AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells.
In most cases, macroautophagy/autophagy serves to alleviate cellular stress and acts in a pro-survival manner. However, the effects of autophagy are highly contextual, and autophagic cell death (ACD) is emerging as an alternative paradigm of (stress- and drug-induced) cell demise. AT 101 ([-]-gossypol), a natural compound from cotton seeds, induces ACD in glioma cells as confirmed here by CRISPR/Cas9 knockout of ATG5 that partially, but significantly rescued cell survival following AT 101 treatment. Global proteomic analysis of AT 101-treated U87MG and U343 glioma cells revealed a robust decrease in mitochondrial protein clusters, whereas HMOX1 (heme oxygenase 1) was strongly upregulated. AT 101 rapidly triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a significant reduction of mitochondrial mass and proteins that did not depend on the presence of BAX and BAK1. Conversely, AT 101-induced reduction of mitochondrial mass could be reversed by inhibiting autophagy with wortmannin, bafilomycin A1 and chloroquine. Silencing of HMOX1 and the mitophagy receptors BNIP3 (BCL2 interacting protein 3) and BNIP3L (BCL2 interacting protein 3 like) significantly attenuated AT 101-dependent mitophagy and cell death. Collectively, these data suggest that early mitochondrial dysfunction and HMOX1 overactivation synergize to trigger lethal mitophagy, which contributes to the cell killing effects of AT 101 in glioma cells. ACD, autophagic cell death; ACN, acetonitrile; AT 101, (-)-gossypol; BAF, bafilomycin A1; BAK1, BCL2-antagonist/killer 1; BAX, BCL2-associated X protein; BH3, BCL2 homology region 3; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; BP, Biological Process; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CC, Cellular Component; Con, control; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; DMEM, Dulbecco's Modified Eagle Medium; DTT, 1,4-dithiothreitol; EM, electron microscopy; ER, endoplasmatic reticulum; FACS, fluorescence-activated cell sorting; FBS, fetal bovine serum; FCCP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GO, Gene Ontology; HAcO, acetic acid; HMOX1, heme oxygenase 1; DKO, double knockout; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry; LPL, lipoprotein lipase, MEFs, mouse embryonic fibroblasts; mPTP, mitochondrial permeability transition pore; MTG, MitoTracker Green FM; mt-mKeima, mito-mKeima; MT-ND1, mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1; PBS, phosphate-buffered saline; PE, phosphatidylethanolamine; PI, propidium iodide; PRKN, parkin RBR E3 ubiquitin protein ligase; SDS, sodium dodecyl sulfate; SQSTM1/p62, sequestome 1; STS, staurosporine; sgRNA, single guide RNA; SILAC, stable isotope labeling with amino acids in cell culture; TFA, trifluoroacetic acid, TMRM, tetramethylrhodamine methyl ester perchlorate; WM, wortmannin; WT, wild-type.


S-Layer From Lactobacillus brevis Modulates Antigen-Presenting Cell Functions via the Mincle-Syk-Card9 Axis.
C-type lectin receptors (CLRs) are pattern recognition receptors that are crucial in the innate immune response. The gastrointestinal tract contributes significantly to the maintenance of immune homeostasis; it is the shelter for billions of microorganisms including many genera of Lactobacillus sp. Previously, it was shown that host-CLR interactions with gut microbiota play a crucial role in this context. The Macrophage-inducible C-type lectin (Mincle) is a Syk-coupled CLR that contributes to sensing of mucosa-associated commensals. In this study, we identified Mincle as a receptor for the Surface (S)-layer of the probiotic bacteria Lactobacillus brevis modulating GM-CSF bone marrow-derived cells (BMDCs) functions. We found that the S-layer/Mincle interaction led to a balanced cytokine response in BMDCs by triggering the release of both pro- and anti-inflammatory cytokines. In contrast, BMDCs derived from Mincle-/-, CARD9-/- or conditional Syk-/- mice failed to maintain this balance, thus leading to an increased production of the pro-inflammatory cytokines TNF and IL-6, whereas the levels of the anti-inflammatory cytokines IL-10 and TGF-β were markedly decreased. Importantly, this was accompanied by an altered CD4+ T cell priming capacity of Mincle-/- BMDCs resulting in an increased CD4+ T cell IFN-γ production upon stimulation with L. brevis S-layer. Our results contribute to the understanding of how commensal bacteria regulate antigen-presenting cell (APC) functions and highlight the importance of the Mincle/Syk/Card9 axis in APCs as a key factor in host-microbiota interactions.


[First determination of the prevalence of celiac disease in a Portuguese population].
The prevalence of celiac disease is unknown in Portugal. In European countries the prevalence is between 1:200 and 1:400. The incidence obtained through diagnosed cases in the paediatric gastroenterology units in Portugal was 1:3648. To determine the best current celiac disease screening method and its prevalence in a portuguese population, 536 sera of teenagers with 14 years +/- 6 months from Braga town schools were tested as follows: a) total IgA, b) anti-tissue transglutaminase antibodies c) anti-endomysium antibodies (AEA). One female adolescent, with negative AEA and anti-transglutaminase antibodies had a diagnosed celiac disease; this patient was under appropriate diet. Eleven adolescents had positive anti-transglutaminase antibodies and 4 of these had also positive AEA. A jejunal biopsy was carried out on the latter adolescents. Three presented intestinal villous atrophy, 2 a flat mucosa and 1 a moderate atrophy. One female adolescent had a normal mucosa. The prevalence was 1:134, [confidence interval at 95%, 1:53-1:500]. Presently, total IgA with determination of anti-tissue transglutaminase antibodies is apparently the best screening method; it is less expensive test and, given the use of ELISA, less dependent on the observer. The celiac disease prevalence found in the present study falls within the range of prevalence recently found in other European populations, which implies that the celiac disease is under-diagnosed in Portugal.


Plasma bile acids are not associated with energy metabolism in humans.
Bile acids (BA) have recently been shown to increase energy expenditure in mice, but this concept has not been tested in humans. Therefore, we investigated the relationship between plasma BA levels and energy expenditure in humans. Type 2 diabetic (T2DM) patients (n = 12) and gender, age and BMI-matched healthy controls (n = 12) were studied before and after 8 weeks of treatment with a BA sequestrant. In addition, patients with liver cirrhosis (n = 46) were investigated, since these display elevated plasma BA together with increased energy expenditure. This group was compared to gender-, age- and BMI-matched healthy controls (n = 20). Fasting plasma levels of total BA and individual BA species as well as resting energy expenditure were determined. In response to treatment with the BA sequestrant, plasma deoxycholic acid (DCA) levels decreased in controls (-60%, p < 0.05) and T2DM (-32%, p < 0.05), while chenodeoxycholic acid (CDCA) decreased in controls only (-33%, p < 0.05). Energy expenditure did not differ between T2DM and controls at baseline and, in contrast to plasma BA levels, was unaffected by treatment with the BA sequestrant. Total BA as well as individual BA species did not correlate with energy expenditure at any time throughout the study. Patients with cirrhosis displayed on average an increase in energy expenditure of 18% compared to values predicted by the Harris-Benedict equation, and plasma levels of total BA (up to 12-fold) and individual BA (up to 20-fold) were increased over a wide range. However, neither total nor individual plasma BA levels correlated with energy expenditure. In addition, energy expenditure was identical in patients with a cholestatic versus a non-cholestatic origin of liver disease while plasma total BA levels differed four-fold between the groups. In conclusion, in the various (patho)physiological conditions studied, plasma BA levels were not associated with changes in energy expenditure. Therefore, our data do not support an important role of circulating BA in the control of human energy metabolism.


Impact of population density on mortality in patients hospitalized for heart failure - JROAD-DPC Registry Analysis.
There is little evidence regarding social and geographic factors in patients with heart failure (HF). We sought to investigate the association between in-hospital mortality of patients with HF and population density of the patients' area of residence in Japan. The present study is a retrospective cohort analysis of the nationwide claim-based database, the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). We selected data of 196,286 hospitalized patients with HF (median age of 81 years and 51.8% males). In-hospital mortality was 14.2%, 11.8%, and 9.5% in the lower, middle, and upper tertiles of population density, respectively. Age sub-analysis showed the largest absolute rural-urban disparity in mortality was 4.6% in the oldest subgroup (≥80 years). Multivariate analysis using mixed logistic regression model revealed that higher population density was associated with lower in-hospital mortality: multivariable-adjusted odds ratio (OR): 0.785, 95% confidence interval (CI): (0.713-0.864), p < 0.001 and 0.687, 95% CI: (0.623-0.757), p < 0.001 in the middle and upper tertiles, in comparison with the lower tertile as a reference, after adjustment for age, sex, the New York Heart Association class, comorbidities, and hospital volume. The same tendency was observed in propensity score analysis using 62,291 (in the lower vs. middle tertile) and 57,228 (in the lower vs. upper tertile) matched pairs (OR: 0.797, 95% CI: 0.725-0.877, p < 0.001 and OR: 0.695, 95% CI: 0.634-0.762, p < 0.001 in the middle and upper tertile, respectively). Higher population density was associated with lower in-hospital mortality in HF. More research is needed to gain insight into causality.


Nup153 Unlocks the Nuclear Pore Complex for HIV-1 Nuclear Translocation in Nondividing Cells.
Human immunodeficiency virus type 1 (HIV-1) displays the unique ability to infect nondividing cells. The capsid of HIV-1 is the viral determinant for viral nuclear import. To understand the cellular factors involved in the ability of HIV-1 to infect nondividing cells, we sought to find capsid mutations that allow the virus to infect dividing but not nondividing cells. Because the interaction of capsid with the nucleoporin protein 153 (Nup153) is important for nuclear import of HIV-1, we solved new crystal structures of hexameric HIV-1 capsid in complex with a Nup153-derived peptide containing a phenylalanine-glycine repeat (FG repeat), which we used to guide structure-based mutagenesis of the capsid-binding interface. HIV-1 viruses with mutations in these capsid residues were tested for their ability to infect dividing and nondividing cells. HIV-1 viruses with capsid N57 substitutions infected dividing but not nondividing cells. Interestingly, HIV-1 viruses with N57 mutations underwent reverse transcription but not nuclear translocation. The mutant capsids also lost the ability to interact with Nup153 and CPSF6. The use of small molecules PF74 and BI-2 prevented the interaction of FG-containing nucleoporins (Nups), such as Nup153, with the HIV-1 core. Analysis of integration sites in HIV-1 viruses with N57 mutations revealed diminished integration into transcriptionally active genes in a manner resembling that of HIV-1 in CPSF6 knockout cells or that of HIV-1-N74D. The integration pattern of the N57 mutant HIV-1 can be explained by loss of capsid interaction with CPSF6, whereas capsid interaction with Nup153 is required for HIV-1 to infect nondividing cells. Additionally, the observed viral integration profiles suggested that integration site selection is a multiparameter process that depends upon nuclear factors and the state of the cellular chromatin.IMPORTANCE One of the key advantages that distinguish lentiviruses, such as HIV-1, from all other retroviruses is its ability to infect nondividing cells. Interaction of the HIV-1 capsid with Nup153 and CPSF6 is important for nuclear entry and integration; however, the contribution of each of these proteins to nuclear import and integration is not clear. Using genetics, we demonstrated that these proteins contribute to different processes: Nup153 is essential for the HIV-1 nuclear import in nondividing cells, and CPSF6 is important for HIV-1 integration. In addition, nuclear factors such as CPSF6 and the state of the chromatin are known to be important for integration site selection; nevertheless, the preferential determinant influencing integration site selection is not known. This work demonstrates that integration site selection is a multiparameter process that depends upon nuclear factors and the state of the cellular chromatin.


A mechanism for revising accreditation standards: a study of the process, resources required and evaluation outcomes.
The study objective was to identify and describe the process, resources and expertise required for the revision of accreditation standards, and report outcomes arising from such activities. Secondary document analysis of materials from an accreditation standards development agency. The Royal Australian College of General Practitioners' (RACGP) documents, minutes and reports related to the revision of the accreditation standards were examined. The RACGP revision of the accreditation standards was conducted over a 12 month period and comprised six phases with multiple tasks, including: review methodology planning; review of the evidence base and each standard; new material development; constructing field trial methodology; drafting, trialling and refining new standards; and production of new standards. Over 100 individuals participated, with an additional 30 providing periodic input and feedback. Participants were drawn from healthcare professional associations, primary healthcare services, accreditation agencies, government agencies and public health organisations. Their expertise spanned: project management; standards development and writing; primary healthcare practice; quality and safety improvement methodologies; accreditation implementation and surveying; and research. The review and development process was shaped by five issues: project expectations; resource and time requirements; a collaborative approach; stakeholder engagement; and the product produced. The RACGP evaluation was that participants were positive about their experience, the standards produced and considered them relevant for the sector. The revision of accreditation standards requires considerable resources and expertise, drawn from a broad range of stakeholders. Collaborative, inclusive processes that engage key stakeholders helps promote greater industry acceptance of the standards.


Time trend of multiple myeloma and associated secondary primary malignancies in Asian patients: a Taiwan population-based study.
Studies involving second malignancies in patients with multiple myeloma are limited for the Asian population. Using data from population-based insurance claims, we assessed the risk of developing secondary malignancies after multiple myeloma, in particular hematologic malignancies. A retrospective cohort study was conducted in 3970 patients with newly diagnosed multiple myeloma from the registry of catastrophic illnesses between 1997 and 2009. A total of 15880 subjects without multiple myeloma were randomly selected as comparisons from the insured population, frequency-matched based on gender, age, and the date of diagnosis. The incidence of secondary malignancies was ascertained through cross-referencing with the National Cancer Registry System. The Cox proportional hazards model was used for analyses. The incidence of multiple myeloma in the insured population increased annually. The overall incidence of secondary malignancy was lower in the multiple myeloma cohort than in the comparison cohort (93.6 vs. 104.5 per 10,000 person-years, IRR = 0.90, 95% CI = 0.78-1.04). The incidence of hematologic malignancies was 11-fold greater for multiple myeloma patients (47.2 vs. 4.09 per 10,000 person-years) with an adjusted HR of 13.0 (95% CI = 7.79-21.6) compared with the comparison cohort. The relative risk of secondary malignancy was also strong for myeloid leukemia (21.2 vs. 1.36 per 10,000 person-years). Gender- and age-specific analysis for secondary hematologic malignancies showed that males and patients with multiple myeloma <60 years of age had a higher risk of secondary malignancy than females and patients with multiple myeloma >60 years of age. In conclusion, patients with multiple myeloma, especially younger patients, are at a high risk of hematologic malignancies.


ReactionFlow: an interactive visualization tool for causality analysis in biological pathways.
Molecular and systems biologists are tasked with the comprehension and analysis of incredibly complex networks of biochemical interactions, called pathways, that occur within a cell. Through interviews with domain experts, we identified four common tasks that require an understanding of the causality within pathways, that is, the downstream and upstream relationships between proteins and biochemical reactions, including: visualizing downstream consequences of perturbing a protein; finding the shortest path between two proteins; detecting feedback loops within the pathway; and identifying common downstream elements from two or more proteins. We introduce ReactionFlow, a visual analytics application for pathway analysis that emphasizes the structural and causal relationships amongst proteins, complexes, and biochemical reactions within a given pathway. To support the identified causality analysis tasks, user interactions allow an analyst to filter, cluster, and select pathway components across linked views. Animation is used to highlight the flow of activity through a pathway. We evaluated ReactionFlow by providing our application to two domain experts who have significant experience with biomolecular pathways, after which we conducted a series of in-depth interviews focused on each of the four causality analysis tasks. Their feedback leads us to believe that our techniques could be useful to researchers who must be able to understand and analyze the complex nature of biological pathways. ReactionFlow is available at https://github.com/CreativeCodingLab/ReactionFlow.


[How to deal with blast injuries. 15 tips for healthcare providers].
The recent terror attacks in Paris and Brussels have made the subject of injuries caused by explosives, also known as 'blast injuries', a very current one. The Netherlands has limited experience with terrorist attacks. This means that Dutch medical care providers possibly do not have sufficient knowledge about dealing with blast injuries. After explaining the mechanisms of explosions and the effects that these have on the human body, we go on to provide 15 tips on the main principles of treating blast injuries. These tips will help healthcare providers to deal with the complex requirements of victims of terror.


[Effect of Chinese tea extract on the immune function of mice bearing tumor and their antitumor activity].
The dynamic changes of cellular immune function and antitumor effect of GTE (green tea extract) in the BALB/c mice bearing EAC, HAC and S-180 tumor were investigated. Results showed that intraperitoneal injection GTE daily dose of 80mg/kg stimulate the proliferation of T-Lymphocyte S-180 tumor bearing mice, the 125-IudR incorporation value (cpm) of control group was 932 and that of GTE treated group increased to 2988. The Natural Killer cell's activity (cpm) of treated group was raised from 10.7% of control group to 41%. Daily dose 50mg/kg inhibited the EAC, HAC and the life span of GTE mice bearing EAC ascites tumor prolonged 128%. The GTE were effective on growth activity against mouse Ehrlich tumor at a dose of 500mg/kg by oral administration (P less than 0.05), the inhibition ratio being about 32%. The authors suggested the mechanism of antitumor effects of GTE possible included both cellular immune function and the inhibition of tumor growth.


Endogenous opioids and their role in odor preference acquisition and consolidation following odor-shock conditioning in infant rats.
We assessed the neurochemical basis of olfactory learning induced by presentations of odor and moderate shock in infant rats. Paradoxically, shock conditioning produces an odor preference in 8-day-olds, but an odor aversion in 12-day-olds. Studies have demonstrated the importance of opioids in early olfactory learning; their specific role remains undefined. In this study, postnatal Days 8 and 12 pups were systemically injected with naltrexone, a nonspecific opioid antagonist, or saline and received either paired or backward presentations of odor-moderate shock or odor-only presentations. Blocking the opioid system during conditioning disrupted acquisition of the Day 8 odor preference, but not the Day 12 odor aversion. Additional Day 8 pups were given naltrexone posttraining. Naltrexone not only blocked consolidation of an odor preference but also yielded an odor aversion. These results suggest that the opioid system has a critical role in both olfactory learning and consolidation of odor preferences during the sensitive period.


Regeneration at the predilective damage sites of nerve trunks in treated leprosy.
Superficially located large and medium sized mixed peripheral limb nerves in active leprosy have previously been shown to have well-recognized fusiform swellings. It is generally agreed that these are the sites of predilective nerve involvement where the severest degeneration and fibrosis occur. A semiquantitative histopathological study on one of these sites, the flexor retinaculum region of the posterior tibial nerve, has been carried out on 14 treated leprosy patients who suffered from total sensory loss to the foot for between 2 and 40 years. The following observations were made: (1) large-scale nerve regeneration was present as characterized by numerous Schwann cells and unmyelinated axons which formed regeneration clusters; (2) thick myelinated axons were either absent or present only in very low numbers; (3) the intraneural fibrosis was usually not severe; (4) the presence of active inflammation probably interfered with nerve regeneration; (5) it appeared that this regeneration started shortly after the onset of therapy and persisted for decades; (6) lepromatous cases were characterized by evenly distributed pathology, whereas borderline tuberculoid cases had an unevenly distributed pathology; (7) the massive nerve regeneration observed was functionally ineffective--these findings indicate that the total nerve damage may affect the more peripheral nerve branches.


Conformational isomerism controls collective flexibility in metal-organic framework DUT-8(Ni).
Metal-organic frameworks (MOFs) are coordination networks with organic ligands containing potential voids. Some MOFs show pronounced structural flexibility that may result in closing and re-opening these pores. Here, we show that collective flexibility in a MOF-DUT-8(Ni) - is controlled by conformational isomerism. DUT-8(Ni), a pillared-layer MOF with Ni2 paddle-wheels, dabco pillars and naphthalene dicarboxylate (ndc) linkers, can crystallize in many conformational isomers that depend on the orientation of the non-linear ndc linkers with respect to each other. While the open form is compatible with several of these conformations, only one of them, with alternating linker orientations, is stable as the closed form. We show, by means of first principles calculations, that in the stable closed form, the appreciable lattice strain is compensated by London-dispersion forces between the ndc linkers that arrange with maximum overlap in a stacking order similar to the stacking in graphite. We substantiate these results by well-tempered metadynamics calculations on the DFT-based Born-Oppenheimer potential energy surface, by refined X-ray diffraction data and by nitrogen adsorption data obtained by experiment and grand-canonical Monte-Carlo simulations based on the DFT-optimized and PXRD-derived geometries. While the reported origin of flexibility cannot be generalized to all flexible MOFs, it offers a rational design concept of folding mechanisms in switchable MOFs by exploitation of the stabilization effect of linker stacking in the closed form.


Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: subgroup analysis from two randomized trials.
We conducted a post-hoc analysis on the effect of recombinant factor VIIa (rFVIIa) on coagulopathic patients from two randomized, placebo-controlled, double-blind trials of rFVIIa as an adjunctive therapy for bleeding in patients with severe trauma. Blunt and penetrating trauma patients were randomly assigned to rFVIIa (200 + 100 + 100 microg/kg) at 0, 1, and 3 hours after transfusion of 8 units of red blood cells (RBCs) or to placebo. Subjects were monitored for 48 hours post-dosing and followed for 30 days. Coagulopathy was retrospectively defined as transfusion of fresh frozen plasma (FFP) (>1 unit of FFP per 4 units of RBCs), FFP in addition to whole blood, and transfusion of platelets and/or cryoprecipitate. Sixty rFVIIa-treated and 76 placebo subjects were retrospectively identified as being coagulopathic. No significant differences were noted in baseline characteristics. The rFVIIa-treated coagulopathic subgroup consumed significantly less blood product: RBC transfusion decreased by 2.6 units for the whole study population (P = 0.02) and by 3.5 units among patients surviving more than 48 hours (P < 0.001). Transfusion of FFP (1,400 versus 660 ml, P < 0.01), platelet (300 versus 100 ml, P = 0.01), and massive transfusions (29% versus 6%, P < 0.01) also dropped significantly. rFVIIa reduced multi-organ failure and/or acute respiratory distress syndrome in the coagulopathic patients (3% versus 20%, P = 0.004), whereas thromboembolic events were equally present in both groups (3% versus 4%, P = 1.00). Coagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy.


Detection of molecular hydrogen in the atmosphere of Mars.
Four hydrogen (H2) lines have been detected in a spectrum of Mars observed with the Far Ultraviolet Spectroscopic Explorer. Three of those lines are excited by the solar Lyman beta photons. The line intensities correspond to a column H2 abundance of 1.17 (+/-0.13) x 10(13) per square centimeter above 140 kilometers on Mars. A photochemical model for the upper atmosphere that simulates the observed H2 abundance results in an H2 mixing ratio of 15 +/- 5 parts per million in the lower atmosphere. The H2 and HD mixing ratios agree with photochemical fractionation of D (deuterium) between H2O and H2. Analysis of D fractionation among a few reservoirs of ice, water vapor, and molecular hydrogen on Mars implies that a global ocean more than 30 meters deep was lost since the end of hydrodynamic escape. Only 4% of the initially accreted water remained on the planet at the end of hydrodynamic escape, and initially Mars could have had even more water (as a proportion of mass) than Earth.


Oxidation of 3-aminobenzanthrone, a human metabolite of carcinogenic environmental pollutant 3-nitrobenzanthrone, by cytochromes P450 - similarity between human and rat enzymes.
3-Aminobenzanthrone (3-ABA) is the main human metabolite of carcinogenic environmental pollutant 3-nitrobenzanthrone (3-NBA). Understanding which cytochrome P450 (CYP) enzymes are involved in metabolism of this toxicant is important in the assessment of individual susceptibility. Characterization of 3-ABA metabolites formed by rat hepatic microsomes containing cytochromes P450 (CYPs) and identification of the major rat and human CYPs participating in this process are aims of this study. HPLC with UV detection was employed for the separation and characterization of 3-ABA metabolites. Inducers and inhibitors of CYPs and rat and human recombinant CYPs were used to characterize the enzymes participating in 3-ABA oxidation. Selective CYP inhibitors and hepatic microsomes of rats pre-treated with specific CYP inducers were used to characterize rat liver CYPs metabolizing 3-ABA (measured as consumption of 3-ABA). Kinetics of these reactions catalyzed by rat hepatic microsomes was also evaluated. Based on these studies, we attribute most of 3-ABA metabolism in rat liver to CYP1A and 3A. Among recombinant rat and human CYP enzymes tested in this study, rat CYP3A2 and human CYP3A4/5, followed by CYP1A1 of both organisms were the most effective enzymes converting 3-ABA. Rat hepatic CYP enzymes oxidize 3-ABA up to three metabolites. Two of them were identified to be the products formed by oxidation of 3-ABA on its amino group back to the parent compound from which 3-ABA is generated in organisms, 3-NBA. Namely, N-hydroxylation metabolite, N-hydroxy-3-ABA and 3-NBA were identified to be these 3-ABA oxidation products. These metabolites are formed by CYPs of a 1A subfamily. Another 3-ABA metabolite, whose structure remains to be characterized, is generated not only by CYP1A but also by other CYP enzymes, predominantly by CYPs of a 3A subfamily. The results found in this study, the first report on the metabolism of 3-ABA by human and rat CYPs, clearly demonstrate that CYPs of 3A and 1A subfamilies are the major enzymes metabolizing 3-ABA.


Very long lasers.
The properties and oscillation characteristics of very long cw xenon lasers are discussed and pertinent long laser experiments described. High-gain 3.508-microm xenon laser amplifiers were used in these experiments. Laser cavity lengths of up to 30 km were studied. Spectrum analyses revealed complex oscillation spectra exhibiting the characteristics of both homogeneous and inhomogeneous laser mode structures. Long laser Doppler experiments, Q-switching studies, and modulation experiments were performed. Applications to atmospheric pollution detection are discussed.


Investigation of the Association Between Alcohol Outlet Density and Alcohol-Related Hospital Admission Rates in England: Study Protocol.
Availability of alcohol is a major policy issue for governments, and one of the availability factors is the density of alcohol outlets within geographic areas. The aim of this study is to investigate the association between alcohol outlet density and hospital admissions for alcohol-related conditions in a national (English) small area level ecological study. This project will employ ecological correlation and cross-sectional time series study designs to examine spatial and temporal relationships between alcohol outlet density and hospital admissions. Census units to be used in the analysis will include all Lower and Middle Super-Output Areas (LSOAs and MSOAs) in England (53 million total population; 32,482 LSOAs and 6781 MSOAs). LSOAs (approximately 1500 people per LSOA) will support investigation at a fine spatial resolution. Spatio-temporal associations will be investigated using MSOAs (approximately 7500 people per MSOA). The project will use comprehensive coverage data on alcohol outlets in England (from 2003, 2007, 2010, and 2013) from a commercial source, which has estimated that the database includes 98% of all alcohol outlets in England. Alcohol outlets may be classified into two broad groups: on-trade outlets, comprising outlets from which alcohol can be purchased and consumed on the premises (eg, pubs); and off-trade outlets, in which alcohol can be purchased but not consumed on the premises (eg, off-licenses). In the 2010 dataset, there are 132,989 on-trade and 51,975 off-trade outlets. The longitudinal data series will allow us to examine associations between changes in outlet density and changes in hospital admission rates. The project will use anonymized data on alcohol-related hospital admissions in England from 2003 to 2013 and investigate associations with acute (eg, admissions for injuries) and chronic (eg, admissions for alcoholic liver disease) harms. The investigation will include the examination of conditions that are wholly and partially attributable to alcohol, using internationally standardized alcohol-attributable fractions. The project is currently in progress. Results are expected in 2017. The results of this study will provide a national evidence base to inform policy decisions regarding the licensing of alcohol sales outlets.


Antibody and cellular responses to HIV vaccine regimens with DNA plasmid as compared with ALVAC priming: An analysis of two randomized controlled trials.
DNA plasmids promise a pragmatic alternative to viral vectors for prime-boost HIV-1 vaccines. We evaluated DNA plasmid versus canarypox virus (ALVAC) primes in 2 randomized, double-blind, placebo-controlled trials in southern Africa with harmonized trial designs. HIV Vaccine Trials Network (HVTN) 111 tested DNA plasmid prime by needle or needleless injection device (Biojector) and DNA plasmid plus gp120 protein plus MF59 adjuvant boost. HVTN 100 tested ALVAC prime and ALVAC plus gp120 protein plus MF59 adjuvant boost (same protein/adjuvant as HVTN 111) by needle. The primary endpoints for this analysis were binding antibody (bAb) responses to HIV antigens (gp120 from strains ZM96, 1086, and TV1; variable 1 and 2 [V1V2] regions of gp120 from strains TV1, 1086, and B.CaseA, as 1086 V1V2 and B.CaseA were correlates of risk in the RV144 efficacy trial), neutralizing antibody (nAb) responses to pseudoviruses TV1c8.2 and MW925.26, and cellular responses to vaccine-matched antigens (envelope [Env] from strains ZM96, 1086, and TV1; and Gag from strains LAI and ZM96) at month 6.5, two weeks after the fourth vaccination. Per-protocol cohorts included vaccine recipients from HVTN 100 (n = 186, 60% male, median age 23 years) enrolled between February 9, 2015, and May 26, 2015 and from HVTN 111 (n = 56, 48% male, median age 24 years) enrolled between June 21, 2016, and July 13, 2017. IgG bAb response rates were 100% to 3 Env gp120 antigens in both trials. Response rates to V1V2 were lower and similar in both trials except to vaccine-matched 1086 V1V2, with rates significantly higher for the DNA-primed regimen than the ALVAC-primed regimen: 96.6% versus 72.7% (difference = 23.9%, 95% CI 15.6%-32.2%, p < 0.001). Among positive responders, bAb net mean fluorescence intensity (MFI) was significantly higher with the DNA-primed regimen than ALVAC-primed for 1086 V1V2 (geometric mean [GM] 2,833.3 versus 1,200.9; ratio = 2.36, 95% CI 1.42-3.92, p < 0.001) and B.CaseA V1V2 (GM 2314.0 versus 744.6, ratio = 3.11, 95% CI 1.51-6.38, p = 0.002). nAb response rates were >98% in both trials, with significantly higher 50% inhibitory dilution (ID50) among DNA-primed positive responders (n = 53) versus ALVAC-primed (n = 182) to tier 1A MW965.26 (GM 577.7 versus 265.7, ratio = 2.17, 95% CI 1.67-2.83, p < 0.001) and to TV1c8.2 (GM 187.3 versus 100.4, ratio = 1.87, 95% CI 1.48-2.35, p < 0.001). CD4+ T-cell response rates were significantly higher with DNA plasmid prime via Biojector than ALVAC prime (91.4% versus 52.8%, difference = 38.6%, 95% CI 20.5%-56.6%, p < 0.001 for ZM96.C; 88.0% versus 43.1%, difference = 44.9%, 95% CI 26.7%-63.1%, p < 0.001 for 1086.C; 55.5% versus 2.2%, difference = 53.3%, 95% CI 23.9%-82.7%, p < 0.001 for Gag LAI/ZM96). The study's main limitations include the nonrandomized comparison of vaccines from 2 different trials, the lack of data on immune responses to other non-vaccine-matched antigens, and the uncertain clinical significance of the observed immunological effects. In this study, we found that further investigation of DNA/protein regimens is warranted given enhanced immunogenicity to the V1V2 correlates of decreased HIV-1 acquisition risk identified in RV144, the only HIV vaccine trial to date to show any efficacy.


International physician survey on management of FOP: a modified Delphi study.
Fibrodysplasia ossificans progressiva (FOP), a disabling disorder of progressive heterotopic ossification (HEO), is caused by heterozygous gain-of- function mutations in Activin receptor A, type I (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Presently, symptomatic management is possible, but no definitive treatments are available. Although extensive guidelines for symptomatic management are widely used, regional preferences exist. In order to understand if there was worldwide consensus among clinicians treating FOP patients, an expert panel of physicians directly involved in FOP patient care was convened. Using a modified Delphi method, broad international consensus was reached on four main topics: diagnosis, prevention of flare-ups, patient and family-centered care and general clinical management issues. This study of physician preferences provides a basis for standardization of clinical management for FOP.


Identification and characterization of human PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2 genes homologous to Drosophila tissue polarity gene prickle.
Drosophila prickle is implicated in tissue polarity or planar polarity. Here, human PRICKLE1 gene corresponding to FLJ31937 cDNA and human PRICKLE2 gene corresponding to DKFZp686D143 cDNA were identified to be homologous to Drosophila prickle gene by using bioinformatics. PRICKLE1 gene was mapped to human chromosome 12p11-q12, and PRICKLE2 gene was mapped to human chromosome 3p14. Mouse Prickle1 and Prickle2 genes were next identified in mouse genome draft sequences NW_000106.1 and NW_000262.1, respectively. Human PRICKLE1, PRICKLE2, Xenopus Prickle, and Drosophila prickle were homologous in the PET domain, three LIM domains, and the C-terminal Prickle homologous (PKH) domain. LMO6 and TESTIN, containing the PET domain and three LIM domains, were found to lack the PKH domain. Therefore, PRICKLE1 and PRICKLE2 rather than LMO6 and TESTIN were found to be human homologs of Drosophila prickle. PRICKLE1 and PRICKLE2 mRNAs were expressed together in brain, eye and testis. PRICKLE1 mRNA was expressed in fetal heart and hematological malignancies, while PRICKLE2 mRNA in fetal brain, adult cartilage, pancreatic islet, gastric cancer with signet-ring cell features, and uterus tumors. Because tissue polarity genes frizzled, dishevelled, flamingo, and Vang are evolutionary and functionary conserved from Drosophila to human, PRICKLE1 and PRICKLE2 might be implicated in the localization of Frizzled and Dishevelled proteins, just like Drosophila prickle. This is the first report on identification and characterization of human PRICKLE1, PRICKLE2, mouse Prickle1, and Prickle2 genes.


Identification and characterization of seminal fluid proteins in the Asian tiger mosquito, Aedes albopictus.
The Asian tiger mosquito (Aedes albopictus) is an important vector for pathogens that affect human health, including the viruses that cause dengue and Chikungunya fevers. It is also one of the world's fastest-spreading invasive species. For these reasons, it is crucial to identify strategies for controlling the reproduction and spread of this mosquito. During mating, seminal fluid proteins (Sfps) are transferred from male mosquitoes to females, and these Sfps modulate female behavior and physiology in ways that influence reproduction. Despite the importance of Sfps on female reproductive behavior in mosquitoes and other insects, the identity of Sfps in Ae. albopictus has not previously been reported. We used transcriptomics and proteomics to identify 198 Sfps in Ae. albopictus. We discuss possible functions of these Sfps in relation to Ae. albopictus reproduction-related biology. We additionally compare the sequences of these Sfps with proteins (including reported Sfps) in several other species, including Ae. aegypti. While only 72 (36.4%) of Ae. albopictus Sfps have putative orthologs in Ae. aegypti, suggesting low conservation of the complement of Sfps in these species, we find no evidence for an elevated rate of evolution or positive selection in the Sfps that are shared between the two Aedes species, suggesting high sequence conservation of those shared Sfps. Our results provide a foundation for future studies to investigate the roles of individual Sfps on feeding and reproduction in this mosquito. Functional analysis of these Sfps could inform strategies for managing the rate of pathogen transmission by Ae. albopictus.


Observation of strongly enhanced ultrashort pulses in 3-D metallic funnel-waveguide.
For strong field enhancement of ultrashort light pulses, a 3-D metallic funnel-waveguide is analyzed using the finite-difference time-domain (FDTD) method. Then the maximum intensity enhancement actually developed by the funnel-waveguide upon the injection of femtosecond laser pulses is observed using two-photon luminescence (TPL) microscopy. In addition, the ultrafast dephasing profile of the localized field at the hot spot of the funnel-waveguide is verified through the interferometric autocorrelation of the TPL signal. Finally it is concluded the funnel-waveguide is an effective 3-D nanostructure that is capable of boosting the peak pulse intensity of stronger than 80 TWcm(-2) by an enhancement factor of 20 dB without significant degradation of the ultrafast spatiotemporal characteristics of the original pulses.


Laser beam complex amplitude measurement by phase diversity.
The control of the optical quality of a laser beam requires a complex amplitude measurement able to deal with strong modulus variations and potentially highly perturbed wavefronts. The method proposed here consists in an extension of phase diversity to complex amplitude measurements that is effective for highly perturbed beams. Named camelot for Complex Amplitude MEasurement by a Likelihood Optimization Tool, it relies on the acquisition and processing of few images of the beam section taken along the optical path. The complex amplitude of the beam is retrieved from the images by the minimization of a Maximum a Posteriori error metric between the images and a model of the beam propagation. The analytical formalism of the method and its experimental validation are presented. The modulus of the beam is compared to a measurement of the beam profile, the phase of the beam is compared to a conventional phase diversity estimate. The precision of the experimental measurements is investigated by numerical simulations.


Diabetic ketoacidosis: clinical characteristics, precipitating factors and outcomes of care.
Diabetic ketoacidosis (DKA) is a common and serious complication of diabetes mellitus (DM). To evaluate the clinical characteristics, hospital management and outcomes of patients with DKA. We performed a retrospective cohort study of patients hospitalized with DKA during the period 1 January 2003 to 1 January 2010. Three groups were compared: patients with mild DKA, with moderate DKA, and with severe DKA. The primary outcome was in-hospital all-cause mortality. The secondary outcomes were 30 days all-cause mortality, length of hospital stay, and complication rate. The study population comprised 220 patients with DKA. In the mild (78 patients) and moderate (116 patients) groups there was a higher proportion of patients with type 1 DM (75.6%, 79.3%) compared with 57.7% in the severe group (26 patients, P = 0.08). HbA1c levels prior to admission were high in all three groups, without significant difference (10.9 +/- 2.2, 10.7 +/- 1.9, and 10.6 +/- 2.4 respectively, P = 0.9). In all groups the most frequent precipitating factors were related to insulin therapy and infections. The patients with severe DKA had more electrolyte abnormalities (hypokalemia, hypomagnesemia, hypophosphatemia) compared with the mild and moderate forms of the disease. While 72.7% of the entire cohort was hospitalized in the general medical ward, 80.8% of those with severe DKA were admitted to the intensive care unit. The in-hospital mortality rate for the entire cohort was 4.1%, comparable with previous data from experienced centers. Advanced age, mechanical ventilation and bedridden state were independent predictors associated with 30 day mortality: hazard ratio (HR) 1.1, 95% confidence interval (CI) 1.02-1.11; HR 6.8, 95% CI 2.03-23.1; and HR 3.8, 95% CI 1.13-12.7, respectively. Patients with DKA in our study were generally poorly controlled prior to their admission, as reflected by high HbA1c levels. Type 2 DM is frequently associated with DKA including the severe form of the disease. The most common precipitating factors for the development of DKA were related to insulin therapy and infections. Advanced age, mechanical ventilation and bedridden state wer independent predictors of 30 day mortality.


Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells.
CD73-derived adenosine acts as potent inhibitor of inflammation, and regulatory T cells (Treg) have been shown to express CD73 as a novel marker. This study explored the role of endogenously formed adenosine in modulating NF-κB activity and cytokine/chemokine release from murine Treg and effector T cells (Teff) including key enzymes/purinergic receptors of extracellular ATP catabolism. Stimulating murine splenocytes and CD4(+) T cells with anti-CD3/anti-CD28 significantly upregulated activated NF-κB in CD73(-/-) T cells (wild type: 4.36 ± 0.21; CD73(-/-): 6.58 ± 0.75; n = 4; P = 0.029). This was associated with an augmented release of proinflammatory cytokines IL-2, TNF-α, and IFN-γ. Similar changes were observed with the CD73 inhibitor APCP (50 μM) on NF-κB and IFN-γ in wild-type CD4(+) T-cells. Treatment of stimulated CD4(+) T-cells with adenosine (25 μM) potently reduced IFN-γ release which is mediated by adenosine A2a receptors (A2aR). AMP (50 μM) also reduced cytokine release which was not inhibited by APCP. In Teff, A2aR activation (CGS21680) potently inhibited the release of IL-1, IL-2, IL-3, IL-4, IL-12, IL-13, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL3, and CCL4. However, in Treg, CGS21680 did not alter cytokine/chemokine release. In summary, CD73-derived adenosine tonically inhibits active NF-κB in CD4(+) T-cells, thereby modulating the release of a broad spectrum of proinflammatory cytokines and chemokines. Downregulation of P2X7 and upregulation of CD73 in Treg after antigenic stimulation may be an important mechanism to maintain the ability of Treg to generate immunosuppressive adenosine.


Biliopancreatic Diversion Decreases Postprandial Apolipoprotein A-IV Levels in Mildly Obese Individuals with Type 2 Diabetes Mellitus: a Prospective Study.
Bariatric surgery usually leads to improvement on the general lipid profile, but its role in the levels of apolipoprotein A-IV (Apo-AIV) is not completely understood. Apo-AIV is a gut-released lipoprotein which is enrolled in satiety regulation and presents anti-inflammatory, anti-atherogenic, and anti-oxidative properties. The objective of this study was to determine the influence of biliopancreatic diversion (BPD) in the levels of Apo-AIV. This is a prospective exploratory study which evaluated eight obese individuals with type 2 diabetes mellitus (T2DM) who underwent BPD (Scopinaro operation) and were followed-up for 12 months. Apo-AIV levels were determined by means of serial dosages through a standard meal tolerance test (MTT) in the immediate preoperative period and then 12 months later. There was a significant change in the Apo-AIV curve following MTT before and after surgery. At 0 and 45 min, the Apo-AIV levels did not significantly differ before and after surgery; at 120 and 180 min, Apo-AIV levels were significantly lower following BPD. We observed a decrease of postprandial levels of Apo-AIV following MTT in mildly obese individuals with T2DM. This finding appears to be related to the suppression in the Apo-AIV response that obese individuals tend to present. Weight reduction itself, endotoxemia, and the large segments of bypassed intestine may be enrolled in this impaired response.


Objective measures of electrode discrimination with electrically evoked auditory change complex and speech-perception abilities in children with auditory neuropathy spectrum disorder.
This study aimed to (1) determine the sensitivity of the electrically evoked auditory change complex (eACC) to changes in stimulating electrode position; and (2) investigate the association between results of eACC measures and behavioral electrode discrimination and their association with speech-perception performance in pediatric cochlear implant (CI) users who have auditory neuropathy spectrum disorder (ANSD). Fifteen children with ANSD ranging in age between 5.4 and 18.6 years participated in this study. All subjects used Cochlear Nucleus devices. For each subject, open-set speech-perception ability was assessed using the Phonetically Balanced Kindergarten word lists presented at 60 dB SPL, using monitored live voice in a sound booth. Behavioral and objective measures of electrode discrimination were assessed in a nonclinical test environment. The stimuli used to elicit these measures were 800 msec biphasic pulse trains delivered by a direct interface to the CI. Data were collected from two basic stimulation conditions. In the standard condition, the entire pulse train was delivered to a mid-array electrode (electrode 11 or 12) at the maximum comfortable level (C level). In the change condition, the stimulus was split into two 400 msec pulse train segments presented sequentially on two different electrodes. The stimulation level of the second 400 msec pulse train was loudness balanced to the C level of the mid-array electrode used in the standard condition. The separation between the pair of stimulating electrodes was systematically varied. For behavioral electrode-discrimination measures, each subject was required to determine whether he or she heard one or two sounds for stimuli presented in different stimulation conditions. For the eACC measures, two replicates of 100 artifact-free sweeps were recorded for each stimulation condition. The eACC in response to changes in stimulating electrode position was recorded from all subjects with ANSD using direct electrical stimulation. Electrode-discrimination thresholds determined with the eACC and behavioral measures were consistent. Children with ANSD using CIs who showed poorer speech performance also required larger separations between the stimulating electrode pair to reliably elicit the eACC than subjects with better speech-perception performance. There was a robust correlation between electrode-discrimination capacities and speech-perception performances in subjects tested in this study. The effect of electrode separation on eACC amplitudes was not monotonic. These results demonstrate the feasibility of using eACC to evaluate electrode-discrimination capacities in children with ANSD. These results suggest that the eACC elicited by changes in stimulating electrode position holds great promise as an objective tool for evaluating spectral-pattern detection in such subjects, which may be predictive of their potential speech-perception performance.


A Computer Vision System Based on Majority-Voting Ensemble Neural Network for the Automatic Classification of Three Chickpea Varieties.
Since different varieties of crops have specific applications, it is therefore important to properly identify each cultivar, in order to avoid fake varieties being sold as genuine, i.e., fraud. Despite that properly trained human experts might accurately identify and classify crop varieties, computer vision systems are needed since conditions such as fatigue, reproducibility, and so on, can influence the expert's judgment and assessment. Chickpea (Cicer arietinum L.) is an important legume at the world-level and has several varieties. Three chickpea varieties with a rather similar visual appearance were studied here: Adel, Arman, and Azad chickpeas. The purpose of this paper is to present a computer vision system for the automatic classification of those chickpea varieties. First, segmentation was performed using an Hue Saturation Intensity (HSI) color space threshold. Next, color and textural (from the gray level co-occurrence matrix, GLCM) properties (features) were extracted from the chickpea sample images. Then, using the hybrid artificial neural network-cultural algorithm (ANN-CA), the sub-optimal combination of the five most effective properties (mean of the RGB color space components, mean of the HSI color space components, entropy of GLCM matrix at 90°, standard deviation of GLCM matrix at 0°, and mean third component in YCbCr color space) were selected as discriminant features. Finally, an ANN-PSO/ACO/HS majority voting (MV) ensemble methodology merging three different classifier outputs, namely the hybrid artificial neural network-particle swarm optimization (ANN-PSO), hybrid artificial neural network-ant colony optimization (ANN-ACO), and hybrid artificial neural network-harmonic search (ANN-HS), was used. Results showed that the ensemble ANN-PSO/ACO/HS-MV classifier approach reached an average classification accuracy of 99.10 ± 0.75% over the test set, after averaging 1000 random iterations.


The role of attention and familiarity in face identification.
How is attention allocated during face identification? Previous work using famous and unfamiliar faces suggests that either no attention or a special attentional mechanism is required. We used a conventional attentional blink (AB) procedure to measure face identification with temporarily reduced attention. The participants viewed a rapid series of face images with one embedded nonface abstract pattern (T1). They judged the texture of T1 and then detected a prespecified face (T2) presented at varying lags after T1. T2 was either famous or unfamiliar, as were distractor faces. Regardless of distractor type, detection of an unfamiliar T2 face was significantly impaired at short versus long T1-T2 lags, indicating an attentional requirement for face identification. Detection of a famous T2 face was unaffected by lag, suggesting that familiarity protects against atemporal attentional bottleneck These findings do not support propositions that face identification is "special" in its need for attentional control


Effectiveness of a smartphone application to promote physical activity in primary care: the SMART MOVE randomised controlled trial.
Physical inactivity is a major, potentially modifiable, risk factor for cardiovascular disease, cancer, and other chronic diseases. Effective, simple, and generalisable interventions that will increase physical activity in populations are needed. To evaluate the effectiveness of a smartphone application (app) to increase physical activity in primary care. An 8-week, open-label, randomised controlled trial in rural, primary care in the west of Ireland. Android smartphone users >16 years of age were recruited. All participants were provided with similar physical activity goals and information on the benefits of exercise. The intervention group was provided with a smartphone app and detailed instructions on how to use it to achieve these goals. The primary outcome was change in physical activity, as measured by a daily step count between baseline and follow-up. A total of 139 patients were referred by their primary care health professional or self-referred. In total, 37 (27%) were screened out and 12 (9%) declined to participate, leaving 90 (65%) patients who were randomised. Of these, 78 provided baseline data (intervention = 37; control = 41) and 77 provided outcome data (intervention = 37; control = 40). The mean daily step count at baseline for intervention and control groups was 4365 and 5138 steps per day respectively. After adjusting, there was evidence of a significant treatment effect (P = 0.009); the difference in mean improvement in daily step count from week 1 to week 8 inclusive was 1029 (95% confidence interval 214 to 1843) steps per day, favouring the intervention. Improvements in physical activity in the intervention group were sustained until the end of the trial. A simple smartphone app significantly increased physical activity over 8 weeks in a primary care population.


IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake.
Interleukin-22 (IL-22) acts protectively and harmfully on intestinal tissue depending on the situation; therefore, IL-22 signaling needs to be tightly regulated. IL-22 binding protein (IL-22BP) binds IL-22 to inhibit IL-22 signaling. It is expressed in intestinal and lymphoid tissues, although its precise distribution and roles have remained unclear. In this study, we show that IL-22BP is highly expressed by CD11b+CD8α- dendritic cells in the subepithelial dome region of Peyer's patches (PPs). We found that IL-22BP blocks IL-22 signaling in the follicle-associated epithelium (FAE) covering PPs, indicating that IL-22BP plays a role in regulating the characteristics of the FAE. As expected, FAE of IL-22BP-deficient (Il22ra2-/-) mice exhibited altered properties such as the enhanced expression of mucus and antimicrobial proteins as well as prominent fucosylation, which are normally suppressed in FAE. Additionally, Il22ra2-/- mice exhibited the decreased uptake of bacterial antigens into PPs without affecting M cell function. Our present study thus demonstrates that IL-22BP promotes bacterial uptake into PPs by influencing FAE gene expression and function.


[Physical factors influencing the floristic relationships of pinyon pine (Pinaceae) from San Luis Potosi, Mexico].
In plant communities, the species distribution patterns and their relationships with environmental factors are of central importance in ecology. In San Luis Potosí of Mexico, woodlands of Pinus cembroides and P. johannis are sympatric, but P. cembroides tends to be located in South and Southwest slopes, in more disturbed sites; unlike, P. johannis, is mostly distributed in mesic areas, in North and Northeast slopes. The aim of this study was to analyze the influence of some physical factors on the floristic similarity of pinyon pine P. cembroides and P. johannis. The study area was located in the Sierra San Miguelito, San Luis Potosí, Mexico. We selected 40 sampling units spread over an area of 50km2. In each unit, we laid out two 20m long lines perpendicular to each other, in which we recorded cover data of the plant species intercepted. We developed two data matrices, the first one including cover values of 91 species, and the second one, considering seven topographical, climatic, and solar radiation variables. We applied cluster analysis and ordination to explore the influence of environmental variables on the floristic differentiation of pinyon pine woodlands. Clustering showed six groups, the first three characterized by P. cembroides. The ordination showed that variance represented by the first three axes was 65.9%. Axis 1 was positively correlated with altitude and negatively with mean annual temperature; axes two and three, showed low correlation with the variables tested. P. cembroides woodlands and accompanying flora tend to be located in lower altitude, higher mean annual temperature, and mainly in South-Southwestern slopes. In contrast, stands of P. johannis, mixed stands of P. johannis-P. cembroides, and Quercus potosina, were usually founded in greater altitudes, mean annual temperature slightly lower, and North-Northeastern exposure. The sites of these monospecific and mixed woodlands with associated species, indicators of environmental variables, generates the pre-diagnosis of the situation of the communities and their condition, so that future actions can be planned in agreement with the natural balance of the ecosystem.


Yeast communities of diverse Drosophila species: comparison of two symbiont groups in the same hosts.
The combination of ecological diversity with genetic and experimental tractability makes Drosophila a powerful model for the study of animal-associated microbial communities. Despite the known importance of yeasts in Drosophila physiology, behavior, and fitness, most recent work has focused on Drosophila-bacterial interactions. In order to get a more complete understanding of the Drosophila microbiome, we characterized the yeast communities associated with different Drosophila species collected around the world. We focused on the phylum Ascomycota because it constitutes the vast majority of the Drosophila-associated yeasts. Our sampling strategy allowed us to compare the distribution and structure of the yeast and bacterial communities in the same host populations. We show that yeast communities are dominated by a small number of abundant taxa, that the same yeast lineages are associated with different host species and populations, and that host diet has a greater effect than host species on yeast community composition. These patterns closely parallel those observed in Drosophila bacterial communities. However, we do not detect a significant correlation between the yeast and bacterial communities of the same host populations. Comparative analysis of different symbiont groups provides a more comprehensive picture of host-microbe interactions. Future work on the role of symbiont communities in animal physiology, ecological adaptation, and evolution would benefit from a similarly holistic approach.


Efficient mode transformations of degenerate Laguerre-Gaussian beams.
We present an approach for efficient conversion of a single-high-order-mode distribution from a laser to a nearly Gaussian distribution and vice versa. It is based on dividing the high-order mode distribution into equal parts that are then combined together coherently. We implement our approach with several optical arrangements that include a combination of discrete elements and some with single interferometric elements. These arrangements are analyzed and experimentally evaluated for converting the TEM01 mode distribution with Mx(2) = 3 to a nearly Gaussian beam with Mx(2) = 1.045 or Mx(2) = 1.15. The basic principle, design, and experimental results obtained with several conversion arrangements are presented. The results reveal that conversion efficiency is typically greater than 90%, compared with theoretical ones. In addition, some arrangement is exploited for converting the fundamental Gaussian-beam distribution into the TEM01 mode distribution.


Does household use of biomass fuel cause lung cancer? A systematic review and evaluation of the evidence for the GBD 2010 study.
Around 2.4 billion people use traditional biomass fuels for household cooking or heating. In 2006, the International Agency for Research on Cancer (IARC) concluded emissions from household coal combustion are a Group 1 carcinogen, while those from biomass were categorised as 2A due to epidemiologic limitations. This review updates the epidemiologic evidence and provides risk estimates for the 2010 Global Burden of Disease study. Searches were conducted of 10 databases to July 2012 for studies of clinically diagnosed or pathologically confirmed lung cancer associated with household biomass use for cooking and/or heating. Fourteen eligible studies of biomass cooking or heating were identified: 13 had independent estimates (12 cooking only), all were case-control designs and provided 8221 cases and 11 342 controls. The ORs for lung cancer risk with biomass for cooking and/or heating were OR 1.17 (95% CI 1.01 to 1.37) overall, and 1.15 (95% CI 0.97 to 1.37) for cooking only. Publication bias was not detected, but more than half the studies did not explicitly describe a clean reference category. Sensitivity analyses restricted to studies with adequate adjustment and a clean reference category found ORs of 1.21 (95% CI 1.05 to 1.39) for men (two reports, compiling five studies) and 1.95 (95% CI 1.16 to 3.27) for women (five reports, compiling eight studies). Exposure-response evidence was seen for men, and higher risk for women in developing compared with developed countries, consistent with higher exposures in the former. There is now stronger evidence for biomass fuel use causing lung cancer, but future studies need better exposure assessment to strengthen exposure-response evidence.


Use of a Smartphone-Based Mobile App for Weight Management in Obese Minority Stroke Survivors: Pilot Randomized Controlled Trial With Open Blinded End Point.
Minorities have an increased incidence of early-onset, obesity-related cerebrovascular disease. Unfortunately, effective weight management in this vulnerable population has significant barriers. Our objective was to determine the feasibility and preliminary treatment effects of a smartphone-based weight loss intervention versus food journals to monitor dietary patterns in minority stroke patients. Swipe out Stroke was a pilot prospective randomized controlled trial with open blinded end point. Minority stroke patients and their caregivers were screened for participation using cluster enrollment. We used adaptive randomization for assignment to a behavior intervention with (1) smartphone-based self-monitoring or (2) food journal self-monitoring. The smartphone group used Lose it! to record meals and communicate with us. Reminder messages (first 30 days), weekly summaries plus reminder messages on missed days (days 31-90), and weekly summaries only (days 91-180) were sent via push notifications. The food journal group used paper diaries. Both groups received 4 in-person visits (baseline and 30, 90, and 180 days), culturally competent counseling, and educational materials. The primary outcome was reduced total body weight. We enrolled 36 stroke patients (n=23, 64% African American; n=13, 36% Hispanic), 17 in the smartphone group, and 19 in the food journal group. Mean age was 54 (SD 9) years; mean body mass index was 35.7 (SD 5.7) kg/m2; education, employment status, and family history of stroke or obesity did not differ between the groups. Baseline rates of depression (Patient Health Questionnaire-9 [PHQ-9] score median 5.5, IQR 3.0-9.5), cognitive impairment (Montreal Cognitive Assessment score median 23.5, IQR 21-26), and inability to ambulate (5/36, 14% with modified Rankin Scale score 3) were similar. In total, 25 (69%) stroke survivors completed Swipe out Stroke (13/17 in the smartphone group, 12/19 in the food journal group); 1 participant in the smartphone group died. Median weight change at 180 days was 5.7 lb (IQR -2.4 to 8.0) in the smartphone group versus 6.4 lb (IQR -2.2 to 12.5; P=.77) in the food journal group. Depression was significantly lower at 30 days in the smartphone group than in the food journal group (PHQ-9 score 2 vs 8; P=.03). Clinically relevant depression rates remained in the zero to minimal range for the smartphone group compared with mild to moderate range in the food journal group at day 90 (PHQ-9 score 3.5 vs 4.5; P=.39) and day 180 (PHQ-9 score 3 vs 6; P=.12). In a population of obese minority stroke survivors, the use of a smartphone did not lead to a significant difference in weight change compared with keeping a food journal. The presence of baseline depression (19/36, 53%) was a confounding variable, which improved with app engagement. Future studies that include treatment of poststroke depression may positively influence intervention efficacy. ClinicalTrials.gov NCT02531074; https://www.clinicaltrials.gov/ct2/show/NCT02531074.


Short-term noise annoyance and electrodermal response as a function of sound-pressure level, cognitive task load, and noise sensitivity.
Two aspects of noise annoyance were addressed in the present laboratory study: (1) the disturbance produced by vehicle pass-by noise while engaging in a challenging non-auditory task, and (2) the evaluative response elicited by the same sounds while imagining to relax at home in the absence of a primary activity. In Experiment 1, N = 29 participants were exposed to short (3-6 s) pass-by recordings presented at graded levels between 50 and 70 dB(A). Concurrent with each sound presentation, they performed a visual multiple-object tracking task, and subsequently rated the annoyance of the sounds on a VAS scale. In Experiment 2, N = 30 participants judged the sounds while imagining to relax, without such a cognitive task. Annoyance was reduced when participants were engaged in the cognitively demanding task, in Experiment 1. Furthermore, when occupied with the task, annoyance slightly, but significantly increased with task load. Across both experiments, the magnitude of simultaneously recorded skin conductance responses in the first 1-4 s after the onset of stimulation increased significantly with sound pressure level. Annoyance ratings tended to be elevated across all sound levels, though significantly only in Experiment 2, in participants classified as noise sensitive based on a 52-item questionnaire. The results suggest that noise annoyance depends on the primary activity the listener is engaged in. They demonstrate that phasic skin conductance responses may serve as an objective correlate of the degree of annoyance experienced. Finally, noise sensitivity is once more shown to augment annoyance ratings in an additive fashion.


Sustained yield forestry in Sweden and Russia: how does it correspond to sustainable forest management policy?
This paper analyzes how sustained yield (SY) forestry is defined and implemented in Sweden and Russia, two countries with different forest-industrial regimes. We first compare definitions of SY forestry in national legislation and policies. Then we study forest management planning in two large forest management units with respect to: delivered forest products and values, how the harvest level of timber is defined, where the harvest takes place, and what treatments are used to sustain desired forest products and values. In Sweden SY forestry is maximum yield based on high-input forest management, and in Russia it is forestry based on natural regeneration with minimum investments in silviculture. We conclude that how SY forestry contributes to SFM depends on the context. Finally, we discuss the consequences of SY forestry as performed in Sweden and Russia related to its ability to support diverse forest functions, as envisioned in sustainable forest management policy.


Control of discontinuous gas exchange in Samia cynthia: effects of atmospheric oxygen, carbon dioxide and moisture.
The evolution of discontinuous gas exchange (DGE) in insects is highly controversial. Adaptive hypotheses which have obtained experimental support include a water savings mechanism for living in dry environments (hygric hypothesis), a reduction in oxidative damage due to a high-performance oxygen delivery system (oxidative damage hypothesis), and the need for steep intratracheal partial pressure gradients to exchange gases under the hypercapnic and/or hypoxic conditions potentially encountered in subterranean environments (chthonic hypothesis). However, few experimental studies have simultaneously assessed multiple competing hypotheses within a strong inference framework. Here, we present such a study at the species level for a diapausing moth pupa, Samia cynthia. Switching gas conditions from controlled normoxic, normocapnic and intermediate humidity to either high or low oxygen, high or low moisture, elevated carbon dioxide, or some combination of these, revealed that DGE was abandoned under all conditions except high oxygen, and high or low gas moisture levels. Thus, support is found for the oxidative damage hypothesis when scored as maintenance of DGE. Modulation of DGE under either dry or hyperoxic conditions suggested strong support for the oxidative damage hypothesis and some limited support for the hygric hypothesis. Therefore, this study demonstrates that the DGE can be maintained and modulated in response to several environmental variables. Further investigation is required using a strong-inference, experimental approach across a range of species from different habitats to determine how widespread the support for the oxidative damage hypothesis might be.


Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase.
Drug combinations are valuable tools for studying biological systems. Although much attention has been given to synergistic interactions in revealing connections between cellular processes, antagonistic interactions can also have tremendous value in elucidating genetic networks and mechanisms of drug action. Here, we exploit the power of antagonism in a high-throughput screen for molecules that suppress the activity of targocil, an inhibitor of the wall teichoic acid (WTA) flippase in Staphylococcus aureus. Well-characterized antagonism within the WTA biosynthetic pathway indicated that early steps would be sensitive to this screen; however, broader interactions with cell wall biogenesis components suggested that it might capture additional targets. A chemical screening effort using this approach identified clomiphene, a widely used fertility drug, as one such compound. Mechanistic characterization revealed the target was the undecaprenyl diphosphate synthase, an enzyme that catalyzes the synthesis of a polyisoprenoid essential for both peptidoglycan and WTA synthesis. The work sheds light on mechanisms contributing to the observed suppressive interactions of clomiphene and in turn reveals aspects of the biology that underlie cell wall synthesis in S. aureus. Further, this effort highlights the utility of antagonistic interactions both in high-throughput screening and in compound mode of action studies. Importantly, clomiphene represents a lead for antibacterial drug discovery.


Biased data reduce efficiency and effectiveness of conservation reserve networks.
Complementarity-based reserve selection algorithms efficiently prioritize sites for biodiversity conservation, but they are data-intensive and most regions lack accurate distribution maps for the majority of species. We explored implications of basing conservation planning decisions on incomplete and biased data using occurrence records of the plant family Proteaceae in South Africa. Treating this high-quality database as 'complete', we introduced three realistic sampling biases characteristic of biodiversity databases: a detectability sampling bias and two forms of roads sampling bias. We then compared reserve networks constructed using complete, biased, and randomly sampled data. All forms of biased sampling performed worse than both the complete data set and equal-effort random sampling. Biased sampling failed to detect a median of 1-5% of species, and resulted in reserve networks that were 9-17% larger than those designed with complete data. Spatial congruence and the correlation of irreplaceability scores between reserve networks selected with biased and complete data were low. Thus, reserve networks based on biased data require more area to protect fewer species and identify different locations than those selected with randomly sampled or complete data.


Muscle ultrasound: Present state and future opportunities.
Muscle ultrasound is a valuable addition to the neuromuscular toolkit in both the clinic and research settings, with proven value and reliability. However, it is currently not fulfilling its full potential in the diagnostic care of patients with neuromuscular disease. This review highlights the possibilities and pitfalls of muscle ultrasound as a diagnostic tool and biomarker, and discusses challenges to its widespread implementation. We expect that limitations in visual image interpretation, posed by user inexperience, could be overcome with simpler scoring systems and the help of deep-learning algorithms. In addition, more information should be collected on the relation between specific neuromuscular disorders, disease stages, and expected ultrasound abnormalities, as this will enhance specificity of the technique and enable the use of muscle ultrasound as a biomarker. Quantified muscle ultrasound gives the most sensitive results but is hampered by the need for device-specific reference values. Efforts in creating dedicated muscle ultrasound systems and artificial intelligence to help with image interpretation are expected to improve usability. Finally, the standard inclusion of muscle and nerve ultrasound in neuromuscular teaching curricula and guidelines will facilitate further implementation in practice. Our hope is that this review will help in unleashing muscle ultrasound's full potential.


Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo.
The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2). Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg). Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional analysis of rhomboid proteases during Toxoplasma invasion.
Host cell invasion by Toxoplasma gondii and other apicomplexan parasites requires transmembrane adhesins that mediate binding to receptors on the substrate and host cell to facilitate motility and invasion. Rhomboid proteases (ROMs) are thought to cleave adhesins within their transmembrane segments, thus allowing the parasite to disengage from receptors and completely enter the host cell. To examine the specific roles of individual ROMs during invasion, we generated single, double, and triple knockouts for the three ROMs expressed in T. gondii tachyzoites. Analysis of these mutants demonstrated that ROM4 is the primary protease involved in adhesin processing and host cell invasion, whereas ROM1 or ROM5 plays negligible roles in these processes. Deletion of ROM4 blocked the shedding of adhesins such as MIC2 (microneme protein 2), causing them to accumulate on the surface of extracellular parasites. Increased surface adhesins led to nonproductive attachment, altered gliding motility, impaired moving junction formation, and reduced invasion efficiency. Despite the importance of ROM4 for efficient invasion, mutants lacking all three ROMs were viable and MIC2 was still efficiently removed from the surface of invaded mutant parasites, implying the existence of ROM-independent mechanisms for adhesin removal during invasion. Collectively, these results suggest that although ROM processing of adhesins is not absolutely essential, it is important for efficient host cell invasion by T. gondii. Importance: Apicomplexan parasites such as Toxoplasma gondii express surface proteins that bind host cell receptors to aid invasion. Many of these adhesins are subject to cleavage by rhomboid proteases (ROMs) within their transmembrane segments during invasion. Previous studies have demonstrated the importance of adhesin cleavage for parasite invasion and proposed that the ROMs responsible for processing would be essential for parasite survival. In T. gondii, ROM5 was thought to be the critical ROM for adhesin shedding due to its robust protease activity in vitro and posterior localization on the parasite surface. Here, we knocked out all three ROMs in T. gondii tachyzoites and found that ROM4, but not ROM5, was key for adhesin cleavage. However, none of the ROMs individually or in combination was essential for cell entry, further emphasizing that essential pathways such as invasion typically rely on redundant pathways to ensure survival.


Characterization of mast cell subtypes, distribution, and antigen-induced activation in the guinea pig esophagus.
The number of esophageal mucosa mast cells (MCs) increases in allergic and inflammation conditions in the esophagus, but their role in these conditions is less clear. MCs are derived from bone marrow, migrate and mature in the peripheral tissues. Two subsets of MCs have been characterized as mucosal MC (MMC) and connective tissue MC (CTMC) defined by anatomic location, granule contents, and functions. Whether esophageal MCs share typical features with either MMC or CTMC has yet to be determined. This study characterized esophageal MCs subtypes, distribution, antigen-induced sensitization, and degranulation as measured by MC staining and histamine release assay. Immunofluorescent double staining of MC tryptase and chymase were performed in the esophagus, intestine, and skin from normal and ovalbumin (OVA) actively sensitized guinea pigs. Histamine release was measured in the esophagus from OVA-sensitized guinea pigs following in vitro antigen challenge. Similar to the MCs in the intestine and skin, esophageal MCs contained three subtypes, which included 62% MCtc (tryptase+/chymase+), 17% MCc (chymase+/tryptase-), and 21% MCt (tryptase+/chymase-). In contrast to the ileal MCs, which were distributed all over the mucosa, submucosa, and serosa, MCs in the esophagus almost all (more than 98%) lined along the lamina propria. OVA active sensitization significantly increased the esophageal MC subtype MCtc. OVA in vitro challenge of the esophagus from sensitized guinea pig significantly decreased tryptase-positive MC subtypes MCtc and MCt, and released a significant amount of tissue histamine content. In conclusion, MCs in the guinea pig esophagus have unique features in immunophenotypes, distribution, and degranulation response to OVA challenge with the release of significant amounts of proteases and histamine into the tissue. These characteristics may indicate that OVA in vitro challenge in OVA-sensitized guinea pig esophagus could be a good model to study the role of esophageal MCs in allergic and inflammation conditions.


Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.
MicroRNAs (miRNAs) are a class of noncoding RNAs that post-transcriptionally regulate gene expression in plants and animals. To investigate the influence of miRNAs on transcript levels, we transfected miRNAs into human cells and used microarrays to examine changes in the messenger RNA profile. Here we show that delivering miR-124 causes the expression profile to shift towards that of brain, the organ in which miR-124 is preferentially expressed, whereas delivering miR-1 shifts the profile towards that of muscle, where miR-1 is preferentially expressed. In each case, about 100 messages were downregulated after 12 h. The 3' untranslated regions of these messages had a significant propensity to pair to the 5' region of the miRNA, as expected if many of these messages are the direct targets of the miRNAs. Our results suggest that metazoan miRNAs can reduce the levels of many of their target transcripts, not just the amount of protein deriving from these transcripts. Moreover, miR-1 and miR-124, and presumably other tissue-specific miRNAs, seem to downregulate a far greater number of targets than previously appreciated, thereby helping to define tissue-specific gene expression in humans.


Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4.
Fuchs corneal dystrophy (FCD) is a hereditary dystrophy of the corneal endothelium and is responsible for majority of the corneal transplantation performed in the United States. Here, we describe three generations of a family with 12 individuals affected by late-onset FCD and in which three individuals are unaffected. Genome-wide mapping provided suggestive linkage at two loci on chromosomal arms 3p and 15q. Alleles at either locus alone were not sufficient to explain FCD; however, considered together, both loci could explain the disorder in this pedigree. Subsequent next-generation sequencing identified a nonsense mutation in AGBL1 in the 15q locus; this mutation would result in a premature termination of AGBL1. Consistent with a causal role for this transcript, further sequencing of our cohort of late-onset-FCD-affected individuals identified two cases harboring the same nonsense mutation and a further three unrelated individuals bearing a second missense allele. AGBL1 encodes a glutamate decarboxylase previously identified in serial analysis of gene expression of corneal endothelium, a finding confirmed by immunohistochemical staining. Wild-type AGBL1 localizes predominantly to the cytoplasm; in sharp contrast, the truncated protein showed distinct nuclear localization. Finally, we show that AGBL1 interacts biochemically with the FCD-associated protein TCF4 and that the mutations found in our cohort of FCD individuals diminish this interaction. Taken together, our data identify a locus for FCD, extend the complex genetic architecture of the disorder, provide direct evidence for the involvement of TCF4 in FCD pathogenesis, and begin to explain how causal FCD mutations affect discrete biochemical complexes.


Adults with dyslexia: how can they achieve academic success despite impairments in basic reading and writing abilities? The role of text structure sensitivity as a compensatory skill.
The aim of this study was to investigate (1) whether a sample of highly educated individuals with dyslexia living under optimal personal, educational, cultural, and socioeconomic conditions continues to display core deficits in reading and writing skills during adulthood (extending prior results in Dutch, English, Hebrew, and Spanish to the Portuguese writing system); (2) whether these individuals can compensate for the effects of persistent core deficits when reading complex academic texts; (3) which cognitive resources, such as reading strategies, are used as compensatory mechanisms; and (4) whether quality of life is affected in these individuals. These questions were examined in a sample of 28 adults with dyslexia (DG) and 28 control participants (CG) paired by sex, age, education, and occupation, with a mean of 15 years of formal education. Participants completed measures of phonological awareness; decoding of syllables, words, and pseudowords; writing; reading comprehension (inferential and literal questions, recall, and sensitivity to the rhetorical structure of the target text); and quality of life. Results showed that (1) core deficits associated with dyslexia persisted into adulthood: participants with dyslexia performed worse than control subjects at all levels of phonological awareness, reading (except word reading accuracy), and spelling; (2) the groups did not differ on any measures of reading comprehension, suggesting a compensation of core deficits; (3) three compensatory mechanisms were identified: slower reading, use of text structure, and verbal ability; (4) participants with dyslexia required more family support and professional help throughout their educational careers, and had more depressive symptoms than control subjects.


Dementia caregiver interventions in Chinese people: A systematic review.
The aim of this systematic review was to examine the characteristics and the efficacy of dementia caregiving interventions among the Chinese population. In recent years, an increasing number of dementia caregiving interventions have been developed for Chinese older adults living in Asia that aim to reduce caregivers' burden, depression and distress, and enhance quality of life. Little is known, however, on the nature and the efficacy of these interventions. Systematic review with narrative summary. We searched four databases for studies published in English between 1 January 1994-30 December 2017. Nineteen studies reported in 23 articles were included in the final analysis. We used a set of criteria from the Cochrane Collaboration tool to assess for the risk of bias across studies. We found that interventions varied in length, frequency, approach, and content, making comparisons across studies challenging. Caregivers' burden, depression, and distress were improved among most included studies. All studies that examined quality of life of caregivers (N = 6) showed improvement. Most of the interventions showed beneficial effects on care recipients' behavioural symptoms, agitation, and depression; cognitive function, however, failed to improve. Although the review found mixed results on intervention outcomes, the majority of interventions showed a potential to improve the health and well-being of dementia caregivers and care recipients. This review provides suggestions for future dementia caregiving research in the Chinese population, such as inclusion of relevant theoretical frameworks and more rigorous research designs.


Loss of efficient import and thylakoid insertion due to N- and C-terminal deletions in the light-harvesting chlorophyll a/b binding protein.
C-terminally truncated precursors of wheat light-harvesting chlorophyll a/b binding protein (LHCP) were synthesized to investigate the origin of the two forms (about 25 kD and 26 kD) of the mature protein observed upon in vitro import into the chloroplast. Precursors p delta 13 and p delta 27, lacking 13 and 27 amino acids, respectively, were successfully imported, and both gave rise to two smaller forms proportional to the size of their deletions. These results demonstrate that there are two N-terminal sites that are cleaved during import of the LHCP precursor, undoubtedly contributing to the heterogeneity of LHCP found in vivo. Significantly, p delta 27 yielded only 50% of mature LHCP when compared with wild type. Although the products of p delta 27 import were localized to the thylakoids, in contrast to p delta 13 they were not correctly inserted into the membranes, indicating that residues essential for this step are missing. p delta 27 is distinguished from p delta 13 by lacking the carboxy end of a domain highly conserved between LHCP of photosystems II and I. Other specific precursor mutants with larger C-terminal deletions were not efficiently transported into the organelle in time course experiments, nor did they insert directly into the thylakoids using chloroplast lysates, in an assay independent of translocation across the envelope. In addition, the mutant p delta 18n, lacking the first 18 amino acids of mature LHCP, was only found bound to the chloroplast envelope. However, both p delta 18n and the mature protein, i.e., LHCP, synthesized in vitro without its 34-amino acid transit peptide inserted into the thylakoids in chloroplast lysates. The overall conformation of the mutant precursor polypeptides was probed using the chloroplast soluble processing enzyme in an organelle-free reaction optimized for the LHCP precursor and the more general protease trypsin. A tightly folded, protease-resistant conformation was not apparent to explain the loss of efficient import.


Human lymphoma cells develop resistance to radiation in the presence of astrocytes in vitro.
Lymphomas growing in the central nervous system exhibit resistance to radiotherapy compared to lymphomas of the lymph nodes. Because astrocytes have been shown to reduce radiation-induced neuronal toxicity, this study hypothesized that astrocytes might protect lymphoma cells from radiation-induced cell killing. A human lymphoma cell line, H9, and normal human astrocytes were grown in culture, exposed to radiation and assessed for cell viability, radiation sensitivity, glutathione content, induction of apoptosis and cell-cycle distribution. Cell survival assays demonstrated that H9 cells growing in an astrocyte-monolayer and also in an astrocyte-conditioned medium displayed radioresistance compared with H9 cells growing under standard conditions. The radioresistance correlated with accumulation of H9 cells in the G(2) phase of the cell cycle, suppression of radiation-induced apoptosis and coincided with a moderate increase in glutathione. The findings of this study suggest that astrocytes may play a role in the radioresistance exhibited by lymphomas of the central nervous system.


MRI detection of macrophages labeled using micrometer-sized iron oxide particles.
To evaluate cellular labeling of immune cells using micron-sized iron oxide particles (MPIOs) and evaluate the MR relaxivity and MRI detection of the labeled cells. Immune cells isolated from mice and rats were labeled with three different sizes of MPIO particles (0.35, 0.90, or 1.63 microm). These labeled cells were characterized using transmission electron microscopy (TEM), fluorescence microscopy, flow cytometry, MR relaxometry, and MRI. Macrophage uptake of MPIOs was found to be highest for the 1.63-microm size particles. MR relaxivity measurements indicated greater spin-spin relaxation for MPIO-labeled cells relative to cells labeled with nanometer-sized ultra-small superparamagnetic iron oxide (USPIO) particles with similar iron content. TEM and fluorescence microscopy indicated cellular uptake of multiple MPIO particles per cell. Macrophages labeled with 1.63-microm MPIOs had an average cellular iron uptake of 39.1 pg/cell, corresponding to approximately 35 particles per cell. Cells labeled with one or more MPIO particles could be readily detected ex vivo at 11.7 Tesla and after infusion of the MPIO-labeled macrophages into the kidney of a rat, hypointense regions of the outer cortex are observed, in vivo, by MRI at 4.7 Tesla.


Absence of Mycobacterium bovis in feral swine (Sus scrofa) from the southern Texas border region.
Free-ranging wildlife, such as feral swine (Sus scrofa), harbor a variety of diseases that are transmissible to livestock and could negatively impact agricultural production. Information is needed regarding the exposure and infection rates of Mycobacterium bovis and many other diseases and parasites in feral swine occurring in the Texas border region. Our main objective was to determine exposure rates and possible infection rates of M. bovis in feral swine by opportunistically sampling animals from the Texas border region. From June to September 2010, we obtained samples from 396 feral swine and tested 98 samples for M. bovis by histopathology and mycobacteriologic culture. We found no evidence of M. bovis infection. We believe that it is important to periodically and strategically sample feral swine for M. bovis in high-risk areas of the United States because they are capable of becoming reservoirs of the disease.


Data privacy considerations in Intensive Care Grids.
Novel eHealth systems are being designed to provide a citizen-centered health system, however the even demanding need for computing and data resources has required the adoption of Grid technologies. In most of the cases, this novel Health Grid requires not only conveying patient's personal data through public networks, but also storing it into shared resources out of the hospital premises. These features introduce new security concerns, in particular related with privacy. In this paper we survey current legal and technological approaches that have been taken to protect a patient's personal data into eHealth systems, with a particular focus in Intensive Care Grids. However, thanks to a security analysis applied over the Intensive Care Grid system (ICGrid) we show that these security mechanisms are not enough to provide a comprehensive solution, mainly because the data-at-rest is still vulnerable to attacks coming from untrusted Storage Elements where an attacker may directly access them. To cope with these issues, we propose a new privacy-oriented protocol which uses a combination of encryption and fragmentation to improve data's assurance while keeping compatibility with current legislations and Health Grid security mechanisms.


Traffic pollution at the home address and pregnancy outcomes in Stockholm, Sweden.
For the past two decades, several studies have reported associations between elevated levels of ambient air pollution and adverse pregnancy outcomes, although with varying conclusions. To examine possible associations between the traffic pollution situation at the home address, for women who did not change address during pregnancy, and three types of pregnancy outcomes: spontaneous preterm delivery, children born small for gestational age (SGA) and pregnancy-induced hypertensive disorders. We used data for the Greater Stockholm Area from the Swedish Medical Birth Register to construct a cohort based on all pregnancies conceived between July 1997 and March 2006, n = 100 190. The pregnancy average nitrogen oxide, NOx, levels and annual mean daily vehicles at the home address were used as exposure variables. Mixed-model logistic regression was performed to assess any associations between exposure and outcome. There was an association between elevated traffic pollution exposure during pregnancy and pregnancy-induced hypertensive disorders. A 10 µg/m(3) increase in the pregnancy average NOx level at the home address resulted in an OR of 1.17 (95% CI 1.10 to 1.26). The 2nd to 4th quartiles of NOx were all associated with an increased risk of SGA, but there was no difference in the risk estimate among the higher quartiles. There was a tendency of a higher risk of spontaneous preterm delivery in relation to higher levels of NOx. There was no evidence of an association between vehicle flow, the cruder indicator of traffic pollution, and the studied outcomes in this study. In this large cohort, there was a fairly strong association between vehicle exhaust levels at the home address and pregnancy-induced hypertensive disorders, after adjustment for important risk factors.