effects on both the breast cancer cells and the cancer stem cells were significantly increased in vitro, respectively. In the MCF-7 xenografts in mice, stealth liposomal daunorubicin plus tamoxifen showed the most favorable antitumor activity due to the passive targeting the tumor tissue and the synergistic effects in eliminating breast cancer cells and cancer stem cells. Stealth liposomal daunorubicin plus tamoxifen could have the potentials in eliminating both breast cancer cells and cancer stem cells.


Single-chip microprocessor that communicates directly using light.
Data transport across short electrical wires is limited by both bandwidth and power density, which creates a performance bottleneck for semiconductor microchips in modern computer systems--from mobile phones to large-scale data centres. These limitations can be overcome by using optical communications based on chip-scale electronic-photonic systems enabled by silicon-based nanophotonic devices. However, combining electronics and photonics on the same chip has proved challenging, owing to microchip manufacturing conflicts between electronics and photonics. Consequently, current electronic-photonic chips are limited to niche manufacturing processes and include only a few optical devices alongside simple circuits. Here we report an electronic-photonic system on a single chip integrating over 70 million transistors and 850 photonic components that work together to provide logic, memory, and interconnect functions. This system is a realization of a microprocessor that uses on-chip photonic devices to directly communicate with other chips using light. To integrate electronics and photonics at the scale of a microprocessor chip, we adopt a 'zero-change' approach to the integration of photonics. Instead of developing a custom process to enable the fabrication of photonics, which would complicate or eliminate the possibility of integration with state-of-the-art transistors at large scale and at high yield, we design optical devices using a standard microelectronics foundry process that is used for modern microprocessors. This demonstration could represent the beginning of an era of chip-scale electronic-photonic systems with the potential to transform computing system architectures, enabling more powerful computers, from network infrastructure to data centres and supercomputers.


Does cognitive behavioral therapy change the brain? A systematic review of neuroimaging in anxiety disorders.
This systematic review aims to investigate neurobiological changes related to cognitive-behavioral therapy (CBT) in anxiety disorders detected through neuroimaging techniques and to identify predictors of response to treatment. Cognitive-behavioral therapy modified the neural circuits involved in the regulation of negative emotions and fear extinction in judged treatment responders. The only study on predictors of response to treatment was regarding obsessive-compulsive disorder and showed higher pretreatment regional metabolic activity in the left orbitofrontal cortex associated with a better response to behavioral therapy. Despite methodological limitations, neuroimaging studies revealed that CBT was able to change dysfunctions of the nervous system.


Role of Carbonyl Modifications on Aging-Associated Protein Aggregation.
Protein aggregation is a common biological phenomenon, observed in different physiological and pathological conditions. Decreased protein solubility and a tendency to aggregate is also observed during physiological aging but the causes are currently unknown. Herein we performed a biophysical separation of aging-related high molecular weight aggregates, isolated from the bone marrow and splenic cells of aging mice and followed by biochemical and mass spectrometric analysis. The analysis indicated that compared to younger mice an increase in protein post-translational carbonylation was observed. The causative role of these modifications in inducing protein misfolding and aggregation was determined by inducing carbonyl stress in young mice, which recapitulated the increased protein aggregation observed in old mice. Altogether our analysis indicates that oxidative stress-related post-translational modifications accumulate in the aging proteome and are responsible for increased protein aggregation and altered cell proteostasis.


Sexual dysfunction risk and quality of life among women with a history of sexual abuse.
To assess scores for sexual dysfunction risk and quality of life in a cohort of women in Brazil who had a history of sexual abuse. The present study was a secondary analysis of a cross-sectional study conducted between February 1, 2011 and May 31, 2012. Women aged 18-49years attending a family planning clinic at the University of Campinas, Brazil, who were in a heterosexual relationship and reported engaging in sexual intercourse in the 4weeks prior to the study were enrolled. Participants were asked to complete the World Health Organization Quality of Life Questionnaire, Abbreviated Version, and the Female Sexual Function Index (FSFI) questionnaire. Data were grouped based on a history of sexual abuse. An FSFI score of no higher than 26.55 was considered the cut off for sexual dysfunction. The prevalence of FSFI-defined sexual dysfunction was higher in participants with a history of sexual abuse (P<0.001) and participants with a history of sexual abuse had significantly lower scores across all quality of life domains. Increased risk of sexual dysfunction among women with a history of sexual abuse suggests potential problems in the sex lives of individuals in this population. Healthcare professionals should be alert to this diagnosis.


An horizon scan of biogeography.
The opportunity to reflect broadly on the accomplishments, prospects, and reach of a field may present itself relatively infrequently. Each biennial meeting of the International Biogeography Society showcases ideas solicited and developed largely during the preceding year, by individuals or teams from across the breadth of the discipline. Here, we highlight challenges, developments, and opportunities in biogeography from that biennial synthesis. We note the realized and potential impact of rapid data accumulation in several fields, a renaissance for inter-disciplinary research, the importance of recognizing the evolution-ecology continuum across spatial and temporal scales and at different taxonomic, phylogenetic and functional levels, and re-exploration of classical assumptions and hypotheses using new tools. However, advances are taxonomically and geographically biased, and key theoretical frameworks await tools to handle, or strategies to simplify, the biological complexity seen in empirical systems. Current threats to biodiversity require unprecedented integration of knowledge and development of predictive capacity that may enable biogeography to unite its descriptive and hypothetico-deductive branches and establish a greater role within and outside academia.


Evolutionary analysis of life span, competition, and adaptive radiation, motivated by the Pacific rockfishes (Sebastes).
The Pacific rockfishes (Sebastes spp) are remarkable for both their diversity (on the order of 100 species) and range of maximum life span ( approximately 10 years for Calico rockfish to approximately 200 years for Rougheye rockfish). We describe the natural history and patterns of diversity and life span in these species and then use independent contrasts to explore correlates of these. When phylogenetic history is taken into account, maximum life span is explained by age at maturity, size at maturity, and the interaction of these two. We introduce a life-history model that allows insight into the origin of these correlations. We then describe a variety of mechanisms that may increase lifepans and diversity. These include fluctuating environments (in which organisms basically have to "wait out" bad periods to reproduce successfully), diversity, and longevity inspired by interspecific competition and physiological complexity in growth and accumulation of cellular damage. All of the results point toward the importance of flat or "indifferent" fitness surfaces as a key element in the evolution of diversity. We conclude that further development of the theory of flat or indifferent fitness surfaces as applied to diversity and life span is clearly warranted.


Nonnucleoside inhibitor binding affects the interactions of the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase with DNA.
Site-directed photoaffinity cross-linking experiments were performed by using human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) mutants with unique cysteine residues at several positions (i.e., positions 65, 67, 70, and 74) in the fingers subdomain of the p66 subunit. Since neither the introduction of the unique cysteine residues into the fingers nor the modification of the SH groups of these residues with photoaffinity cross-linking reagents caused a significant decrease in the enzymatic activities of RT, we were able to use this system to measure distances between specific positions in the fingers domain of RT and double-stranded DNA. HIV-1 RT is quite flexible. There are conformational changes associated with binding of the normal substrates and nonnucleoside RT inhibitors (NNRTIs). Cross-linking was used to monitor intramolecular movements associated with binding of an NNRTI either in the presence or in the absence of an incoming deoxynucleoside triphosphate (dNTP). Binding an incoming dNTP at the polymerase active site decreased the efficiency of cross-linking but caused only modest changes in the preferred positions of cross-linking. This finding suggests that the fingers of p66 are closer to an extended template in the "open" configuration of the enzyme with the fingers away from the active site than in the closed configuration with the fingers in direct contact with the incoming dNTP. NNRTI binding caused increased cross-linking in experiments with diazirine reagents (especially with a diazirine reagent with a longer linker) and a moderate shift in the preferred sites of interaction with the template. Cross-linking occurred closer to the polymerase active site for RTs modified at positions 70 and 74. The effects of NNRTI binding were more pronounced in the absence of a bound dNTP; pretreatment of HIV-1 RT with an NNRTI reduced the effect of dNTP binding. These observations can be explained if the binding of NNRTI causes a decrease in the flexibility in the fingers subdomain of RT-NNRTI complex and a decrease in the distance from the fingers to the template extension.


Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies.
HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D1-R/D2-R/5-HT2A -R/H3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.


Magnolol protects against ischemic-reperfusion brain damage following oxygen-glucose deprivation and transient focal cerebral ischemia.
In the present study, the neuroprotective potential of magnolol against ischemia-reperfusion brain injury was examined via in vivo and in vitro experiments. Magnolol exhibited strong radical scavenging and antioxidant activity, and significantly inhibited the production of interleukin‑6, tumor necrosis factor‑a and nitrite/nitrate (NOX) in lipopolysaccharide-stimulated BV2 and RAW 264.7 cells when applied at concentrations of 10 and 50 µM, respectively. Magnolol (100 µM) also significantly attenuated oxygen‑glucose deprivation‑induced damage in neonatal rat hippocampal slice cultures, when administered up to 4 h following the insult. In a rat model of stable ischemia, compared with a vehicle‑treated ischemic control, pretreatment with magnolol (0.01‑1 mg/kg, intravenously) significantly reduced brain infarction following ischemic stroke, and post‑treatment with magnolol (1 mg/kg) remained effective and significantly reduced infarction when administered 2 h following the onset of ischemia. Additionally, magnolol (0.3 and 1 mg/kg) significantly reduced the accumulation of superoxide anions at the border zones of infarction and reduced oxidative damage in the ischemic brain. This was assessed by measuring the levels of NOX, malondialdehyde and myeloperoxidase, the ratio of glutathione/oxidized glutathione and the immunoreactions of 8‑hydroxy‑2'‑deoxyguanosine and 4‑hydroxynonenal. Thus, magnolol was revealed to protect against ischemia‑reperfusion brain damage. This may be partly attributed to its antioxidant, radical scavenging and anti‑inflammatory effects.


Plasmodium berghei histamine-releasing factor favours liver-stage development via inhibition of IL-6 production and associates with a severe outcome of disease.
Plasmodium spp., which causes malaria, produces a histamine-releasing factor (HRF), an orthologue of mammalian HRF. Histamine-releasing factor produced by erythrocytic stages of the parasite is thought to play a role in the pathogenesis of severe malaria. Here, we show in a rodent model that HRF is not important during the erythrocytic but pre-erythrocytic phase of infection, which mainly consists in the transformation in the liver of the mosquito-injected parasite form into the erythrocyte-infecting form. Development of P. berghei ANKA cl15cy1 liver stages lacking HRF is impaired and associated with an early rise in systemic IL-6, a cytokine that strongly suppresses development of Plasmodium liver stages. The defect is rescued by injection of anti-IL-6 antibodies or infection in IL-6-deficient mice and parasite HRF is sufficient to decrease IL-6 synthesis, indicating a direct role of parasite HRF in reducing host IL-6. The target cells modulated by HRF for IL-6 production at early time points during liver infection are neutrophils. Parasite HRF is thus used to down-regulate a cytokine with anti-parasite activity. Our data also highlight the link between a prolonged transition from liver to blood-stage infection and reduced incidence of experimental cerebral malaria.


Simulated and experimental study of laser-beam-induced thermal aberrations in precision optical systems.
Precision optical systems that utilize laser beams as working media usually suffer from thermal aberrations caused by absorbed energy. Based on a specially designed three-lens system, the causes and contributions of mechanical structures to the system's thermal aberrations are studied. The contribution of three thermal effects, surface deformation, change of refractive index, and stress birefringence on the system's thermal aberrations, is analyzed respectively through an integrated optomechanical simulation method. The impact of the structure's thermal dissipating capability and structure configuration on the system's thermal aberrations is analyzed, too. Experiments have been carried out to validate the correctness and accuracy of the simulation method. Both the simulated and tested results can provide a reference for structure design and thermal aberration analysis of the similar optical systems.


A new set of ESTs and cDNA clones from full-length and normalized libraries for gene discovery and functional characterization in citrus.
Interpretation of ever-increasing raw sequence information generated by modern genome sequencing technologies faces multiple challenges, such as gene function analysis and genome annotation. Indeed, nearly 40% of genes in plants encode proteins of unknown function. Functional characterization of these genes is one of the main challenges in modern biology. In this regard, the availability of full-length cDNA clones may fill in the gap created between sequence information and biological knowledge. Full-length cDNA clones facilitate functional analysis of the corresponding genes enabling manipulation of their expression in heterologous systems and the generation of a variety of tagged versions of the native protein. In addition, the development of full-length cDNA sequences has the power to improve the quality of genome annotation. We developed an integrated method to generate a new normalized EST collection enriched in full-length and rare transcripts of different citrus species from multiple tissues and developmental stages. We constructed a total of 15 cDNA libraries, from which we isolated 10,898 high-quality ESTs representing 6142 different genes. Percentages of redundancy and proportion of full-length clones range from 8 to 33, and 67 to 85, respectively, indicating good efficiency of the approach employed. The new EST collection adds 2113 new citrus ESTs, representing 1831 unigenes, to the collection of citrus genes available in the public databases. To facilitate functional analysis, cDNAs were introduced in a Gateway-based cloning vector for high-throughput functional analysis of genes in planta. Herein, we describe the technical methods used in the library construction, sequence analysis of clones and the overexpression of CitrSEP, a citrus homolog to the Arabidopsis SEP3 gene, in Arabidopsis as an example of a practical application of the engineered Gateway vector for functional analysis. The new EST collection denotes an important step towards the identification of all genes in the citrus genome. Furthermore, public availability of the cDNA clones generated in this study, and not only their sequence, enables testing of the biological function of the genes represented in the collection. Expression of the citrus SEP3 homologue, CitrSEP, in Arabidopsis results in early flowering, along with other phenotypes resembling the over-expression of the Arabidopsis SEPALLATA genes. Our findings suggest that the members of the SEP gene family play similar roles in these quite distant plant species.


Perceptions of colon cancer screening by stage of screening test adoption.
Colorectal cancer remains the second leading cause of cancer death in the United States. To fully realize the benefits of early detection of colorectal cancer, screening rates must improve. This study assessed differences in beliefs (from the Health Belief Model) by stage of screening behavior adoption (based on the Transtheoretical Model of Change) as a foundation for intervention development. More people were in the precontemplation stage (not thinking about having the screening test) for fecal occult blood test and sigmoidoscopy versus contemplation (thinking about having the test) or action (adherent with screening). Those in precontemplation stage for fecal occult blood test had lower perceived risk than those in contemplation, lower perceived benefits than those in action, and higher barriers than both those in contemplation and those in action. For sigmoidoscopy stage of readiness, again, precontemplators had lower perceived risk and self-efficacy than contemplators and higher barriers than both contemplators and actors. Given the popularity of the transtheoretical model and the success of stage-based interventions to increase other cancer screening, especially mammography, we should begin to translate such effective interventions to colorectal cancer screening. As such, this study is one of very few to quantify beliefs across stages of colorectal cancer and identify significant differences across stages, laying the foundation for the development and testing of stage-based interventions.


Incidence and mortality of hip fracture among the elderly population in South Korea: a population-based study using the national health insurance claims data.
The lack of epidemiologic information on osteoporotic hip fractures hampers the development of preventive or curative measures against osteoporosis in South Korea. We conducted a population-based study to estimate the annual incidence of hip fractures. Also, we examined factors associated with post-fracture mortality among Korean elderly to evaluate the impact of osteoporosis on our society and to identify high-risk populations. The Korean National Health Insurance (NHI) claims database was used to identify the incidence of hip fractures, defined as patients having a claim record with a diagnosis of hip fracture and a hip fracture-related operation during 2003. The 6-month period prior to 2003 was set as a 'window period,' such that patients were defined as incident cases only if their first record of fracture was observed after the window period. Cox's proportional hazards model was used to investigate the relationship between survival time and baseline patient and provider characteristics available from the NHI data. The age-standardized annual incidence rate of hip fractures requiring operation over 50 years of age was 146.38 per 100,000 women and 61.72 per 100,000 men, yielding a female to male ratio of 2.37. The 1-year mortality was 16.55%, which is 2.85 times higher than the mortality rate for the general population (5.8%) in this age group. The risk of post-fracture mortality at one year is significantly higher for males and for persons having lower socioeconomic status, living in places other than the capital city, not taking anti-osteoporosis pharmacologic therapy following fracture, or receiving fracture-associated operations from more advanced hospitals such as general or tertiary hospitals. This national epidemiological study will help raise awareness of osteoporotic hip fractures among the elderly population and hopefully motivate public health policy makers to develop effective national prevention strategies against osteoporosis to prevent hip fractures.


Validation of cyanoacrylate method for collection of stratum corneum in human skin for lipid analysis.
Lipids in the stratum corneum (SC) are of major importance for the skin barrier function. Many different methods have been used for the collection of SC for the analysis of SC lipids. The objective of the present study was to validate the cyanoacrylate method for the collection of SC in relation to lipid analysis. The results of the lipid analysis (ceramide/cholesterol and ceramide profile) of SC samples obtained by the cyanoacrylate method were compared to the results of the lipid analysis of mechanically removed SC samples. The intra- and interindividual variations in lipid composition were assessed when using the cyanoacrylate method, and lipid compositions in cyanoacrylate samples and samples taken from different depths of SC were compared. No statistically significant differences were found between mean values of lipids from the mechanically removed total thickness of the SC and cyanoacrylate samples. With respect to the cyanoacrylate samples, the intraindividual variation was significantly smaller than the interindividual variation, and the results did not indicate a change in lipid profile related to the depth of SC. The results clearly indicate that the cyanoacrylate method used for obtaining SC for lipid analysis is a useful and valid method for the purpose.


The complex structure of polyhydroxybutyrate (PHB) granules: four orthologous and paralogous phasins occur in Ralstonia eutropha.
Analysis of the genome sequence of the polyhydroxyalkanoate- (PHA) accumulating bacterium Ralstonia eutropha strain H16 revealed three homologues (PhaP2, PhaP3 and PhaP4) of the phasin protein PhaP1. PhaP1 is known to constitute the major component of the layer at the surface of poly(3-hydroxybutyrate), poly(3HB), granules. PhaP2, PhaP3 and PhaP4 exhibited 42, 49 and 45 % identity or 61, 62 and 63 % similarity to PhaP1, respectively. The calculated molecular masses of PhaP1, PhaP2, PhaP3 and PhaP4 were 20.0, 20.2, 19.6 and 20.2 kDa, respectively. RT-PCR analysis showed that phaP2, phaP3 and phaP4 were transcribed under conditions permissive for accumulation of poly(3HB). 2D PAGE of the poly(3HB) granule proteome and analysis of the detected proteins by MALDI-TOF clearly demonstrated that PhaP1, PhaP3 and PhaP4 are bound to the poly(3HB) granules in the cells. PhaP3 was expressed at a significantly higher level in PhaP1-negative mutants. Occurrence of an unknown protein with an N-terminal amino-acid sequence identical to that of PhaP2 in crude cellular extracts of R. eutropha had previously been shown by others. Although PhaP2 could not be localized in vivo on poly(3HB) granules, in vitro experiments clearly demonstrated binding of PhaP2 to these granules. Further analysis of complete or partial genomes of other poly(3HB)-accumulating bacteria revealed the existence of multiple phasin homologues in Ralstonia solanacearum, Burkholderia fungorum and Azotobacter vinelandii. These new and unexpected findings should affect our current models of PHA-granule structure and may also have a considerable impact on the establishment of heterologous production systems for PHAs.


Lizard epidermal gland secretions I: Chemical characterization of the femoral gland secretion of the sungazer, Cordylus giganteus.
The giant girdled lizard or sungazer, Cordylus giganteus, is endemic to South Africa. It has been suggested that in this species, as in other lizard species, epidermal glands in the femoral, pre-cloacal regions, and cloacal glands are the main sources of semiochemicals and that these secretions could play an important role at different levels of the social biology of the animals. To gain a better understanding of the nature of the femoral gland secretions of the sungazer, characterization of the constituents of the secretions was carried out. By using GC-MS analysis, in conjunction with auxiliary techniques, such as solventless sample introduction and trimethylsilyl derivatization, 53 relatively involatile compounds, including carboxylic acids, alcohols, ketones, esters, and steroids, were identified in the secretions of both sexes. The study showed that the secretions of male and female sungazers contain only semi-volatile chemicals.


Identification of another surface protein antigen I/II gene, paaB, and a putative transcriptional regulator gene, par, from Streptococcus cricetus.
The flanking region of the antigen I/II gene, paaA, in Streptococcus cricetus was examined using the gene-walking technique. In the region downstream of the paaA gene, another antigen I/II gene designated as paaB was found. The paaB gene was disrupted at the alanine-rich region (A region) by a novel insertion sequence element, ISScr1. ISScr1 is a member of the IS982 family and is composed of a 962-bp sequence and duplicated target DNA (the sequence 5'-TAGCTAAAT-3') resulting from its insertion. To clarify the structural divergence of the two antigen I/II proteins (PAaA and PAaB), computational analysis of the paaB gene was performed and the two structures were compared. The amino acid sequence homology indicated that PAaB resembled PAaA, but the middle region showed little similarity to that of PAaA. Phylogenetic analysis showed that PAaB was better classified in a major group with S. mutans PAc and S. gordonii SspA and SspB than with PAaA. The transcriptional expression of paaA and paaB was demonstrated by reverse transcription (RT)-PCR. In the region upstream of the paaA gene, three genes homologous to the genes located in the region upstream of the S. sobrinus antigen I/II gene (pag) were found. Of the three genes, ORF3 showed homology to the par gene encoding a transcriptional repressor for the pag gene in S. sobrinus. Therefore, ORF3 was designated the par gene of S. cricetus. Southern hybridization revealed that the par gene of S. cricetus was not found in other oral streptococci examined in this study.


Plant foods and brain aging: a critical appraisal.
In the 21st century, human aging will be one of the biggest challenges for most societies throughout the world. The decline in human fitness is a typical hallmark of the aging process. Aside from the cardiovascular system, the brain most often suffers significantly from the life-long impact of stressors, such as reactive oxygen and nitrogen species. Oxytosis, i.e. oxidative stress-induced cell death, has been identified to play a major role in the development and onset of chronic diseases. Foods, especially of plant origin, are rich in antioxidants and numerous in vivo data suggest that a diet rich in fruits and vegetables supports the maintenance of animal and human health. These beneficial effects also extend to the central nervous system, which, due to the presence of the blood-brain barrier, tightly controls the influx of metabolites and nutrients. In earlier studies the impact of antioxidant vitamins, such as alpha-tocopherol and ascorbic acid, on brain health has been of interest. Recently, the focus moved to assessing the potential of unsaturated fatty acids and secondary plant metabolites, particularly of polyphenols, to act as neuroprotectants. Considerable experimental evidence suggests that polyphenols and other plant-derived bioactivities affect animal and human brain function not only by directly lowering oxidative stress load but also by modulating various signal transduction pathways.


