The Complete Sequence and Comparative Analysis of a Multidrug-Resistance and Virulence Multireplicon IncFII Plasmid pEC302/04 from an Extraintestinal Pathogenic Escherichia coli EC302/04 Indicate Extensive Diversity of IncFII Plasmids.
Extraintestinal pathogenic Escherichia coli (ExPEC) that causes extraintestinal infections often harbor plasmids encoding fitness traits such as resistance and virulence determinants that are of clinical importance. We determined the complete nucleotide sequence of plasmid pEC302/04 from a multidrug-resistant E. coli EC302/04 which was isolated from the tracheal aspirate of a patient in Malaysia. In addition, we also performed comparative sequence analyses of 18 related IncFIIA plasmids to determine the phylogenetic relationship and diversity of these plasmids. The 140,232 bp pEC302/04 is a multireplicon plasmid that bears three replication systems (FII, FIA, and FIB) with subtype of F2:A1:B1. The plasmid is self-transmissible with a complete transfer region. pEC302/04 also carries antibiotic resistance genes such as bla TEM-1 and a class I integron containing sul1, cml and aadA resistance genes, conferring multidrug resistance (MDR) to its host, E. coli EC302/04. Besides, two iron acquisition systems (SitABCD and IutA-IucABCD) which are the conserved virulence determinants of ExPEC-colicin V or B and M (ColV/ColBM)-producing plasmids were identified in pEC302/04. