Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects with schizophrenia.
Estrogen signaling pathways affect cortical function and metabolism, are thought to play a role in the pathophysiology of schizophrenia, and exert neuroprotective effects in female subjects at risk. However, the molecular signatures of estrogen signaling in normal and diseased cerebral cortex remain largely unexplored. Expression of the estrogen-sensitive small RNA, microRNA-30b (miR-30b), was studied in 30 controls and 30 matched samples from subjects diagnosed with schizophrenia from prefrontal cortex (PFC), as well as in 23 samples from parietal cortex (12 controls and 11 schizophrenia cases). The majority of case and control samples were genotyped for an estrogen receptor α (Esr1) sequence variant (rs2234693) previously associated with genetic risk, and a subset of them were subjected to further analysis to determine expression of mature and precursor forms of miR-30b (pre/pri-miR-30b). Gender-dimorphic expression was also explored in mouse frontal cortex and hippocampus. A significant interaction between gender and diagnosis was discovered for changes in mature miR-30b levels, so that miR-30b expression was significantly reduced in the cerebral cortex of female but not male subjects with schizophrenia. In addition, disease-related changes in miR-30b expression in a subset of female subjects were further modulated by Esr1 genotype. Changes after antipsychotic drug exposure remained insignificant. These preliminary findings point to the possibility that disease-related changes in the expression of small noncoding RNAs such as miR-30b in schizophrenia could be influenced by gender and potentially regulated by estrogen signaling.


A retrospective analysis of the merits and challenges associated with simultaneous bilateral THA using the direct anterior approach.
15%-20% of patients presenting for total hip arthroplasty (THA) have bilateral disease. While simultaneous bilateral THA is of interest to patients and surgeons, debate persists regarding its merits. The majority of previous reports on simultaneous bilateral THA involve patients in the lateral decubitus position, which require repositioning, prepping and draping, and exposure of a fresh wound to pressure and manipulation for the contralateral THA. The purpose of this study was to compare complications, component position, and financial parameters for simultaneous versus staged bilateral THAs using the direct anterior approach (DAA). Medical records were reviewed for patient demographics, medical history, operative time, estimated blood loss (EBL), change in hemoglobin, transfusion, tranexamic acid (TXA) use, length of stay (LOS), discharge disposition, leg length discrepancy, acetabular cup position, and perioperative complications. Cost and reimbursement data were analysed. 44 patients were included in the sequential group and fifteen patients in the simultaneous group. Operative time, EBL, hemoglobin drop, transfusion rate, and LOS were significantly increased for simultaneous group. There was no significant difference in component position, complications, or readmissions between groups. Profit per hip was significantly higher for the simultaneous group. While simultaneous DAA THA presents challenges, our results suggest that simultaneous DAA THA may add value to the healthcare system without resulting in increased complications compared to sequential hip arthroplasty.


Normative data and validation of a regression based summary score for assessing meaningful neuropsychological change.
Reliable detection and quantification of longitudinal cognitive change are of considerable importance in many neurological disorders, particularly to monitor central nervous system effects of disease progression and treatment. In the current study, we developed normative data for repeated neuropsychological (NP) assessments (6 testings) using a modified standard regression-based (SRB) approach in a sample that includes both HIV-uninfected (HIV-, N = 172) and neuromedically stable HIV-infected (HIV+, N = 124) individuals. Prior analyses indicated no differences in NP change between the infected and uninfected participants. The norms for change included correction for factors found to significantly affect follow-up performance, using hierarchical regression. The most robust and consistent predictors of follow-up performance were the prior performance on the same test (which contributed in all models) and a measure of prior overall NP competence (predictor in 97% of all models). Demographic variables were predictors in 10-46% of all models and in small amounts; while test-retest interval contributed in only 6% of all models. Based on the regression equations, standardized change scores (z scores) were computed for each test measure at each interval; these z scores were then averaged to create a total battery change score. An independent sample of HIV- participants who had completed 8 of the 15 tests was used to validate an abridged summary change score. The normative data are available in an electronic format by e-mail request to the first author. Correction for practice effects based on normative data improved the consistency of NP impairment classification in a clinically stable longitudinal cohort after baseline.


The effects of changes in the referential problem space of infants and toddlers (Homo sapiens): Implications for cross-species comparisons.
Recent reviews have highlighted the tendency in the comparative literature to make claims about species' relative evolutionarily adaptive histories based on studies comparing different species tested with procedurally and methodologically different protocols. One particularly contentious area is the use of the object-choice task, used to measure an individual's ability to use referential cues, which is a core attribute of joint attention. We tested human children with versions of the object-choice task that have been previously used with dogs and nonhuman primates to see if manipulating the setup would lead to behavioral changes. In Study 1, we compared the responses of 18-month-olds and 36-month-olds when tested with and without a barrier. The presence of a barrier between the child and the reward did not suppress performance but did elicit more communicative behavior. Moreover, the barrier had a greater facilitating effect on the younger children, who displayed more communicative behavior in comparison with older children, who more frequently reached through the barrier in acts of direct prehension. In Study 2, we compared the behavior of 36-month-olds when the reward was within reaching distance (proximal) and when it was out of reach (distal). The children used index-finger points significantly more in the distal condition and grabbed more in the proximal condition, showing that they were making spatial judgments about the accessibility of the reward rather than just grabbing per se. We discuss the implications of these within-species differences in behavioral responses for cross-species comparisons. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Hypoxia sensing by hepatic stellate cells leads to VEGF-dependent angiogenesis and may contribute to accelerated liver regeneration.
Portal vein ligation (PVL) induces liver growth prior to resection. Associating liver partition and portal vein ligation (PVL plus transection=ALPPS) or the addition of the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to PVL both accelerate growth via stabilization of HIF-α subunits. This study aims at clarifying the crosstalk of hepatocytes (HC), hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) in accelerated liver growth. In vivo, liver volume, HC proliferation, vascular density and HSC activation were assessed in PVL, ALPPS, PVL+DMOG and DMOG alone. Proliferation of HC, HSC and LSEC was determined under DMOG in vitro. Conditioned media experiments of DMOG-exposed cells were performed. ALPPS and PVL+DMOG accelerated liver growth and HC proliferation in comparison to PVL. DMOG alone did not induce HC proliferation, but led to increased vascular density, which was also observed in ALPPS and PVL+DMOG. Activated HSC were detected in ALPPS, PVL+DMOG and DMOG, again not in PVL. In vitro, DMOG had no proliferative effect on HC, but conditioned supernatant of DMOG-treated HSC induced VEGF-dependent proliferation of LSEC. Transcriptome analysis confirmed activation of proangiogenic factors in hypoxic HSC. Hypoxia signaling in HSC induces VEGF-dependent angiogenesis. HSC play a crucial role in the cellular crosstalk of rapid liver regeneration.


The Costs of Close Contacts: Visualizing the Energy Landscape of Cell Contacts at the Nanoscale.
Cell-cell contacts often underpin signaling between cells. For immunology, the binding of a T cell receptor to an antigen-presenting pMHC initiates downstream signaling and an immune response. Although this contact is mediated by proteins on both cells creating interfaces with gap sizes typically around 14 nm, many, often contradictory observations have been made regarding the influence of the contact on parameters such as the binding kinetics, spatial distribution, and diffusion of signaling proteins within the contact. Understanding the basic physical constraints on probes inside this crowded environment will help inform studies on binding kinetics and dynamics of signaling of relevant proteins in the synapse. By tracking quantum dots of different dimensions for extended periods of time, we have shown that it is possible to obtain the probability of a molecule entering the contact, the change in its diffusion upon entry, and the impact of spatial heterogeneity of adhesion protein density in the contact. By analyzing the contacts formed by a T cell interacting with adhesion proteins anchored to a supported lipid bilayer, we find that probes are excluded from contact entry in a size-dependent manner for gap-to-probe differences of 4.1 nm. We also observed probes being trapped inside the contact and a decrease in diffusion of up to 85% in dense adhesion protein contacts. This approach provides new, to our knowledge, insights into the nature of cell-cell contacts, revealing that cell contacts are highly heterogeneous because of topography- and protein-density-related processes. These effects are likely to profoundly influence signaling between cells.


Review of functional MRI in HIV: effects of aging and medication.
HIV-associated neurocognitive disorder (HAND) is a frequently occurring comorbidity of HIV infection. Evidence suggests this condition starts subclinical before a progression to a symptomatic stage. Blood oxygenated level dependent (BOLD) fMRI has shown to be a sensitive tool to detect abnormal brain function in an early stage and might therefore be useful to evaluate the effect of HIV infection on brain function. An extensive literature search was performed in June 2015. Eligibility criteria for included studies were as follows: (1) conducting with HIV-positive patients, (2) using BOLD fMRI, and (3) including a HIV-negative control group. A total of 19 studies were included in the review including 931 participants. Differences in activation between HIV-positive and -negative participants were found when testing multiple domains, i.e., attention, (working) memory, and especially executive functioning. Overall, HIV-positive patients showed hyperactivation in task-related brain regions despite equal performances as controls. Task performance was degraded only for the most complex tasks. A few studies investigated the effect of aging on fMRI, and most of them found no interaction with HIV infection. Only three studies evaluated the effect of combination antiretroviral therapy (cART) on functional data suggesting an increase in activation with the use of cART. fMRI is a sensitive instrument to detect subtle cognitive changes in HIV patients. Open questions remain regarding the effects of cART on fMRI and the effects of aging on fMRI.


Comparisons of the structural and chemical properties of melanosomes isolated from retinal pigment epithelium, iris and choroid of newborn and mature bovine eyes.
Melanosomes were isolated from the retinal pigment epithelium (RPE), iris and choroid of mature (age >2 years) and newborn (age <1 week) bovine eyes. Scanning electron microscopy was utilized to analyze the morphology of the melanosomes, which were found to vary among different tissues and different ages. While the total content of amino acids differs slightly (ranging from 9% to 15% by mass), the distributions of the amino acids are similar. The pheomelanin content is low in the choroid and the RPE (0.1-0.5%), and moderate in the iris (<2%); therefore, the major melanin component of bovine eye melanosomes is eumelanin, independent of the shape of the melanosomes. The yields of pyrrole-2,3,5-tricarboxylic acid from melanosomes decrease in the following order: choroid > iris > RPE, and exhibit decreasing yields with age. 13C solid-state nuclear magnetic resonance (NMR) spectroscopic analysis of iris and choroid melanosomes indicates the same trends. These observations suggest that the 5,6-dihydroxyindole-2-carboxylic acid contents decrease in the following order: choroid > iris > RPE, and decrease with age. Moreover, the 13C solid-state NMR spectra show (1) for the same age samples, the CH:Cq ratio for choroid is larger than that for iris melanosomes; and (2) an increase in the concentration of carbonyl groups with age within each type of melanosome.


Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich's ataxia YG8R mouse model.
Oxidative stress is thought to be involved in Friedreich's ataxia (FRDA), yet it has not been demonstrated in the target neurons that are first to degenerate. Using the YG8R mouse model of FRDA, microarray and neuritic growth experiments were carried out in the dorsal root ganglion (DRG), the primary site of neurodegeneration in this disease. YG8R hemizygous mice exhibited defects in movement, and DRG neurites had growth defects. Microarray of DRG tissue identified decreased transcripts encoding the antioxidants, including peroxiredoxins, glutaredoxins, and glutathione S-transferase, and these were confirmed by immunoblots and quantitative real-time PCR. Because the decreased gene transcripts are the known targets of the antioxidant transcription factor nuclear factor-E2-related factor-2 (Nrf2), Nrf2 expression was measured; it was significantly decreased at the transcript and protein level in both the DRG and the cerebella of the YG8R hemizygous mouse; further, frataxin expression was significantly correlated with Nrf2 expression. Functionally, in YG8R hemizygous DRG, the total glutathione levels were reduced and explanted cells were more sensitive to the thioredoxin reductase (TxnRD) inhibitor auranofin, a thiol oxidant. In cell models of FRDA, including Schwann and the DRG, frataxin deficiency caused a decreased expression of the Nrf2 protein level in the nucleus, but not a defect in its translocation from the cytosol. Further, frataxin-deficient cells had decreased enzyme activity and expression of TxnRD, which is regulated by Nrf2, and were sensitive the TxnRD inhibitor auranofin. These results support a mechanistic hypothesis in which frataxin deficiency decreases Nrf2 expression in vivo, causing the sensitivity to oxidative stress in target tissues the DRG and the cerebella, which contributes to the process of neurodegeneration.


A demand-centered, hybrid life-cycle methodology for city-scale greenhouse gas inventories.
Greenhouse gas (GHG) accounting for individual cities is confounded by spatial scale and boundary effects that impact the allocation of regional material and energy flows. This paper develops a demand-centered, hybrid life-cycle-based methodology for conducting city-scale GHG inventories that incorporates (1) spatial allocation of surface and airline travel across colocated cities in larger metropolitan regions, and, (2) life-cycle assessment (LCA) to quantify the embodied energy of key urban materials--food, water, fuel, and concrete. The hybrid methodology enables cities to separately report the GHG impact associated with direct end-use of energy by cities (consistent with EPA and IPCC methods), as well as the impact of extra-boundary activities such as air travel and production of key urban materials (consistent with Scope 3 protocols recommended by the World Resources Institute). Application of this hybrid methodology to Denver, Colorado, yielded a more holistic GHG inventory that approaches a GHG footprint computation, with consistency of inclusions across spatial scale as well as convergence of city-scale per capita GHG emissions (approximately 25 mt CO2e/person/year) with state and national data. The method is shown to have significant policy impacts, and also demonstrates the utility of benchmarks in understanding energy use in various city sectors.


Twins as Participants in Randomized Controlled Trials: A Review of Published Literature.
Monozygotic (MZ) and dizygotic (DZ) twins participate in research that partitions variance in health, disease, and behavior into genetic and environmental components. However, there are other innovative roles for twins in medical research. One such way is involving MZ and/or DZ twins in co-twin control-designed randomized controlled trials (RCTs). To our knowledge, no reviews have been conducted that summarizes the involvement of twins in RCTs. Therefore, we conducted a systematic literature search using the U.S. Clinical Trials Database, NHS electronic databases, MEDLINE, EMBASE, and PsychINFO for RCTs on publications involving MZ and/or DZ twins as RCT participants. Out of the 186,027 clinical trials registered in the U.S. clinical trial register ClinicaTrails.gov, only six RCTs used twins as participants. From 1,598 articles identified in our search, 50 peer-reviewed English language publications met our pre-defined inclusion criteria. Sample sizes for RCTs have ranged from a total number of participants from 2 to 1,162; however, 32 (64%) studies had a sample size of 100 or less, and of those, 12 (24%) had fewer than 10. Both MZ and DZ twins have been recruited to the RCTs. In most instances (33/50) each twin from a pair were assigned to different study arms. Most of those studies included MZ twins only. Despite the methodological advantages, the use of MZ and DZ twins as participants in interventional RCTs appeared limited. The continuous development of innovative twin designs, especially RCTs, indicates that twin research can extend beyond the more widely recognized heritability estimates.


Exposure to a cutinase-like serine esterase triggers rapid lysis of multiple mycobacterial species.
Mycobacteria are shaped by a thick envelope made of an array of uniquely structured lipids and polysaccharides. However, the spatial organization of these molecules remains unclear. Here, we show that exposure to an esterase from Mycobacterium smegmatis (Msmeg_1529), hydrolyzing the ester linkage of trehalose dimycolate in vitro, triggers rapid and efficient lysis of Mycobacterium tuberculosis, Mycobacterium bovis BCG, and Mycobacterium marinum. Exposure to the esterase immediately releases free mycolic acids, while concomitantly depleting trehalose mycolates. Moreover, lysis could be competitively inhibited by an excess of purified trehalose dimycolate and was abolished by a S124A mutation affecting the catalytic activity of the esterase. These findings are consistent with an indispensable structural role of trehalose mycolates in the architectural design of the exposed surface of the mycobacterial envelope. Importantly, we also demonstrate that the esterase-mediated rapid lysis of M. tuberculosis significantly improves its detection in paucibacillary samples.


Distribution, aerodynamic characteristics, and removal of the major cat allergen Fel d 1 in British homes.
Sensitisation to cat allergen (Fel d 1) is an important risk factor for asthma in the UK. A study was undertaken to investigate the distribution of cat allergen in British homes, the aerodynamic characteristics and particle size distribution of airborne Fel d 1, and the method of removing it. Dust was collected from 50 homes with a cat and from 50 homes without a cat, and airborne levels of Fel d 1 were measured in 50 homes with a cat and 75 homes without a cat. Particle size distribution was determined using an Andersen sampler (8 hours/day) in 10 homes with cats. This was repeated on five separate days in a house with four cats, and then one, two, four, seven, and 14 days after the cats were removed from the living room area. The effect of high efficiency particulate air (HEPA) cleaner on airborne levels of Fel d 1 was investigated in seven homes with cats. Samples were collected on two separate days from two rooms of each house concurrently, one of which contained the cat, one day with the HEPA cleaner on and the other day as a control. Three one hourly samples were collected over a nine hour period (baseline, 4-5 hours, 8-9 hours) using a high volume dust sampler (air flow rate 60 l/min) and the air sample was collected onto a microglass fibre filter (pore size 0.3 micron). Fel d 1 concentrations were much lower in houses without a cat than in those with a cat (260-fold difference (95% CI 167 to 590) in living room carpets: geometric mean (GM) 0.9 microgram/g (range 0.06-33.93) versus 237 micrograms/g (range 2.8-3000); 314-fold difference (95% CI 167 to 590) in upholstered furniture: 1.21 micrograms/g (range 0.06-61.9) versus 380 micrograms/g (range 7.1-6000); 228-fold difference (95% CI 109 to 478) in bedroom carpets: 0.24 microgram/g (range 0.06-2.24) versus 55 micrograms/g (range 0.06-2304); and 215-fold difference (95% CI 101 to 456) in mattresses: 0.2 microgram/g (range 0.06-2.3) versus 55 micrograms/g (range 0.06-3400). Airborne levels of Fel d 1 were detected in all houses with cats, and the levels varied greatly between the homes (range 0.7-38 ng/m3). Low concentrations of airborne Fel d 1 (range 0.24-1.78 ng/m3) were found in 22 of 75 homes without a cat. Although airborne Fel d 1 was mostly associated with large particles (> 9 microns, approximately 49% of the allergen recovered), small particles (< 4.7 microns) comprised approximately 23% of the total airborne allergen. Total airborne Fel d 1 was reduced by 61.7% two days after removal of the cat but this was due predominantly to the decrease in larger particles (> 4.8 microns) which fell to 13% of their baseline level. Fel d 1 levels associated with small particles (< 4.8 microns) remained largely unchanged on days 1, 2 and 4 and then slowly decreased to 33% of the baseline levels at day 14. With HEPA cleaner a significant reduction in airborne Fel d 1 was observed compared with the control sampling (GM 5.04-0.88 ng/m3 versus 3.79-1.56 ng/m3 at baseline and 8 hours, active versus control group; p = 0.008). Airborne Fel d 1 was detectable in undisturbed conditions in all homes with cats and in almost a third of homes without cats. In houses with cats a significant proportion (23%) of airborne Fel d 1 was associated with small particles (< 4.7 microns diameter). Removal of the cat from the living room and bedroom areas of the home and the use of HEPA air cleaner reduced airborne levels of cat allergen in homes with cats, but the reduction following cat removal was not evenly spread across the particle size range.


Silicon photonics-wireless interface ICs for micro-/millimeter-wave fiber-wireless networks.
We present two types of Si photonics-wireless interface (PWI) integrated circuits (ICs) realized in standard Si technology. Our PWI ICs convert optical signals into radio-frequency (RF) signals for downlink remote antenna units in fiber-wireless networks. Characterization and modeling of Si avalanche photodetectors (APDs) fabricated in two different Si technologies are carried out and used for PWI IC design. A 5-GHz RF-over-fiber PWI IC composed of APD, preamplifier, and power amplifier (PA) is fabricated in 0.18-μm CMOS technology and its performance is verified by 54-Mb/s wireless local area network data transmission. A 60-GHz baseband-over-fiber PWI IC containing APD, baseband photoreceiver, 60-GHz binary phase-shift keying (BPSK) modulator, and 60-GHz PA is realized in 0.25-μm SiGe BiCMOS technology. Error-free transmission of 1.6-Gb/s BPSK data in 60 GHz with this PWI IC is successfully achieved.


Aberrant PD-1 ligand expression contributes to the myocardial inflammatory injury caused by Coxsackievirus B infection.
Coxsackievirus group B (CVB) is considered as one of the most common pathogens of human viral myocarditis. CVB-induced myocarditis is mainly characterized by the persistence of the virus infection and immune-mediated inflammatory injury. Costimulatory signals are crucial for the activation of adaptive immunity. Our data reveal that the CVB type 3 (CVB3) infection altered the expression profile of costimulatory molecules in host cells. CVB3 infection caused the decrease of PD-1 ligand expression, partially due to the cleavage of AU-rich element binding protein AUF1 by the viral protease 3Cpro, leading to the exacerbated inflammatory injury of the myocardium. Moreover, systemic PD-L1 treatment, which augmented the apoptosis of proliferating lymphocytes, alleviated myocardial inflammatory injury. Our findings suggest that PD1-pathway can be a potential immunologic therapeutic target for CVB-induced myocarditis.


Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2.
The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in p53-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.


Avoidance of contaminated sediments by an amphipod (Melita plumulosa), A harpacticoid copepod (Nitocra spinipes), and a snail (Phallomedusa solida).
The distribution of contaminants is seldom homogeneous in aquatic systems. In the present study, the avoidance response of Melita plumulosa, Nitocra spinipes, and Phallomedusa solida when exposed to contaminated sediments was investigated. Test vessels were designed to allow the congruent placement of two sediments and assessment of the movement of organisms between the sediments. When exposed to reference sediment, each species dispersed evenly between test chambers regardless of differences in sediment particle size. In the presence of contaminated sediment, the magnitude and rate of avoidance varied. Avoidance assays showed that test species avoided contaminated sediment as early as 6, 6, and 24 h following exposure for N. spinipes, P. solida, and M. plumulosa, respectively. The 48-h avoidance response of M. plumulosa for nine contaminated sediments of varying toxicity showed that avoidance was generally greater for sediments which elicited greater 10-d lethality to this species. The study demonstrated that each of these species has the ability to respond to chemical cues in the environment to inhabit sediment that provides the best opportunity for survival. The avoidance response for each species indicates the potential for developing rapid screening methods to assess sediment quality. Evidence suggests that avoidance was related to sediment toxicity and that static 10-d toxicity methods are likely to overestimate toxicity for species, which would avoid contamination in heterogeneous field settings.


Time-course of changes in inflammatory response after whole-body cryotherapy multi exposures following severe exercise.
The objectives of the present investigation was to analyze the effect of two different recovery modalities on classical markers of exercise-induced muscle damage (EIMD) and inflammation obtained after a simulated trail running race. Endurance trained males (n = 11) completed two experimental trials separated by 1 month in a randomized crossover design; one trial involved passive recovery (PAS), the other a specific whole body cryotherapy (WBC) for 96 h post-exercise (repeated each day). For each trial, subjects performed a 48 min running treadmill exercise followed by PAS or WBC. The Interleukin (IL) -1 (IL-1), IL-6, IL-10, tumor necrosis factor alpha (TNF-α), protein C-reactive (CRP) and white blood cells count were measured at rest, immediately post-exercise, and at 24, 48, 72, 96 h in post-exercise recovery. A significant time effect was observed to characterize an inflammatory state (Pre vs. Post) following the exercise bout in all conditions (p<0.05). Indeed, IL-1β (Post 1 h) and CRP (Post 24 h) levels decreased and IL-1ra (Post 1 h) increased following WBC when compared to PAS. In WBC condition (p<0.05), TNF-α, IL-10 and IL-6 remain unchanged compared to PAS condition. Overall, the results indicated that the WBC was effective in reducing the inflammatory process. These results may be explained by vasoconstriction at muscular level, and both the decrease in cytokines activity pro-inflammatory, and increase in cytokines anti-inflammatory.


Polymeric Thioxanthones as Potential Anticancer and Radiotherapy Agents.
Thioxanthone (TX) and its derivatives, which are widely used as photoinitiators in UV curing technology, hold promising research interest in biological applications. In particular, the use of TXs as anticancer agent has recently been manifested as an outstanding additional property of this class of molecules. Incorporation of TX molecules into specially designed polymers widens their practical use in such applications. In this study, two water-soluble, biocompatible, and stable polymers, namely poly(vinyl alcohol) and poly(ethylene glycol), possessing TX moieties at the side chains and chain ends, respectively, are prepared and used as anticancer and radiotherapy agents. The findings confirm that both polymers are potential candidates for therapeutic agents as they possess useful features including water-solubility, radiosensitizer effect, and anticancer activity in a polymeric scaffold.


Role of apoptosis-inducing factor, proline dehydrogenase, and NADPH oxidase in apoptosis and oxidative stress.
Flavoproteins catalyze a variety of reactions utilizing flavin mononucleotide or flavin adenine dinucleotide as cofactors. The oxidoreductase properties of flavoenzymes implicate them in redox homeostasis, oxidative stress, and various cellular processes, including programmed cell death. Here we explore three critical flavoproteins involved in apoptosis and redox signaling, ie, apoptosis-inducing factor (AIF), proline dehydrogenase, and NADPH oxidase. These proteins have diverse biochemical functions and influence apoptotic signaling by unique mechanisms. The role of AIF in apoptotic signaling is two-fold, with AIF changing intracellular location from the inner mitochondrial membrane space to the nucleus upon exposure of cells to apoptotic stimuli. In the mitochondria, AIF enhances mitochondrial bioenergetics and complex I activity/assembly to help maintain proper cellular redox homeostasis. After translocating to the nucleus, AIF forms a chromatin degrading complex with other proteins, such as cyclophilin A. AIF translocation from the mitochondria to the nucleus is triggered by oxidative stress, implicating AIF as a mitochondrial redox sensor. Proline dehydrogenase is a membrane-associated flavoenzyme in the mitochondrion that catalyzes the rate-limiting step of proline oxidation. Upregulation of proline dehydrogenase by the tumor suppressor, p53, leads to enhanced mitochondrial reactive oxygen species that induce the intrinsic apoptotic pathway. NADPH oxidases are a group of enzymes that generate reactive oxygen species for oxidative stress and signaling purposes. Upon activation, NADPH oxidase 2 generates a burst of superoxide in neutrophils that leads to killing of microbes during phagocytosis. NADPH oxidases also participate in redox signaling that involves hydrogen peroxide-mediated activation of different pathways regulating cell proliferation and cell death. Potential therapeutic strategies for each enzyme are also highlighted.