Emerging areas of research reported during the CDC National Conference on Pfiesteria: from biology to public health.
Since its identification in 1996, the marine dinoflagellate Pfiesteria piscicida Steidinger & Burkholder has been the focus of intense scientific inquiry in disciplines ranging from estuarine ecology to epidemiology and from molecular biology to public health. Despite these research efforts, the extent of human exposure and the degree of human illness directly associated with Pfiesteria is still in the process of being defined. Unfortunately, during this same time Pfiesteria has also stimulated media coverage that in some instances jumped ahead of the science to conclude that Pfiesteria presents a widespread threat to human health. Political and economic forces also came into play when the tourism and seafood industries were adversely impacted by rumors of toxin-laden water in estuaries along the east coast of the United States. Amid this climate of evolving science and public concern, Pfiesteria has emerged as a highly controversial public health issue. In October 2000 Centers for Disease Control and Prevention sponsored the National Conference on Pfiesteria: From Biology to Public Health to bring together Pfiesteria researchers from many disparate disciplines. The goal of this meeting was to describe the state of the science and identify directions for future research. In preparation for the conference an expert peer-review panel was commissioned to review the existing literature and identify research gaps; the summary of their review is published in this monograph. During the meeting primary Pfiesteria researchers presented previously unpublished results. The majority of those presentations are included as peer-reviewed articles in this monograph. The discussion portion of the conference focused upon researcher-identified research gaps. This article details the discussion segments of the conference and makes reference to the presentations as it describes emerging areas of Pfiesteria research.


Assessment of the Health Risk Induced by Accumulated Heavy Metals from Anaerobic Digestion of Biological Sludge of the Lettuce.
Heavy metals are a group of pollutants in biological sludge. Many agencies regulated guidelines for heavy metal concentrations for various applications of sludge such as agricultural application. In this study, we tried to determine heavy metal fate after anaerobic digestion. Additionally, we determined the bioaccumulation rate of heavy metals in lettuce cultivated on a sludge-applied land. Heavy metal (As, Pb, Hg, Cd) contents of solid and liquid parts of raw and anaerobically digested sludge were separately measured by ICP-OES. For this purpose, the samples were digested using nitric acid, hydrochloric acid, and boric acid. Then, the raw and anaerobically digested sludge were used for cultivation of lettuce in separate farms. The heavy metal concentrations in the harvested lettuce were measured by the same procedure. The results showed that the main part of heavy metals in the raw sludge was in the liquid part (67%), while, the main part of heavy metals in the anaerobically digested samples was in the solid part of the sludge. Because of washout of dissolved heavy metals in the liquid part of the sludge, the lettuce cultivated by anaerobically digested sludge had higher content of the heavy metals in comparison to that of the lettuce cultivated by the raw sludge. This study showed that application of anaerobically digested sludge can increase the bioaccumulation rate of heavy metals in the crops and induce more human health risk.


What do you need to learn in paediatric psycho-oncology?
Paediatric psycho-oncology is an evolving speciality and is increasingly being recognised as an essential component in children's cancer care. Modern paediatric oncology services aspire to integrate physical care with psycho-social care and build capacity within clinical teams to address the emotional needs of parents and children side by side with other aspects of medical care. This article discusses the unique challenges of paediatric psycho-oncology and common situations where psychological assessment and management of children and young people with cancer become especially important. The authors propose a tiered structure of training. Providing empathic evidence-based psycho-social care is 'everyone's business' in paediatric oncology and not merely that of mental health professionals. However, there are times when a more specialist intervention by a paediatric liaison psychiatrist and/or a clinical psychologist is needed for optimum outcome. Learning interviewing techniques suitable for children and adolescents should be a core part of the training in paediatric psycho-oncology. Professionals should be encouraged to reflect on their own emotional wellbeing, which in turn will provide a stable foundation of emotionally matured care to children, young people and their families.


Promoter hypermethylation and quantitative expression analysis of CDKN2A (p14ARF and p16INK4a) gene in esophageal squamous cell carcinoma.
Abnormal hypermethylation of the CDKN2A (p14ARF and p16INK4a) gene can lead to repression of gene expression and contribute to carcinogenesis and tumor progression. In esophageal squamous cell carcinoma (ESCC), the promoter methylation of the p14ARF and p16INK4a gene was investigated in 38 cases by methylation-specific PCR and the expression of each gene in 18 cases was quantified by real-time quantitative reverse transcription-PCR. Aberrant methylation of p14ARF and of p16INK4a was detected in 23 (61%) and 29 (76%) cases, respectively. No relationship was found between clinicopathological variables and p14ARF or p161NK4a promoter methylation. A statistically significant association between p14ARF methylation status and mRNA expression was found (p=0.0441). Regarding p14ARF, a low expression group showed a significantly higher proportion of cases with deep invasion of tumor, lymph node metastasis, and a high TNM stage of disease (p=0.0474, 0.0474, and 0.0441, respectively), and a significantly poor prognosis (p=0.0402). Regarding p161NK4a, no relationship was found among the methylation status, mRNA expression and clinicopathological variables, including survival. Our results suggest that methylation is the predominant mechanism of inactivation of the p14ARF gene in ESCC. The decrease in p14ARF gene expression associated with invasive and metastatic phenotypes may be significant as an indicator of the malignant potential of human ESCC.


Photoinduced electron transfer from quantum dots to TiO2: elucidating the involvement of excitonic and surface states.
Colloidal semiconductor quantum dots (QDs) exhibit excitonic and surface states, both of which may participate in charge-transfer processes relevant to solar energy conversion. To explore this inherent complexity of the charge-transfer mechanisms of QDs, we used steady-state and time-resolved emission measurements to characterize excited-state electron transfer (ET) from core-only CdSe QDs and core/shell CdSe/ZnS QDs to TiO2 nanoparticles (NPs). Core-only QDs transferred electrons from both excitonic and surface states to TiO2 with rate constants of ET (ket) of approximately (1-3) × 10(8) s(-1) and (4-7) × 10(7) s(-1), respectively. Efficiencies of ET (ηet) from excitonic and surface states were approximately 71-82% and 64-76%, respectively. Thus, trapping of electrons lowered their potential energy but did not greatly affect the efficiency of their transfer to TiO2. Photogenerated holes were transferred from core-only CdSe QDs to adsorbed 3-mercaptopropionic acid (MPA), which linked the QDs to TiO2. We characterized core/shell CdSe/ZnS QDs as alternatives to core-only QDs. The ZnS shell eliminated the undesirable trapping of electrons and transfer of photogenerated holes to MPA. We measured ket of approximately (1-3) × 10(8) s(-1) and ηet of approximately 66-85% for ET from excitonic states of core/shell CdSe/ZnS QDs to TiO2 NPs. The insensitivity of ket to the presence of the ZnS shell may have arisen from increased cross-linking of core/shell QDs to TiO2. Our results highlight the involvement of surface states in excited-state ET processes of core-only QDs and, for the heterostructures reported here, the improved performance of core/shell CdSe/ZnS QDs relative to core-only CdSe QDs.


The future of seawater desalination: energy, technology, and the environment.
In recent years, numerous large-scale seawater desalination plants have been built in water-stressed countries to augment available water resources, and construction of new desalination plants is expected to increase in the near future. Despite major advancements in desalination technologies, seawater desalination is still more energy intensive compared to conventional technologies for the treatment of fresh water. There are also concerns about the potential environmental impacts of large-scale seawater desalination plants. Here, we review the possible reductions in energy demand by state-of-the-art seawater desalination technologies, the potential role of advanced materials and innovative technologies in improving performance, and the sustainability of desalination as a technological solution to global water shortages.


A Middle Eastern journey of integrating Interprofessional Education into the healthcare curriculum: a SWOC analysis.
Interprofessional education (IPE) is an emerging concept in the Middle East with a number of health professional degree programs continually striving to meet international accreditation requirements to enhance the quality of education and ensure high standards are maintained. Using the College of Pharmacy at Qatar University (CPH QU) as a model, this article describes the IPE initiatives coordinated through the College's IPE Committee, with representation from fourteen programs at four Healthcare institutions: Qatar University; Weill Cornell Medical College in Qatar; the University of Calgary in Qatar; and the College of North Atlantic in Qatar. These activities are based on the model proposed by the University of British Columbia across the different pharmacy professional years. Learning objectives for these initiatives were selected from the IPE shared competency domains and competency statements developed for Qatar context. A meeting with six faculty members, who have been instrumental to designing and executing the IPE activities in the previous 2 years, was convened. Faculty members reflected on IPE activities and collaborations with other participating programs. A structured SWOC (Strengths, Weaknesses, Opportunities, Challenges) framework was used to guide discussion. The discussion was recorded and notes were taken during the meeting. Raised points were categorized into each SWOC category for the final analysis. Implementation of IPE program is a major undertaking with a number of challenges that require invested time to overcome. This article highlights the importance of incorporating IPE into healthcare curricula to graduate students ready for collaborative practice in the workforce. Learning objectives for IPE initiatives need to be based on shared competency domains. When developing and implementing an IPE program it is necessary to align activities under a strong theoretical framework. This should be done under the leadership of an IPE steering group or committee to oversee the integration of IPE into the healthcare curriculum. The article presents many lessons learned through IPE implementation that are relevant to other academic institutions keen to incorporate IPE into their programs and also provides a successful model for integrating IPE into healthcare curricula.


Nucleotide sequences of the 26S mRNAs of the viruses defining the Venezuelan equine encephalitis antigenic complex.
Genetic relationships among viruses defining the Venezuelan equine encephalitis (VEE) virus antigenic complex were determined by analyzing the 3'-terminal 561 nucleotides of the nonstructural protein 4 gene and the entire 26S RNA region of the genome. New sequence information is reported for VEE 78V-3531 (VEE subtype-variety IF), Mucambo (IIIA), Tonate (IIIB), 71D-1252 (IIIC), Pixuna (IV), Cabassou (V), and AG80-663 (VI) viruses. The results reported here and by previous investigators largely support the current classification scheme of these viruses, while clearly identifying Everglades (II) as a subtype I virus. A genetic relationship between 78V-3531 (IF) and AG80-663 (VI) viruses contradicted previous serologic results. Mutations near the amino terminus of the E2 envelope proteins of Pixuna and AG80-663 viruses probably account for the previously reported low reactivity of the protective monoclonal antibody 1A2B-10 with these two viruses. Variations in the distribution of potential glycosylation sites in the E2 glycoprotein are discussed.


Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder.
Bipolar I disorder (BD) has a poorer longer-term outcome than previously thought, with persistent cognitive impairment and functional decline. The neurobiological underpinnings that might underlie these changes remain unknown. Changes in brain-derived neurotrophic factor (BDNF) levels and cytokines are potential candidates. The aim of this study was to examine both cytokine and BDNF levels and their relationship in BD patients in the early and late stages of the disorder. We measured serum BDNF, TNF-alpha, IL-6 and IL-10 levels in a total of 60 patients with BD I and we compared those in early stages of illness with those in late stages of illness and also compared both groups with 60 matched healthy controls. BDNF was decreased only in those patients in the late stage of bipolar disorder. Moreover, BDNF levels were negatively correlated with length of illness. In contrast, all interleukins and TNF-alpha were increased in the early stages of BD, compared to controls. While TNF-alpha and IL-6 continued to be significantly higher than controls at late stages of BD, IL-10 did not. When levels were compared between patients at early and late stages of illness, there was a significant decrease in BDNF and IL-6 in the later stage of BD compared to the early stage. Inversely, TNF-alpha showed a significant increase at the later stage. Failure of inflammatory defences in the late stage of the disorder may account for reduction in BDNF and continued elevations in cytokines; thus these may have the potential to serve as markers of illness progression in BD.


Stroke with negative brain magnetic resonance imaging.
Magnetic resonance imaging (MRI) of the brain is replacing computed tomography in the diagnostic evaluation of acute ischemic strokes. Past studies have suggested that MRI may not visualize all acute strokes, but few clinical details were included. To better understand the clinical characteristics of strokes not detected by MRI, we collected and reviewed case histories of several patients with acute stroke who had negative MRI scans. Patients with a clinical diagnosis of stroke and negative brain MRI scans were ascertained from hospital records dating from 1989 to mid-1991. Patients with transient ischemic attacks, postictal paralysis, functional examinations, central nervous system infections, other nonstroke diagnoses, or equivocal findings were excluded. The MRI scans were performed with a GE Signa 1.5-T magnet in an axial plane (spin-echo repetition time/echo time: 500 msec/20 msec; 2,500 msec, 30 msec/80 msec). One patient received contrast material. We identified seven patients with clinically diagnosed ischemic stroke and negative brain MRI scan. Six of seven patients were scanned within 7 days of symptom onset and two patients within 24 hours. One patient was scanned 3 months after symptom onset. The strokes not detected by MRI were clinically localized to the cortex (n = 3), brain stem (n = 3), and subcortical/lacunar area (n = 1). One patient underwent two MRI scans, one with gadolinium. These cases, while selected, illustrate some potential limitations of MRI for diagnosing stroke.


The use of RGD-engineered exosomes for enhanced targeting ability and synergistic therapy toward angiogenesis.
Promoted therapeutic angiogenesis is a major objective in the area of regenerative medicine, and sufficient vascularization of artificial tissues or organs is one of the main difficulties for the realization of tissue engineering methods. The identification of new kinds of pro-angiogenic materials will greatly profit developments in regenerative medicine. The use of exosomes for this intention is a considerably new idea developed in recent years. However, several limitations need to be addressed before their use as clinical therapeutics, including the lack of efficient exosome enrichment and methods to endow exosomes with targeting ability. Herein, we pioneered biomimetic particles with topographic structures for exosome isolation. Using this system, nearly 80% of exosomes were isolated in 30 min. Through a donor cell-assisted membrane modification strategy, the isolated exosomes exhibited increased targeting to blood vessels due to the modified Arg-Gly-Asp (RGD) peptide on the exosome membrane, and simultaneously possessed a synergistic therapeutic angiogenesis effect and angiogenesis imaging attributed to metabolic labeling by click chemistry both in vitro and in vivo. The engineered exosomes represent a potential new therapeutic tool for angiogenesis therapy and imaging in a bio-friendly manner.


[Extraction of di-2-ethylhexyl phthalate from a cardiopulmonary bypass circuit].
We measured levels of di-2-ethylhexyl phthalate (DEHP) in a priming solution of a cardiopulmonary bypass circuit. The circuit consisted of a venous reservoir, an oxygenator, and polyvinyl chloride (PVC) tubes. Eight circuits were used in this study. In 4 circuits a heparin-coating PVC tube was used and, in the others, a non-coating PVC tube. After they were primed with 1,500 ml of saline, the saline was circulated for 30 minutes at a rate of 6 l/min at 42 degrees C. Another four samples were collected directly from the saline in a polyethylene container as a control. Then the concentrations of DEHP in them were determined by means of gas chromatography. No detectable DEHP was found in controls. But, a small amount was detected in the saline from the circuits (2.75 +/- 4.27 ppb, and 3.75 +/- 4.99 ppb, respectively). DEHP was considered to be leached from the circuit to the priming solution because the tubes were made of PVC containing DEHP as a plasticizer. We suppose the DEHP concentration is probably at a safe level. However, the data on the endocrinologically toxic level of blood DEHP are insufficient. Therefore, the use of plastic in a circuit may require closer scrutiny to determine whether DEHP leached from PVC contributes to exposure to xenoestrogens.


Gene expression analysis of purified hematopoietic stem cells and committed progenitors.
Lifelong self-renewal is a unique property of somatic stem cells. Recently, several primitive multipotent yet committed (non-self-renewing) hematopoietic progenitor populations were identified in mouse bone marrow. We have characterized the expression of 1200 selected mouse genes using the Atlas cDNA array in highly purified hematopoietic stem cells (HSCs) and 6 closely related progenitor populations: common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs), common lymphoid progenitors (CLPs), and pro-T and pro-B cells. Cluster analysis revealed that nearly half of all differentially expressed transcripts are associated with HSCs, supporting the notion of an active transcriptional status of HSCs. Genes found enriched in the HSC cluster encompass many developmentally regulated genes, some previously associated with HSC self-renewal. In contrast, genes that are enriched in committed progenitors are mostly associated with hematopoietic differentiation, immune regulation, and metabolism. Thus, the transition from HSCs toward committed progenitors correlates with the down-regulation of a large number of HSC-associated genes and progressive up-regulation of a limited number of lineage-specific genes. These genetic analyses revealed both quantitative and qualitative differences between the transcripts associated with HSCs versus downstream progenitors and produced a list of the candidate genes, potentially involved in HSC self-renewal.


Kinetic models and phenomenological analysis of passive lipid translocation in single-file.
Passive movement of lipids through a membrane-embedded pore is analysed with kinetic equations of transport in single-file. The number of lipids arranged along the translocation coordinate in the pore is not limited in the calculations. The assumption is made that the energetic state of a pore is independent of the sequence of lipids contained in it. The results are valid for an arbitrary number of species with identical kinetic constants. It is shown that infinitely fast diffusion of one vacant site is equivalent to the filled pore approximation, which has been used here. We introduce the concept of non-strict single-file, which allows also for exchanges of neighbouring lipids inside the pore at specified rates. The model successfully simulates the redistribution of lipids between the monolayers of red blood cell plasma membranes under operation of an active aminophospholipid translocase. Kinetic equations are related to linear flux force relations. Phenomenological coefficients are expressed and analysed in terms of kinetic constants. Plausible kinetic pore model parameters are derived from comparison with a reference simulation of a thermodynamic model of the erythrocyte transmembrane lipid distribution. Mechanical forces due to differences in compressions of the lipid molecules between the monolayers are incorporated in kinetic rate constants. It is seen how the active inward transport of aminophospholipids causes an unsymmetrical passive redistribution of the other components due to mechanical effects and cross-coupling of fluxes.


Application of the Integrated Behavioral Model to oral self-care behavior of community-dwelling middle-aged and older people in Taiwan.
This study evaluated the Integrated Behavioral Model and examined oral self-care behavior of community-dwelling middle-aged and older people. A cross-sectional design was used. Purposive sampling was employed to recruit middle and older age community-dwelling individuals, with research locations in public health centers in northern Taiwan. Structured questionnaires comprised: participant demographics, oral health literacy, oral self-care attitude, self-efficacy, intention, and behavior, and significant others' perceptions and beliefs as well as environmental constraints. The Model verification was evaluated by path analysis. Two hundred and sixty-three participants (N = 263) completed the questionnaire survey. Results identified significant direct effects of the independent variables of oral health care literacy, intention of oral self-care, and perception of environmental constraints on the dependent variable of oral self-care behavior; and significant indirect effects on attitude of oral self-care, perception of significant other beliefs, self-efficacy of oral self-care. Public health nurses work with the whole community and can potentially improve the oral self-care behavior of middle-aged and older adults by enhancing their oral health knowledge, maintaining their positive attitudes, assisting acceptance of recognition and support from others, increasing their ability to perform oral self-care, reducing environmental constraints, and thereby enhancing their oral self-care awareness.


Thermal molecular focusing: tunable cross effect of phoresis and light-driven hydrodynamic focusing.
The control of solute flux by either microscopic phoresis or hydrodynamic advection is a fundamental way to transport molecules, which are ubiquitously present in nature and technology. We study the transport of large solutes such as DNA driven by a time-dependent thermal field in a polymer solution. Heat propagation of a heat spot moving back and forth gives rise to the molecular focusing of DNA with frequency-tunable control. We develop a model where the viscoelastic expansion of a solution and the viscosity gradient of a smaller solute are coupled, which explains the underlying hydrodynamic focusing. This effect offers novel non-invasive manipulation of soft and biological materials in a frequency-tunable manner.


Conjugation of glutathione with a toxic metabolite of valproic acid, (E)-2-propyl-2,4-pentadienoic acid, catalyzed by rat hepatic glutathione-S-transferases.
The hepatotoxic metabolite of the anticonvulsant drug valproic acid (VPA), namely (E)-2-propyl-2,4-pentadienoic acid (E)-2,4-diene VPA), is known to react with glutathione (GSH) in vivo. Although glutathione-S-transferase (GST) was suspected of being the catalyst for this conjugation reaction, this was yet to be confirmed. In this study, GST activities were detected in the hepatic cytosolic and sonic-disrupted mitoplast fractions isolated from male Sprague-Dawley rats by using 1-chloro-2,4-dinitrobenzene as a substrate. An elevation of GST activities by 45 to 100% was observed after pretreatment of rats with phenobarbital (PB). Subsequently, these apparent GST activities were examined for their effects on the in vivo conjugation of GSH with N-acetyl-S-((E)-2-propyl-2,4-pentadienoyl)cysteamine (2,4-diene VPA-NACA), a structural mimic of (E)-2,4-diene VPA coenzyme A thioester. Reaction products were identified and quantitated by combined liquid chromatography-tandem mass spectrometry. The GST-mediated conjugation of GSH with 2,4-diene VPA-NACA produced two structural isomers via either 5,6- or 1,6-addition of GSH. Only the 1,6- addition product was found for the spontaneous conjugation reaction (control). Quantitatively, GSH conjugates formed in the cytosolic fraction were 23-fold that of control. An additional 1.5-fold enhancement was observed in the cytosolic fraction from PB-treated rats. The production of the GSH conjugates was increased by 2-fold for reactions involving the sonic-disrupted mitoplasts, either from untreated or PB-treated rats. Partially purified GST was found to catalyze the conjugation reactions in a fashion similar to that of the isolated subcellular fractions. No reaction with GSH could be detected for the free acid form of (E)-2,4-diene VPA. As was the case with the in vitro data, two structural isomers of GSH conjugates were detected in the bile of rats that received (E)-2,4-diene VPA. These results indicate that in vivo production of the GSH conjugates of (E)-2,4-diene VPA is most likely catalyzed by GST enzymes, with the esterified diene being essential for the conjugation reaction. In a separate experiment, 2,4-diene VPA-NACA was observed to alkylate reduced oxytocin through one or both cysteine residues. Thus, the toxicity of (E)-2,4-diene VPA might be produced via either GST-promoted depletion of cellular GSH, or a direct modification of key proteins, or both.


Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer Review Groups.
The efficacy and tolerability of vigabatrin (VGB) as an add-on therapy in the treatment of infantile spasm (IS) prompted physicians to explore its use as the first drug in this seizure type. Our retrospective study included 250 infants diagnosed with IS; the data obtained were subjected to peer-group review. Of this infant population, 192 infants were considered to have classic IS and had received VGB as their first treatment for the spasms. There was a slight preponderance of boys (57%) in this population. Mean age of IS onset was 5.8 months; 60% had typical hypsarrhythmia. Initial suppression of spasms was obtained in 68% of infants with a median time to response of 4 days at an average VGB dose of 99 mg/kg/day. The best response was seen in those infants with tuberous sclerosis (96% response) and in those younger than 3 months at onset of spasms (90% response). Of these infants, 43 (22%) of 192 subsequently had other types of seizures, and a recurrence of infantile spasms occurred in 28 (21%) of 131 responders. At the end of this study, 96 of 192 infants who could be evaluated were seizure free with VGB monotherapy. Treatment appeared to be well tolerated, with only 33 (13%) infants with adverse events, of which the most common were somnolence (15 patients) and hyperkinesia (eight patients). In only two cases did adverse events require VGB withdrawal. This study supports the opinion that VGB may be considered an initial treatment for IS regardless of cause.


Profile of Justice-Involved Marijuana and Other Substance Users: Demographics, Health and Health Care, Family, and Justice System Experiences.
Substance users are more likely to have co-occurring health problems, and this pattern is intensified among those involved with the criminal justice system. Interview data for 1977 incarcerated men in 5 states from the Multi-site Family Study on Incarceration, Parenting, and Partnering that was conducted between December 2008 and August 2011 were analyzed to compare pre-incarceration substance use patterns and health outcomes between men who primarily used marijuana, primarily used alcohol, primarily used other drugs, and did not use any illicit substances during that time. Using regression modeling, we examined the influence of substance use patterns on physical and mental health. Primary marijuana users comprised the largest portion of the sample (31.5%), closely followed by nonusers (30.0%), and those who primarily used other drugs (30.0%); primary alcohol users comprised the smallest group (19.6%). The substance user groups differed significantly from the nonuser group on many aspects of physical and mental health. Findings suggest that even among justice-involved men who are not using "hard" drugs, substance use merits serious attention. Expanding the availability of substance use treatment during and after incarceration might help to promote physical and mental health during incarceration and reentry.


Disrupting butterfly caterpillar microbiomes does not impact their survival and development.
Associations with gut microbes are believed to play crucial roles in the physiology, immune function, development and behaviour of insects. However, microbiome sequencing has recently suggested that butterflies are an anomaly, because their microbiomes do not show strong host- and developmental stage-specific associations. We experimentally manipulated butterfly larval gut microbiota and found that disrupting gut microbes had little influence on larval survival and development. Larvae of the butterflies Danaus chrysippus and Ariadne merione that fed on chemically sterilized or antibiotic-treated host plant leaves had significantly reduced bacterial loads, and their gut bacterial communities were disrupted substantially. However, neither host species treated this way suffered a significant fitness cost: across multiple experimental blocks, treated and control larvae had similar survival, growth and development. Furthermore, re-introducing microbes from the excreta of control larvae did not improve larval growth and survival. Thus, these butterfly larvae did not appear to rely on specialized gut bacteria for digestion, detoxification, biomass accumulation and metamorphosis. Our experiments thus show that dependence on gut bacteria for growth and survival is not a universal phenomenon across insects. Our findings also caution that strategies which target gut microbiomes may not always succeed in controlling Lepidopteran pests.


Outcome of surgery for obstructive jaundice is not associated with reduced levels of plasma fibronectin.
Reduced levels of plasma fibronectin have been implicated in the septicaemia and/or endotoxaemia that can accompany trauma or burns. Patients undergoing surgery for the relief of obstructive jaundice are also at risk of developing endotoxaemia or septicaemia. In this study, levels of plasma fibronectin were measured by immunoassay and bioassay in 16 such patients. No patient had a significantly reduced level of plasma fibronectin. Even in the case of patients developing a fatal septicaemia and general system failure there was no significant decrease in circulating fibronectin. It is concluded that measurement of plasma fibronectin is of no prognostic value and similarly infusion of fibronectin-rich cryoprecipitate would be of no therapeutic benefit.


Height-resolved quantification of microstructure and texture in polycrystalline thin films using TEM orientation mapping.
A method is presented for the quantitative investigation of microstructure and texture evolution in polycrystalline thin films based on in-plane automated crystal orientation mapping in transmission electron microscopy, from the substrate up. To demonstrate the method we apply it to the example of low pressure metal-organic chemical vapor deposited ZnO layers. First, orientation mapping is applied to standard cross-section and plan-view transmission electron microscopy samples of films, illustrating how plan-view samples both reduce the occurrence of grain overlap that is detrimental to reliable orientation mapping and also improve sampling statistics compared to cross-sections. Motivated by this, orientation mapping has been combined with a double-wedge method for specimen preparation developed by Spiecker et al. (2007) [1], which creates a large area plan-view sample that traverses the film thickness. By measuring >10,000 grains in the film, the resulting data give access to grain size, orientation and misorientation distributions in function of height above the substrate within the film, which are, in turn, the inputs necessary for quantitative assessment of growth models and simulations. The orientation data are directly related to microstructural images, allowing correlation of orientations with in-plane and out-of-plane grain sizes and shapes. The spatial correlation of the entire data set gives insights into previously unnoticed growth mechanisms such as the presence of renucleation or preferred misorientations. Finally, the data set can be used to guide targeted, local studies by other transmission electron microscopy techniques. This is demonstrated by the site-specific application of nano-beam diffraction to validate the presence of coherent [21̄1̄0]/(011̄3) twin boundaries first suggested by the orientation mapping.


"With every passing day I feel like a candle, melting little by little." experiences of long-term displacement amongst Syrian refugees in Shatila, Lebanon.
Long term displacement and exposure to challenging living conditions can influence family dynamics; gender roles; violence at home and in the community and mental well-being. This qualitative study explores these issues as perceived by Syrian refugees who have been living in Shatila, a Palestinian camp in South Beirut, Lebanon, for at least 2 years. Twenty eight in-depth interviews with men and women were conducted between February and June 2018. Women were recipients of mental health services, and men were recruited from the local community. Interviews were conducted in Arabic, translated, transcribed, coded and analysed using thematic content analysis. Our results show patterns of harsh living conditions similar to those described earlier in the course of the Syrian refugee crisis. Lack of infrastructure, overcrowding, cramped rooms and violence were all reported. Participants also described a lack of social support, discrimination and harassment within the host community, as well as limited social support networks within their own Syrian refugee community. Family dynamics were affected by the increased responsibilities on men, women and children; with additional economic and employment demands on men, women assuming the roles of 'mother and father' and children having to work and contribute to the household. Participants discussed several types of violence, including parental violence against children and violence in the community. Violence against women was also reported. Reported mental health issues included depression, anxiety, sadness, frustration, hopelessness, self-neglect and a loss of sense of self and self-worth. Some participants expressed a wish to die. This study describes experiences of changing gender roles, family dynamics, violence and mental health after long-term displacement in in Shatila camp, South Beirut as perceived by Syrian refugees. A lack of safety and security coupled with economic hardship rendered refugees even more susceptible to exploitation and harassment. Parental violence was the most commonly reported type of domestic violence.


Late sequelae of paralytic poliomyelitis: a clinical and electromyographic study.
A prospective study was carried out on 24 volunteers who had suffered from paralytic poliomyelitis up to 51 years earlier. A quantitative EMG was carried out in each subject. Grossly raised mean amplitudes of the interference patterns were found in many strong muscles as well as in weak muscles. Such muscles frequently showed "contraction fasciculation", a manifestation of loss of normal small motor units. In many subjects the clinical and EMG evidence of chronic partial denervation were more widespread than the subjects had realised. It is suggested that if, with advancing age, minor damage occurs to the peripheral nervous system and the complement of motor neurones is already depleted by poliomyelitis, there will be an exaggerated response with increase in the lower motor neurone signs.


Nitric oxide is involved in the inhibitory neurotransmission and endothelium-dependent relaxations of human small penile arteries.
1. Alteration in the flow of blood to the penis is thought to be the most frequent organic cause of erectile dysfunction or impotence. However, information concerning the penile small arteries (helicine arteries) which control blood flow between the arterial systemic circulation and the cavernous sinusoids is scarce. Therefore, the purpose of the present study was to investigate the involvement of nitric oxide, which is considered to be the main neurotransmitter in corpus cavernosum, in both the non-adrenergic non-cholinergic inhibitory neurotransmission and the endothelium-dependent responses in human penile small arteries. 2. Penile small arteries (lumen diameter 200-700 microns), which were branches of the human deep penile arteries obtained either from patients undergoing penile surgery or from organ donors, were mounted in microvascular myographs for isometric tension recording and electrical field stimulation was performed in the presence of guanethidine and atropine to block adrenergic neurotransmission and muscarinic receptors, respectively. 3. In phenylephrine-contracted penile small arteries, electrical field stimulation (0.5-32 Hz) induced frequency-dependent relaxations of both endothelium-intact and -denuded preparations. The inhibitor of nitric oxide synthase, NG-nitro-L-arginine (3 x 10(-5) mol/l), abolished the relaxations at the lowest frequencies, while slow-developing relaxations were still observed at high frequencies (16 and 32 Hz). The inhibitory effect of NG-nitro-L-arginine was reversed in the presence of L-arginine (3 x 10(-3) mol/l). Tetrodotoxin totally abolished the relaxations to electrical field stimulation. In contracted small penile arteries in the presence of NG-nitro-L-arginine, the nitrovasodilator sodium nitroprusside induced potent relaxations. 4. The endothelium-dependnet vasodilator acetylcholine induced relaxations of penile small arteries, which were only partially reduced in the presence of NG-nitro-L-arginine. In contrast, the relaxations to acetylcholine of trabecular corpus cavernosum preparations were almost abolished in the presence of NG-nitro-L-arginine. 5. The present study suggests that relaxations of human intracavernosal small penile arteries induced by non-adrenergic non-cholinergic nerve stimulation partially involve nitric oxide and also another inhibitory transmitter causing relaxations resistant to nitric oxide synthase blockade. In addition, endothelium-dependnet relaxations in human small penile arteries are mediated by both nitric oxide and a factor resistant to NG-nitro-L-arginine.


The economic burden of migraine to society.
The financial burden of migraine on society comprises direct costs, associated with medical care, and indirect costs, caused by absence from work and reduced productivity. Recent studies have revealed that direct costs are generally relatively low in Europe, but are much higher in North America, probably because of increased use of emergency room and specialist consultations for the treatment of migraine. Most individuals who experience migraine headaches take medication (over-the-counter, prescription-only or a combination of both) for their condition; in Europe and North America, most patients who experience migraines have consulted a physician at some time because of their condition. In general, the estimated indirect costs of migraine are substantial and are much higher than estimates of direct costs. On average, work losses related to reduced productivity are higher than those related to work absence. These data demonstrate the importance of the societal impact of migraine and illustrate the need for improved strategies to target migraine treatment.


Does directly observed therapy improve tuberculosis treatment? More evidence is needed to guide tuberculosis policy.
Tuberculosis (TB) now ranks alongside HIV as the leading infectious disease cause of death worldwide and incurs a global economic burden of over $12 billion annually. Directly observed therapy (DOT) recommends that TB patients complete the course of treatment under direct observation of a treatment supporter who is trained and overseen by health services to ensure that patients take their drugs as scheduled. Though the current WHO End TB Strategy does not mention DOT, only "supportive treatment supervision by treatment partners", many TB programs still use it despite the fact that the has not been demonstrated to be statistically significantly superior to self-administered treatment in ensuring treatment success or cure. DOT is designed to promote proper adherence to the full course of drug therapy in order to improve patient outcomes and prevent the development of drug resistance. Yet over 8 billion dollars is spent on TB treatment each year and thousands undergo DOT for all or part of their course of treatment, despite the absence of rigorous evidence supporting the superior effectiveness of DOT over self-administration for achieving drug susceptible TB (DS-TB) cure. Moreover, the DOT component burdens patients with financial and opportunity costs, and the potential for intensified stigma. To rigorously evaluate the effectiveness of DOT and identify the essential contributors to both successful treatment and minimized patient burden, we call for a pragmatic experimental trial conducted in real-world program settings, the gold standard for evidence-based health policy decisions. It is time to invest in the rigorous evaluation of DOT and reevaluate the DOT requirement for TB treatment worldwide. Rigorously evaluating the choice of treatment supporter, the frequency of health care worker contact and the development of new educational materials in a real-world setting would build the evidence base to inform the optimal design of TB treatment protocol. Implementing a more patient-centered approach may be a wise reallocation of resources to raise TB cure rates, prevent relapse, and minimize the emergence of drug resistance. Maintaining the status quo in the absence of rigorous supportive evidence may diminish the effectiveness of TB control policies in the long run.


Global restoration opportunities in tropical rainforest landscapes.
Over 140 Mha of restoration commitments have been pledged across the global tropics, yet guidance is needed to identify those landscapes where implementation is likely to provide the greatest potential benefits and cost-effective outcomes. By overlaying seven recent, peer-reviewed spatial datasets as proxies for socioenvironmental benefits and feasibility of restoration, we identified restoration opportunities (areas with higher potential return of benefits and feasibility) in lowland tropical rainforest landscapes. We found restoration opportunities throughout the tropics. Areas scoring in the top 10% (i.e., restoration hotspots) are located largely within conservation hotspots (88%) and in countries committed to the Bonn Challenge (73%), a global effort to restore 350 Mha by 2030. However, restoration hotspots represented only a small portion (19.1%) of the Key Biodiversity Area network. Concentrating restoration investments in landscapes with high benefits and feasibility would maximize the potential to mitigate anthropogenic impacts and improve human well-being.


Endothelial Prohibitin Mediates Bidirectional Long-Chain Fatty Acid Transport in White and Brown Adipose Tissues.
The function of prohibitin-1 (PHB1) in adipocyte mitochondrial respiration, adaptive thermogenesis, and long-chain fatty acid (LCFA) metabolism has been reported. While intracellular PHB1 expression is ubiquitous, cell surface PHB1 localization is selective for adipocytes and endothelial cells of adipose tissue. The importance of PHB1 in adipose endothelium has not been investigated, and its vascular cell surface function has remained unclear. Here, we generated and analyzed mice with PHB1 knock-out specifically in endothelial cells (PHB1 EC-KO). Despite the lack of endothelial PHB1, mice developed normally and had normal vascularization in both white adipose tissue and brown adipose tissue (BAT). Tumor and ex vivo explant angiogenesis assays also have not detected a functional defect in PHB1 KO endothelium. No metabolic phenotype was observed in PHB1 EC-KO mice raised on a regular diet. We show that both male and female PHB1 EC-KO mice have normal body composition and adaptive thermogenesis. However, PHB1 EC-KO mice displayed higher insulin sensitivity and increased glucose clearance when fed a high-fat diet. We demonstrate that the efficacy of LCFA deposition by adipocytes is decreased by PHB1 EC-KO, in particular in BAT. Consistent with that, EC-KO mice have a defect in clearing triglycerides from systemic circulation. Free fatty acid release upon lipolysis induction was also found to be reduced in PHB1 EC-KO mice. Our results demonstrate that PHB1 in endothelial cells regulates bidirectional LCFA transport and thereby suppresses glucose utilization.


The role of calcium in the control of renin release.
The effects of removing external calcium and inhibiting entry of calcium into the cell by treatment with D-600 on renin release from renal cortical slices of male Sprague-Dawley rats were examined. Baseline renin release, angiotensin II (AII)-induced inhibition, and isoproterenol-induced stimulation of renin release were studied. Removal of external calcium by chelation with 5 mM EGTA inhibited basal renin release while treatment with 1 mM EGTA stimulated basal renin release slightly. Incubation of slices with zero calcium medium containing 1 mM EGTA had no effect on isoproterenol-induced stimulation of renin release. In contrast, similar treatment reduced the inhibitory effect of AII from 58.7% of baseline to 85.3% (p less than 0.001). Similarly, blockage of calcium entry into cells with D-600 had no effect on isoproterenol-induced stimulation of renin release but abolished AII-induced inhibition. Replacement of sodium in the bathing medium with choline had no effect on baseline renin release or on AII-induced inhibition of renin release, ruling out the possibility that D-600 altered renin release via an effect on sodium influx. Taken together, the data strongly suggest that AII-induced inhibition of renin release is partially dependent on the presence of external calcium but that isoproterenol-induced stimulation of renin release is not.


Are preoperative sex-related differences of affective symptoms in primary brain tumor patients associated with postoperative histopathological grading?
Our objective was to explore the impact of the histopathological tumor type on affective symptoms before surgery among male and female patients with supratentorial primary brain tumors. A total of 44 adult patients were included in the study. Depression and anxiety were measured using the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory. Additionally, clinical interviews, including the Hamilton Depression Rating Scale (HDRS), were conducted. The general function of patients was measured with the Karnofsky Performance Status scale (KPS). All measures were obtained before surgery and therefore before the final histopathological diagnosis. All self-rating questionnaires but not the HDRS, showed significantly higher scores in female patients. The functional status assessed with the KPS was lower in female patients and correlated to the somatic part of the BDI. We further found a tendency for higher HDRS scores in male patients with a WHO grade 4 tumor stage compared to female patients. This finding was supported by positive correlations between HDRS scores and WHO grade in male and negative correlations between HDRS scores and WHO grade in female patients. In conclusion the preoperative evaluation of affective symptoms with self-rating questionnaires in patients with brain tumors may be invalidated by the patient's functional status. Depression should be explored with clinical interviews in these patients. Sex differences of affective symptoms in this patient group may also be related to the malignancy of the tumor, but further studies are needed to disentangle this relationship.