Whole-proteome prediction of protein function via graph-theoretic analysis of interaction maps.
Determining protein function is one of the most important problems in the post-genomic era. For the typical proteome, there are no functional annotations for one-third or more of its proteins. Recent high-throughput experiments have determined proteome-scale protein physical interaction maps for several organisms. These physical interactions are complemented by an abundance of data about other types of functional relationships between proteins, including genetic interactions, knowledge about co-expression and shared evolutionary history. Taken together, these pairwise linkages can be used to build whole-proteome protein interaction maps. We develop a network-flow based algorithm, FunctionalFlow, that exploits the underlying structure of protein interaction maps in order to predict protein function. In cross-validation testing on the yeast proteome, we show that FunctionalFlow has improved performance over previous methods in predicting the function of proteins with few (or no) annotated protein neighbors. By comparing several methods that use protein interaction maps to predict protein function, we demonstrate that FunctionalFlow performs well because it takes advantage of both network topology and some measure of locality. Finally, we show that performance can be improved substantially as we consider multiple data sources and use them to create weighted interaction networks. http://compbio.cs.princeton.edu/function


Assessing the effects of the introduction of the New Zealand Smokefree Environment Act 2003 on acute myocardial infarction hospital admissions in Christchurch, New Zealand.
To examine trends in Acute Myocardial Infarction (AMI) hospital admissions in Christchurch, New Zealand before and after the implementation of the New Zealand Smokefree Environments Act 2003 in December 2004. Data on AMI hospital admissions to Christchurch Public Hospital were extracted for the period 2003 to 2006. Poisson regression was used to calculate rate ratios by comparing for AMI rates of hospital admissions before (2003/04) and after (2005/06) the introduction of the Smokefree legislation, and to assess whether there was a significant change over time. The introduction of the smokefree legislation was associated with a 5% reduction in AMI admissions. The 55-74 age group recorded the greatest decrease in admissions (9%) and this figure rose to 13% among never smokers in this group. Reductions were more marked for men. Adding the effects of area deprivation increased the reduction to 21% among 55-74 year olds living in more affluent (quintile 2) areas. Overall however, the statistical association of changing levels of AMI admissions with smoking status and with deprivation was not consistently significant. At this early stage following the smokefree legislation, there are hints emerging of a positive impact on AMI admissions but these suggestions cannot yet be treated with certainty. Further research could usefully evaluate the longer-term effects of smoking legislation on the prevalence of smoking and exposure to second hand smoke, especially in more deprived urban communities.


Gynecologic Cancer InterGroup (GCIG) consensus review for uterine serous carcinoma.
Uterine serous carcinoma (USC) represents a rare and aggressive histologic subtype of endometrial cancer, associated with a poor prognosis. This article critically reviews the literature pertinent to the epidemiology, pathology, molecular biology, diagnosis, management, and perspectives of patients with USC. As one of a series of The Gynecologic Cancer InterGroup (GCIG) Rare Tumor Working Group in London, November 2013, we discussed about USC many times with various experts among international GCIG groups. Both USC and approximately 25% of high-grade endometrioid tumors represent extensive copy number alterations, few DNA methylation changes, low estrogen and progesterone levels, and frequent P53 mutations. Uterine serous carcinoma shares molecular characteristics with ovarian serous and basal-like breast carcinomas. In addition to optimal surgery, platinum- and taxane-based chemotherapy should be considered in the treatment of both early- and advanced-stage disease. The combination of radiation and chemotherapy appears to be associated with the highest survival rates. The role of radiation therapy in the management of this disease, with a high propensity for distant failures, remains elusive. Uterine serous carcinoma is a unique and biologically aggressive subtype of endometrial cancer and should be studied as a distinct entity. Futures studies should identify the optimized chemotherapy and radiation regimens, sequence of therapy and schedule, and the role of targeted biologic therapy.


Environmental tobacco smoke and the risk of cardiovascular disease.
Disease risk due to smoking is not limited to smokers only. Passive smoking, exposure to environmental tobacco smoke, is associated with adverse health effects, and it increases the risk of several diseases. This paper summarizes the cardiovascular effects of tobacco smoke and the current data on the effects of environmental tobacco smoke on the development of cardiovascular disease. According to the results of epidemiologic and experimental studies, environmental tobacco smoke has marked harmful effects on the cardiovascular system. It is estimated that it increases the risk of an acute event of coronary heart disease by 25-35%. Even though the number of studies conducted in the work environment is small, there is no reason to assume that the cardiovascular effects of environmental tobacco smoke differ markedly between the home and the workplace. Firm and timely actions are needed to protect people from exposure to environmental tobacco smoke, both in occupational and other environments.


No asymptomatic malaria parasitaemia found among 108 young children at one health facility in Dar es Salaam, Tanzania.
Asymptomatic malaria parasitaemia has been reported in areas with high malaria transmission. It may serve as a reservoir for continued transmission, and furthermore complicates diagnostics, as not all individuals with a positive malaria test are necessarily ill due to malaria, although they may present with malaria-like symptoms. Asymptomatic malaria increases with age as immunity to malaria gradually develops. As mortality and morbidity of malaria is higher among younger children it is important to know the prevalence of asymptomatic malaria parasitaemia in this population in order to interpret laboratory results for malaria correctly. A total of 108 children that had neither been treated for malaria nor had a fever the previous four weeks were recruited consecutively at a maternal and child health clinic (MCHC) in Dar es Salaam, Tanzania. A rapid diagnostic test (RDT) for malaria and dried blood spot (DBS) on filter paper were taken from each child. Social and clinical data were recorded. DNA was extracted from the DBS of study participants by a method using InstaGene™ matrix. PCR targeting the Plasmodium mitochondrial genome was performed on all samples. Median age was 4.6 months (range 0.5-38). All the RDTs were negative. PCR was negative for all study subjects. The study suggests that asymptomatic malaria may not be present in apparently healthy children up to the age of three years in Dar es Salaam, Tanzania. However, because of the small sample size and low median age of the study population, the findings cannot be generalized. Larger studies, including higher age groups, need to be done to clarify whether asymptomatic malaria parasitaemia is present in the general population in the Dar es Salaam area.


Evaluation of the presence of MMP-2, TIMP-2, BMP2/4, and TGFβ3 in the facial tissue of children with cleft lip and palate.
Cleft lip and palate (CLP) is the most common defect affecting the face. The treatment consists of surgical reconstruction of the anatomical structures of the cleft. Part of the surgical treatment is reconstruction of the alveolar bone by means of autogenic bone grafting (osteoplasty). This study aimed to evaluate the levels of expression of extracellular matrix remodeling factors in the facial tissue of children with a complete unilateral (CU) and a complete bilateral (CB) CLP to assess whether the wound healing process is adequate. Twenty-two CLP patients were enrolled in this study. Tissue samples were collected during alveolar osteoplasty for unilateral (n = 12) or bilateral (n = 10) cleft palate, (age range from 6 years 8 months to 12 years 2 months). Control material was obtained in the case of tooth extraction (age range from 6 years 9 months to 14 years 5 months). Immunohistochemistry was used to assess the levels of matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), bone morphogenetic proteins 2 and 4 (BMP2/4), and transforming growth factor β3 (TGFβ3). Numbers of positively stained cells were graded semi-quantitatively. Data were analysed using the Kraskel-Wallis rank test and the Bonferroni correction. The total number of MMP2-positive cells was significantly lower in the CBCLP and in the control group than in the CUCLP (p < 0.001 after the Bonferroni correction). The total number of TIMP2-positive cells was significantly higher in the CUCLP than in the CBCLP and in the control group (p < 0.001; p < 0.003 after the Bonferroni correction). The overall number of BMP2/4, TGFβ3-positive cells was significantly higher in the CUCLP than in the CBCLP and in the control group (p < 0.001 after the Bonferroni correction). The decrease of the relative amount of statistically significant BMP2/4, TGFβ3, MMP-2, TIMP-2 containing bone cells in CBCLP patients identifies affected alveolar bone regeneration and remodeling process.


Immunohistochemical localization of chromogranin A in gonadotrophs and somatotrophs of the turkey and chicken pituitary.
In the course of producing monoclonal antibodies to turkey prolactin, three monoclonal antibodies to turkey chromogranin A (CgA) were also produced, apparently arising from minor contamination of the turkey prolactin immunogen with peptide fragments of CgA. The identity of the antigen recognized by these antibodies was established by tandem mass spectrometry de novo sequencing of seven tryptic peptides from a turkey pituitary protein purified by immunoaffinity chromatography. These peptides showed high homology with distinctly separate regions of mammalian and ostrich CgA, and in silico cloned chicken CgA sequences. Chromogranin A immunostaining patterns on Western blots and pituitary tissue sections differed from those of prolactin, growth hormone, or luteinizing hormone (LH). Dual-label fluorescent immunohistochemistry revealed that CgA was co-localized with LH in most avian gonadotrophs in young chickens and turkeys, but not in adult, laying birds. Conversely, CgA was found in a majority of somatotrophs in laying birds but was absent from somatotrophs in young, growing chickens and turkeys. Lactotrophs contained no detectable CgA immunoreactivity in the tissues studied. These results suggest that CgA may modulate hormone secretion by gonadotrophs and somatotrophs in a manner that differs between cell type with age or reproductive state.


Hyperplastic dental follicle - review of literature and report of two cases in one family.
Hyperplastic dental follicle is an extremely rare lesion. The practitioner should be able to differentiate it from a dentigerous cyst. The present article will review related literature and report on two cases in one family. A 12-year-old white female and her 15-year-old brother were referred for exposure of unerupted canines. No systemic diseases or syndromes were present. Intra-oral examinations were unremarkable, except for the absence of all eight canines. Radiographic examinations revealed impacted canines with each unerupted tooth surrounded by a well-demarcated radiolucency, which passed beyond the cementoenamel junction. The teeth were surgically exposed and tissue specimens surrounding the unerupted teeth were analysed histologically. Histology revealed fibrous connective tissue with areas demonstrating some ground substance and multiple odontogenic epithelial rests. Some surfaces were partially lined by reduced enamel epithelium. A diagnosis of hyperplastic dental follicle was made. Sometimes, it is difficult to differentiate hyperplastic dental follicle from odontogenic fibroma, both simple and central forms. A correct diagnosis should be based on clinical, radiographic and histological findings.


Rapid induction of lung adenocarcinoma by fibroblast growth factor 9 signaling through FGF receptor 3.
Fibroblast growth factors (FGF) are expressed in many non-small cell lung carcinoma (NSCLC) primary tumors and derived cell lines, and mutations in FGF receptor 3 (FGFR3) have been identified in human lung adenocarcinoma. FGF9 has been implicated in the pathogenesis of NSCLC by synergizing with EGFR pathways or by providing an escape pathway mediating resistance to EGFR inhibition. To model pathogenic mechanisms mediated by FGF signals, we have established a mouse model in which FGF9 expression can be induced in adult lung epithelium. Here, we show that induced expression of FGF9 in adult lung leads to the rapid proliferation of distal airway epithelial cells that express the stem cell marker, Sca-1, and the proximal and distal epithelial markers, Sftpc and CC10, the rapid formation of Sftpc-positive adenocarcinomas, and eventual metastasis in some mice. Furthermore, we have identified FGFR3 as the obligate receptor mediating the FGF9 oncogenic signal. These results identify an FGF9-FGFR3 signal as a primary oncogenic pathway for lung adenocarcinoma and suggest that this pathway could be exploited for customized therapeutic applications for both primary tumors and those that have acquired resistance to inhibition of other signaling pathways.


Measurements of the [Formula: see text] production cross sections in association with jets with the ATLAS detector.
This paper presents cross sections for the production of a [Formula: see text] boson in association with jets, measured in proton-proton collisions at [Formula: see text] with the ATLAS experiment at the large hadron collider. With an integrated luminosity of [Formula: see text], this data set allows for an exploration of a large kinematic range, including jet production up to a transverse momentum of [Formula: see text] and multiplicities up to seven associated jets. The production cross sections for [Formula: see text] bosons are measured in both the electron and muon decay channels. Differential cross sections for many observables are also presented including measurements of the jet observables such as the rapidities and the transverse momenta as well as measurements of event observables such as the scalar sums of the transverse momenta of the jets. The measurements are compared to numerous QCD predictions including next-to-leading-order perturbative calculations, resummation calculations and Monte Carlo generators.


Overexpression of synphilin-1 promotes clearance of soluble and misfolded alpha-synuclein without restoring the motor phenotype in aged A30P transgenic mice.
Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures are composed of fibrillized and ubiquitinated alpha-synuclein suggesting that impaired protein clearance is an important event in aggregate formation. The A30P mutation is known for its fast oligomerization, but slow fibrillization rate. Despite its toxicity to neurons, mechanisms involved in either clearance or conversion of A30P alpha-synuclein from its soluble state into insoluble fibrils and their effects in vivo are poorly understood. Synphilin-1 is present in Lewy bodies, interacting with alpha-synuclein in vivo and in vitro and promotes its sequestration into aggresomes, which are thought to act as cytoprotective agents facilitating protein degradation. We therefore crossed animals overexpressing A30P alpha-synuclein with synphilin-1 transgenic mice to analyze its impact on aggregation, protein clearance and phenotype progression. We observed that co-expression of synphilin-1 mildly delayed the motor phenotype caused by A30P alpha-synuclein. Additionally, the presence of N- and C-terminal truncated alpha-synuclein species and fibrils were strongly reduced in double-transgenic mice when compared with single-transgenic A30P mice. Insolubility of mutant A30P and formation of aggresomes was still detectable in aged double-transgenic mice, paralleled by an increase of ubiquitinated proteins and high autophagic activity. Hence, this study supports the notion that co-expression of synphilin-1 promotes formation of autophagic-susceptible aggresomes and consecutively the degradation of human A30P alpha-synuclein. Notably, although synphilin-1 overexpression significantly reduced formation of fibrils and astrogliosis in aged animals, a similar phenotype is present in single- and double-transgenic mice suggesting additional neurotoxic processes in disease progression.


Evaluating the accessibility and utility of HIV-related point-of-care diagnostics for maternal health in rural South Africa: a study protocol.
Poor healthcare access is a major barrier to receiving antenatal care and a cause of high maternal mortality in South Africa (SA). 'Point-of-care' (POC) diagnostics is a powerful emerging healthcare approach to improve healthcare access. This study focuses on evaluating the accessibility and utility of POC diagnostics for maternal health in rural SA primary healthcare (PHC) clinics in order to generate a model framework of implementation of POC diagnostics in rural South African clinics. We will use several research methods, including a systematic review, quasi-experiments, survey, key informant interviews and audits. We will conduct a systematic review and experimental study to determine the impact of POC diagnostics on maternal health. We will perform a cross-sectional case study of 100 randomly selected rural primary healthcare clinics in KwaZulu-Natal to measure the context and patterns of POC diagnostics access and usage by maternal health providers and patients. We will conduct interviews with relevant key stakeholders to determine the reasons for POC deficiencies regarding accessibility and utility of HIV-related POC diagnostics for maternal health. We will also conduct a vertical audit to investigate all the quality aspects of POC diagnostic services including diagnostic accuracy in a select number of clinics. On the basis of information gathered, we will propose a model framework for improved implementation of POC diagnostics in rural South African public healthcare clinics. Statistical (Stata-13) and thematic (NVIVO) data analysis will be used in this study. The study protocol was approved by the Ethics Committee of the University of KwaZulu-Natal (BE 484/14) and the KwaZulu-Natal Department of Health based on the Helsinki Declaration (HRKM 40/15). Findings of this study will be disseminated electronically and in print. They will be presented to conferences related to HIV/AIDS, diagnostics, maternal health and strengthening of health systems.


The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits.
3,4-Methylenedioxymethamphetamine (MDMA)-induced serotonergic neurotoxicity was assessed in the striatum, hippocampus and frontal cortex of rats by using [3H]paroxetine binding to label serotonin (5-HT) uptake sites and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels as markers of serotonergic function. NMDA (40 mg/kg) induced a significant decrease in both [3H]paroxetine binding Bmax and 5-HT and 5-HIAA levels 7 days after treatment. The monoamine oxidase-B inhibitor L-deprenyl (2 mg/kg) administered 30 min before MDMA blocked these decreases. MDMA (40 mg/kg) also maximally increased the formation of thiobarbituric acid reactive substances (an indicator of lipid peroxidation) 12 hr after treatment in all three brain regions studied. This increase in malondialdehyde formation was also blocked by pretreatment with L-deprenyl. Tryptophan hydroxylase (TPH) activity was also significantly reduced 18 hr after MDMA. L-Deprenyl reversed this decrease in TPH activity. Another experiment confirmed that a significant fraction of [3H]dopamine uptake into hippocampal synaptosomes was blocked by 500 nM fluoxetine, a selective 5-HT uptake inhibitor. These data suggest that the deamination by monoamine oxidase-B of excessive dopamine within the 5-HT terminal generates hydrogen peroxide that may lead to membrane lipid peroxidation, and perhaps other oxidative insults, resulting in selective 5-HT terminal degeneration subsequent to MDMA treatment.


Brucellosis in childhood in the Western Cape.
Human brucellosis, a multisystem disease which may mimic other conditions, has a low incidence in childhood and the diagnosis may easily be missed. Over a 7-month period 9 children with brucellosis presented to the Department of Paediatrics and Child Health, Tygerberg Hospital. Six of the children had consumed unpasteurized milk. The main presenting symptoms were fever, fatigue, headache, myalgia and haematuria. Clinical signs included lymphadenopathy (3), nasopharyngitis (2), features of lower respiratory tract infection (2), splenomegaly (2) and pyrexia (1). The diagnosis was made on the basis of a positive serological titre (> 1:160) for Brucella abortus. The prozone phenomenon was encountered in 6 cases; however, the Coombs test confirmed the diagnosis in these cases. Children under 7 years were treated with co-trimoxazole and rifampicin and those over 7 years with tetracycline and rifampicin, for at least 6 weeks. No relapses were detected on follow-up.


Predicting HIV-1 coreceptor usage with sequence analysis.
Bioinformatics approaches are increasingly being used to identify and understand the genetic variation underlying changes in HIV-1 biological phenotype. The variable regions of the viral envelope are the major determinant of virus coreceptor usage and cell tropism. Specifically, amino acids 11 and 25 in the 3rd variable (V3) loop have been found to strongly influence viral syncytium inducing capacity and coreceptor usage. Many additional V3 loop changes, however, as well as changes elsewhere in Env, are thought to contribute to phenotype. In this review we describe several recently developed methods to analyze this variability and their use to predict biological phenotype based on sequence information. These approaches have identified changes in the V3 loop, in addition to the known changes at positions 11 and 25, that affect phenotype and significantly enhance our ability to predict phenotype from genotype. Besides improving phenotype prediction, methods that score V3 sequences on a continuous scale can also assist in the interpretation of evolutionary information about shifts in phenotype, and the relationship between that evolution and pathogenesis. Several examples and potential practical applications of this scoring are discussed. We conclude that advances in computational approaches have enhanced both our ability to predict and to understand HIV-1 biological phenotype evolution. Further development of these methods, by extending analysis to regions outside the V3 loop and to clades beyond subtype B, will extend our understanding of HIV-1 pathogenesis and inform treatment strategies.


Thermodynamics of the self-assembly of non-ionic chromonic molecules using atomistic simulations. The case of TP6EO2M in aqueous solution.
Atomistic molecular dynamic simulations have been performed for the non-ionic chromonic liquid crystal 2,3,6,7,10,11-hexa-(1,4,7-trioxa-octyl)-triphenylene (TP6EO2M) in aqueous solution. TP6EO2M molecules consist of a central poly-aromatic core (a triphenylene ring) functionalized by six hydrophilic ethyleneoxy (EO) chains, and have a strong tendency to aggregate face-to-face into stacks even in very dilute solution. We have studied self-assembly of the molecules in the low concentration range corresponding to an isotropic solution of aggregates, using two force fields GAFF and OPLS. Our results reveal that the GAFF force field, even though it was successfully used previously for modelling of ionic chromonics, overestimates the attraction of TP6EO2M molecules in water. This results in an aggregation free energy which is too high, a reduced hydration of EO chains and, therefore, molecular self-assembly into compact disordered clusters instead of stacks. In contrast, use of the OPLS force field, leads to self-assembly into ordered stacks in agreement with earlier experimental studies of triphenylene-based chromonics. The free energy of association follows a "quasi-isodesmic" pattern, where the binding free energy of two molecules to form a dimer is of the order of 2.5 RT larger than the corresponding energy of addition of a molecule into a stack. The obtained value for the binding free energy, ΔG=-12 RT, is found to be in line with the published values for typical ionic chromonics (-7 to -12 RT), and agrees reasonably well with the experimental results for this system. The calculated interlayer distance between the molecules in a stack is 0.37 nm, which is at the top of the range found for typical chromonics (0.33-0.37 nm). We suggest that the relatively large layer spacing can be attributed to the repulsion between EO side chains.


Frequent silencing of low density lipoprotein receptor-related protein 1B (LRP1B) expression by genetic and epigenetic mechanisms in esophageal squamous cell carcinoma.
Low-density lipoprotein receptor-related protein 1B (LRP1B) is frequently deleted in tumors of various types, but its status and expression in esophageal squamous cell carcinomas (ESCs) have never been reported. In the course of a program to screen ESC cell lines for copy-number aberrations using array-based comparative genomic hybridization, we identified a homozygous deletion of LRP1B. Genomic PCR experiments revealed homozygous deletions of LRP1B in additional ESC cell lines (total, 6 of 43; 14.0%) and in primary esophageal tumors (30 of 70; 42.9%). Moreover, expression of LRP1B mRNA was frequently silenced in ESC lines without homozygous deletions (14 of 37; 37.8%). Using bisulfite-PCR analysis and sequencing, we found that LRP1B-nonexpressing cells without homozygous deletions were highly methylated at a CpG island of LRP1B, a sequence possessing promoter activity. Treatment with 5-aza-2'-deoxycytidine restored expression of LRP1B in those ESC lines. Histone acetylation status correlated directly with expression of LRP1B and inversely with the methylation status of the CpG island. Methylation of LRP1B was also detected in primary esophageal tumors. Restoration of LRP1B expression in ESC cells reduced colony formation. These results suggest that loss of LRP1B function in esophageal carcinogenesis most often occurs either by homozygous deletion or by transcriptional silencing through hypermethylation of its CpG island.


Syk activation is required for spreading and H2O2 release in adherent human neutrophils.
Chemoattractant-stimulated polymorphonuclear leukocytes (PMNs) that are adherent to extracellular matrix proteins exhibit a massive, sustained respiratory burst that requires cell spreading. However, the signaling pathways culminating in PMN spreading are not well characterized. Studies showing that protein tyrosine phosphorylation increases with PMN spreading suggest that phosphorylation is critical for this process. In the present study, we observed increased tyrosine phosphorylation of both focal adhesion kinase and Syk in FMLP-activated PMNs that had been plated onto fibrinogen; an increase in Syk activity, but not focal adhesion kinase activity, was apparent. The time course of Syk phosphorylation correlated with the initiation of cell spreading and H2O2 release. Pretreatment of PMNs with piceatannol, a Syk-selective inhibitor, blocked Syk activity, cell spreading, and H2O2 release, indicating that Syk activity was required for the activation of adherent PMNs. Paxillin is a cytoskeletally associated protein that is also tyrosine phosphorylated during PMN spreading and H2O2 release. Paxillin phosphorylation is kinetically slower than Syk phosphorylation and is inhibited with piceatannol, suggesting that paxillin is a substrate for Syk. An analysis of Syk immunoprecipitates indicated that Syk and paxillin associate during PMN spreading. This interaction is not mediated by the src kinases Lyn and Fgr, since neither kinase coprecipitated with Syk. Syk from FMLP-activated, adherent PMNs phosphorylated paxillin-glutathione S-transferase, suggesting that paxillin is a substrate for Syk in vivo. These results indicate that PMN spreading and H2O2 release require a Syk-dependent signaling pathway leading to paxillin phosphorylation.


Implementing Evidence-Based Guidelines for Falls Prevention: Observations of Nursing Activities During the Care of Older People With Cognitive Impairment.
Evidence-based guidelines assist clinicians in practice, but how the guidelines are implemented is less established. To describe the nurses' implementation of activities recommended in evidence-based guidelines for falls prevention and care of older people with cognitive impairment. Structured observation with a categorical checklist was used. Nursing personnel were recruited from one subacute and two acute wards in two hospitals in one tertiary-level health service in south-eastern Queensland, Australia. The data collection instrument identified 31 activities drawn directly from the evidence-based guidelines, which were categorized into six domains of nursing practice: clinical care, comfort, elimination, mobility, nutrition and hydration, and social engagement. Four-hour observation periods, timed to occur across the morning and evening shifts, were conducted over 2 months. Nineteen registered nurses, six enrolled nurses, and 16 assistants in nursing (N = 41) were observed for 155 hr of observation. There was variability in adherence with specific activities, ranging from 21% to 100% adherence. Three categories with the highest adherence were nutrition and hydration, mobilization safety, and social engagement. The clinical care, comfort, and elimination categories had lower adherence, with lowest adherence in activities of education provision about falls risk, pain assessment, using a clock or calendar to reorient to time and place, and bowel care. Nursing care is delivered within an interdisciplinary team. Therefore, responsibility for the everyday fundamental care activities known to prevent falls in older people with cognitive impairment requires localized negotiation. A practical guide for preventing in-hospital falls in older people with cognitive impairment addressing the interdisciplinary context of practice is required. Interdisciplinary teams should develop strategies to enhance the implementation of pain assessment and prevention of constipation in the context of regularly implemented hydration, nutrition, and mobilization care strategies.


Welfare state regimes and differences in self-perceived health in Europe: a multilevel analysis.
The aim of this study was to determine the degree to which welfare state regime characteristics explained the proportional variation of self-perceived health between European countries, when individual and regional variation was accounted for, by undertaking a multilevel analysis of the European Social Survey (2002 and 2004). A total of 65,065 individuals, from 218 regions and 21 countries, aged 25 years and above were included in the analysis. The health outcomes related to people's own mental and physical health, in general. The study showed that almost 90% of the variation in health was attributable to the individual-level, while approximately 10% was associated with national welfare state characteristics. The variation across regions within countries was not significant. Type of welfare state regime appeared to account for approximately half of the national-level variation of health inequalities between European countries. People in countries with Scandinavian and Anglo-Saxon welfare regimes were observed to have better self-perceived general health in comparison to Southern and East European welfare regimes.


Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial.
The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings. ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staff were masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than -10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413. The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4·75 log10 copies per mL (IQR 0·88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94·1% for efavirenz 400 mg and 92·2% for 600 mg (difference 1·85%, 95% CI -2·1 to 5·79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0·01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89·1%, efavirenz 600=88·4%; difference 0·75%, 95% CI -4·19 to 5·69; p=0·77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference -10·5%, 95% CI -18·2 to -2·8; p=0·01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference -3·96%, 95% CI -6·96 to -0·95; p=0·01). Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care. Bill & Melinda Gates Foundation, University of New South Wales.


A stamped PEDOT:PSS-silicon nanowire hybrid solar cell.
A novel stamped hybrid solar cell was proposed using the stamping transfer technique by stamping an active PEDOT:PSS thin layer onto the top of silicon nanowires (SiNWs). Compared to a bulk-type counterpart that fully embeds SiNWs inside PEDOT:PSS, an increase in the photovoltaic efficiency was observed by a factor of ∼4.6, along with improvements in both electrical and optical responses for the stamped hybrid cell. Such improvements for hybrid cells was due to the formation of well-connected and linearly aligned active PEDOT:PSS channels at the top ends of the nanowires after the stamping process. These stamped channels facilitated not only to improve the charge transport, light absorption, but also to decrease the free carriers as well as exciton recombination losses for stamped hybrid solar cells.


Abnormal asymmetries in subcortical brain volume in schizophrenia.
Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.


Low- and medium-molecular-weight hydroxyethyl starches: comparison of their effect on blood coagulation.
High-molecular-weight hydroxyethyl starch (HES) compromises blood coagulation more than medium-molecular-weight HES. The authors compared medium molecular weight HES (200 kd [HES200]) and low-molecular-weight HES (70 kd [HES70]). In a prospective, double-blind, randomized-sequence crossover study, 22 male volunteers received 15 ml/kg HES200 and HES70. Blood samples were taken before and 5 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after infusion. The following parameters were analyzed at all time points: prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, antigenetic and functional von Willebrand factor, platelets, Thrombelastograph analysis parameters (reaction time, coagulation time, maximum amplitude, angle alpha, and clot lysis 30 and 60 min after maximum amplitude), ionized calcium, hematocrit, HES plasma concentration, molecular weight (weight average and number average), molar substitution, and polydispersity (weight average/number average). Repeated-measures analysis of variance (P < 0.05) was used to compare the response of the aforementioned parameters to the infusion of HES70 and HES200. Both HES solutions had a significant impact on all parameters. A slightly greater compromise with HES200 was found in activated partial thromboplastin time (P = 0.010), factor VIII (P = 0.009), antigenetic von Willebrand factor (P = 0.041), functional von Willebrand factor (P = 0.026), maximum amplitude (P = 0.008), and angle alpha (P = 0.003). No difference was established with the other parameters. HES concentration (P < 0.001), weight average (P < 0.001), number average (P < 0.001), and polydispersity (P < 0.001) were higher with HES200. There was no difference with molar substitution (P = 0.091). Low-molecular-weight hydroxyethyl starch (70 kd) compromises blood coagulation slightly less than HES200, but it is unclear whether this is clinically relevant.


Separation, purification, and characterization of digitoxigenin-monodigitoxoside UDP-glucuronosyltransferase activity.
Glucuronidation of digitoxigenin-monodigitoxoside was investigated in liver microsomes from spironolactone-induced male Wistar rats. Isolation of a specific digitoxigenin-monodigitoxoside UDP-glucuronosyltransferase was possible utilizing chromatofocusing chromatography with a gradient from pH 10.1 to 8.0 after solubilizing the microsomal protein with the nonionic detergent Emulgen 911. The digitoxigenin-monodigitoxoside UDP-glucuronosyltransferase was further purified using UDP-hexanolamine Sepharose 4B affinity chromatography. The highly purified (75-fold) enzyme showed activity toward digitoxigenin-monodigitoxoside and slight activity toward digitoxigenin-bisdigitoxoside, whereas digitoxin and substrates for p-nitrophenol, 17 beta-OH steroid, and 3 alpha-OH steroid UDP-glucuronosyltransferases were not glucuronidated. In addition, bilirubin, morphine, estrone, 4-hydroxybiphenyl, and aromatic amines were not glucuronidated by this protein. These results strongly confirm the presence of a form of UDP-glucuronosyltransferase, which is highly specific for the glucuronidation of digitoxigenin-monodigitoxoside.


Surgical treatment of nonpalpable primary invasive and in situ breast cancer.
Breast cancer is the most-common cancer among women worldwide, and over one-third of all cases diagnosed annually are nonpalpable at diagnosis. The increasingly widespread implementation of breast-screening programmes, combined with the use of advanced imaging modalities, such as magnetic resonance imaging (MRI), will further increase the numbers of patients diagnosed with this disease. The current standard management for nonpalpable breast cancer is localized surgical excision combined with axillary staging, using sentinel-lymph-node biopsy in the clinically and radiologically normal axilla. Wire-guided localization (WGL) during mammography is a method that was developed over 40 years ago to enable lesion localization preoperatively; this technique became the standard of care in the absence of a better alternative. Over the past 20 years, however, other technologies have been developed as alternatives to WGL in order to overcome the technical and outcome-related limitations of this technique. This Review discusses the techniques available for the surgical management of nonpalpable breast cancer; we describe their advantages and disadvantages, and highlight future directions for the development of new technologies.


Crossing borders for fertility treatment: motivations, destinations and outcomes of UK fertility travellers.
There are few systematic studies of the incidence of cross-border fertility care and even fewer reports of qualitative research with those undertaking treatment outside their country of origin. This paper reports findings from a qualitative study of UK residents with experience of cross-border care: the socio-demographic characteristics of UK travellers; their reasons for seeking treatment abroad; the treatments they sought; the destinations they chose and the outcomes of their treatment. Data regarding cross-border fertility treatment were collected from a purposive sample of 51 people by means of in-depth, semi-structured interviews between May 2009 and June 2010. Data were analysed using a systematic thematic coding method and also subjected to quantitative translation. Patient motivations for travelling abroad are complex. A desire for timely and affordable treatment with donor gametes was evident in a high number of cases (71%). However, most people gave several reasons, including: the cost of UK treatment; higher success rates abroad; treatment in a less stressful environment and dissatisfaction with UK treatment. People travelled to 13 different countries, the most popular being Spain and the Czech Republic. Most organized their own treatment and travel. The mean age of women seeking treatment was 38.8 years (range 29-46 years) and the multiple pregnancy rate was 19%. UK residents have diverse reasons for, and approaches to, seeking overseas treatment and do not conform to media stereotypes. Further research is needed to explore implications of cross-border treatment for donors, offspring and healthcare systems.


Roles for H2A.Z and its acetylation in GAL1 transcription and gene induction, but not GAL1-transcriptional memory.
H2A.Z is a histone H2A variant conserved from yeast to humans, and is found at 63% of promoters in Saccharomyces cerevisiae. This pattern of localization suggests that H2A.Z is somehow important for gene expression or regulation. H2A.Z can be acetylated at up to four lysine residues on its amino-terminal tail, and acetylated-H2A.Z is enriched in chromatin containing promoters of active genes. We investigated whether H2A.Z's role in GAL1 gene regulation and gene expression depends on H2A.Z acetylation. Our findings suggested that H2A.Z functioned both in gene regulation and in gene expression and that only its role in gene regulation depended upon its acetylation. Our findings provided an alternate explanation for results that were previously interpreted as evidence that H2A.Z plays a role in GAL1 transcriptional memory. Additionally, our findings provided new insights into the phenotypes of htz1Delta mutants: in the absence of H2A.Z, the SWR1 complex, which deposits H2A.Z into chromatin, was deleterious to the cell, and many of the phenotypes of cells lacking H2A.Z were due to the SWR1 complex's activity rather than to the absence of H2A.Z per se. These results highlight the need to reevaluate all studies on the phenotypes of cells lacking H2A.Z.


DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis - a randomised controlled trial.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2-3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4(®) diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure. The Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure. The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy. Eligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥ 18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1 : 1 non-deterministic minimisation. Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost-utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy. In total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25; p = 0.01). Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure. It may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further. Current Controlled Trials ISRCTN53817913. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.


A high biodiversity mitigates the impact of ocean acidification on hard-bottom ecosystems.
Biodiversity loss and climate change simultaneously threaten marine ecosystems, yet their interactions remain largely unknown. Ocean acidification severely affects a wide variety of marine organisms and recent studies have predicted major impacts at the pH conditions expected for 2100. However, despite the renowned interdependence between biodiversity and ecosystem functioning, the hypothesis that the species' response to ocean acidification could differ based on the biodiversity of the natural multispecies assemblages in which they live remains untested. Here, using experimentally controlled conditions, we investigated the impact of acidification on key habitat-forming organisms (including corals, sponges and macroalgae) and associated microbes in hard-bottom assemblages characterised by different biodiversity levels. Our results indicate that, at higher biodiversity, the impact of acidification on otherwise highly vulnerable key organisms can be reduced by 50 to >90%, depending on the species. Here we show that such a positive effect of a higher biodiversity can be associated with higher availability of food resources and healthy microbe-host associations, overall increasing host resistance to acidification, while contrasting harmful outbreaks of opportunistic microbes. Given the climate change scenarios predicted for the future, we conclude that biodiversity conservation of hard-bottom ecosystems is fundamental also for mitigating the impacts of ocean acidification.


A Rigid Hinge Region Is Necessary for High-Affinity Binding of Dimannose to Cyanovirin and Associated Constructs.
Mutations in the hinge region of cyanovirin-N (CVN) dictate its preferential oligomerization state. Constructs with the Pro51Gly mutation preferentially exist as monomers, whereas wild-type cyanovirin can form domain-swapped dimers under certain conditions. Because the hinge region is an integral part of the high-affinity binding site of CVN, we investigated whether this mutation affects the shape, flexibility, and binding affinity of domain B for dimannose. Our studies indicate that the capability of monomeric wild-type CVN to resist mechanical perturbations is enhanced when compared to that of constructs in which the hinge region is more flexible. Our computational results also show that enhanced flexibility leads to blocking of the binding site by allowing different rotational isomeric states of Asn53. Moreover, at higher temperatures, this observed flexibility leads to an interaction between Asn53 and Asn42, further hindering access to the binding site. On the basis of these results, we predicted that binding affinity for dimannose would be more favorable for cyanovirin constructs containing a wild-type hinge region, whereas affinity would be impaired in the case of mutants containing Pro51Gly. Experimental characterization by isothermal titration calorimetry of a set of cyanovirin mutants confirms this hypothesis. Those possessing the Pro51Gly mutation are consistently inferior binders.


The fate of miRNA* strand through evolutionary analysis: implication for degradation as merely carrier strand or potential regulatory molecule?
During typical microRNA (miRNA) biogenesis, one strand of a approximately 22 nt RNA duplex is preferentially selected for entry into a silencing complex, whereas the other strand, known as the passenger strand or miRNA* strand, is degraded. Recently, some miRNA* sequences were reported as guide miRNAs with abundant expression. Here, we intended to discover evolutionary implication of the fate of miRNA* strand by analyzing miRNA/miRNA* sequences across vertebrates. Mature miRNAs based on gene families were well conserved especially for their seed sequences across vertebrates, while their passenger strands always showed various divergence patterns. The divergence mainly resulted from divergence of different animal species, homologous miRNA genes and multicopy miRNA hairpin precursors. Some miRNA* sequences were phylogenetically conserved in seed and anchor sequences similar to mature miRNAs, while others revealed high levels of nucleotide divergence despite some of their partners were highly conserved. Most of those miRNA precursors that could generate abundant miRNAs from both strands always were well conserved in sequences of miR-#-5p and miR-#-3p, especially for their seed sequences. The final fate of miRNA* strand, either degraded as merely carrier strand or expressed abundantly as potential functional guide miRNA, may be destined across evolution. Well-conserved miRNA* strands, particularly conservation in seed sequences, maybe afford potential opportunities for contributing to regulation network. The study will broaden our understanding of potential functional miRNA* species.


Comparing photosynthetic and photovoltaic efficiencies and recognizing the potential for improvement.
Comparing photosynthetic and photovoltaic efficiencies is not a simple issue. Although both processes harvest the energy in sunlight, they operate in distinctly different ways and produce different types of products: biomass or chemical fuels in the case of natural photosynthesis and nonstored electrical current in the case of photovoltaics. In order to find common ground for evaluating energy-conversion efficiency, we compare natural photosynthesis with present technologies for photovoltaic-driven electrolysis of water to produce hydrogen. Photovoltaic-driven electrolysis is the more efficient process when measured on an annual basis, yet short-term yields for photosynthetic conversion under optimal conditions come within a factor of 2 or 3 of the photovoltaic benchmark. We consider opportunities in which the frontiers of synthetic biology might be used to enhance natural photosynthesis for improved solar energy conversion efficiency.


Alcohol Consumption, Aldehyde Dehydrogenase 2 Gene Polymorphisms, and Cardiovascular Health in Korea.
Alcohol consumption is a serious health issue in Korea in terms of the amount consumed and the behavior related to its consumption. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism that degrades acetaldehyde to nontoxic acetic acid. The enzyme is coded by the ALDH2 gene, which is commonly polymorphic in East Asian populations. A point mutation in the ALDH2 gene (the rs671 allele) yields an inactive form of ALDH2 that causes acetaldehyde accumulation in the body after alcohol consumption, thereby inhibiting normal alcohol metabolism. Individuals who are homozygous for polymorphism in ALDH2 tend to refrain from drinking alcohol, decreasing their chances of developing alcoholism and exposure to the associated risks. Mendelian randomization (MR) studies have demonstrated that alcohol consumption predicted by ALDH2 genotype is causally related to cardiovascular risks. Moreover, recent MR studies suggest that the ALDH2 variant has mechanistic effects on some disease outcomes or mortality through increased blood levels of acetaldehyde, showing differences therein between heterozygotes (ALDH2*2*2) and homozygotes (ALDH2*1*2) in those who consume alcohol. Accordingly, consideration of ALDH2 genotype in alcohol prevention programs is warranted. In conclusion, strategies that incorporate genetic information and provide an evidential basis from which to help people make informed decisions on alcohol consumption are urgently required.


Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.
The human homologue of the Drosophila segment polarity gene patched (PTCH) has recently been identified as the tumor suppressor gene responsible for the nevoid basal cell carcinoma (BCC) syndrome (H. Hahn et al., Cell, 85: 841-851, 1996; R. L. Johnson et al., Science (Washington DC), 272: 1668-1671, 1996). In addition to multiple BCCs, patients with nevoid BCC syndrome have a predisposition for the development of primitive neuroectodermal tumors (PNETs) of the central nervous system. We have analyzed 9 sporadic BCCs and 37 PNETs for mutation and expression of the PTCH gene. PTCH mutations were found in 3 BCCs (33.3%) and in 5 PNETs (14%), including 1 of 5 cerebral PNETs, 2 of 15 medulloblastomas, and 2 of 17 desmoplastic medulloblastomas. The sequence changes in six of these tumors (four PNETs, two BCCs) were mutations predicted to result in truncated proteins. Missense mutations were detected in one PNET and one BCC each. In addition, novel sequence polymorphisms were found in exon 2, intron 5, intron 10, and intron 14 of PTCH. Reverse transcription-PCR analysis revealed increased PTCH expression levels compared to nonneoplastic brain tissue and normal skin in the majority of PNETs and BCCs investigated. Our data suggest that genetic alterations of PTCH are not only of significance in hereditary and sporadic BCCs but are also involved in the molecular pathogenesis of a subset of sporadic central nervous system PNETs.


Cross-reactive cellular and humoral immune responses to Salmonella enterica serovars Typhimurium and Enteritidis are associated with protection to heterologous re-challenge.
Chickens infected with Salmonella enterica serovars Typhimurium (ST) and Enteritidis (SE) still represent a major source of human food poisoning via consumption of contaminated meat and eggs. Vaccination represents a sustainable approach to control Salmonella in the chicken and the serovar specificity of immunity has the potential to impact on the need for multivalent vaccines. The issue of cross-reactive immune responses and cross-serovar protection was examined in these experiments. Cellular and humoral immune responses were measured by antigen-specific ELISA and splenocyte proliferation assays during primary infections (with ST and SE) and during a second challenge with homologous or heterologous serovars. Primary infection with ST or SE induced strong lymphocyte proliferation and high levels of specific antibody (IgM, IgG and IgA) responses with substantial serovar cross-reactivity. The occurrence of high levels of splenocyte proliferation and strong antibody responses corresponded to the initiation of clearance with both ST and SE. Re-challenge of ST and SE infection-primed chickens with either serovar resulted in significant levels of protection (assessed by bacterial numbers and rate of clearance) with little difference between homologous or heterologous challenge schedules. Relatively low levels of antigen-specific splenocyte proliferation were detected during secondary infection, which may be caused by splenic T cells exiting to the gut. In contrast, the more rapid specific antibody responses (compared with primary infection controls) indicate the development of a secondary antigen-specific adaptive response. The substantial level of cross-protection between serovars and the level of antigenic cross-reactivity indicates the potential for single serovar live vaccines to protect against both group B and D salmonellae.


Developing the Synergy Model Patient Acuity Tool for Admission, Discharge, and Transfer.
The Admission Discharge Transfer-Synergy Model Acuity Tool (ADT-SMAT) was developed to quantify patient intervention intensity and patient response variability and to capture nurses' critical thinking. The tool is based on the American Association of Critical-Care Nurses Synergy Model for Patient Care. To determine whether the ADT-SMAT is reliable and valid for predicting the level of care for admission, discharge, and transfer of critically ill patients. Methods Reliability was examined by using interrater reliability, intraclass coefficient, and effect size analyses to evaluate physiological variables and total calculated ADT-SMAT score in 246 patients. Content validity was determined in consultation with critical care nurses, and construct validity was examined by assessing the correlation between ADT-SMAT scores and other convergent and divergent constructs. The ADT-SMAT showed strong reliability for measuring the physiological variables and total score, with an intraclass coefficient of 0.930. The value of Cohen d determining the effect size for each element of the ADT-SMAT was less than 0.20 for every element, indicating that substantial differences in scoring did not occur. The validity of the ADT-SMAT requires additional testing. This is the first study attempting to correlate Synergy Model patient characteristics and acuity while integrating nurses' critical decision-making process. With further testing, the ADT-SMAT could be a valuable tool to quantify and standardize patient characteristics in determining the appropriate level of care associated with admission, discharge, and transfer decisions.


Local Immunotherapy of Cancer: Innovative Approaches to Harnessing Tumor-Specific Immune Responses.
Modern cancer immunotherapies represent a major shift in paradigm with respect to how we understand innate and adaptive responses to malignancy. Successful tumors co-opt normal immunosurveillance mechanisms by potent interactions between the tumor and local draining lymph nodes. Tumor cells mediate a complex and dynamic immunoediting procedure that results in increased vascular efflux into the draining lymphatics, an immunosuppressive microenvironment rich in regulatory T-lymphocytes, dysfunctional antigen presentation, and downregulation of normal effector lymphocyte responses. Our current approach to reversing this process for antitumor effect involves mainly systemic administration of immunotherapeutic agents, many of which have become standard of care in the management of a variety of cancers. Despite this, we are still learning how best to administer these drugs alone and in combination to maximize efficacy while minimizing adverse events. Increasing evidence suggests that comparable efficacy may be achieved by local administration of immunotherapies in the tumor or tumor-draining lymph nodes with substantially lower doses and better tolerability, even with combination therapy. Herein, we review the literature on intratumoral and intranodal immunotherapies in preclinical models and early-phase studies, with particular emphasis on approaches potentially suitable for translation to larger-scale clinical trials.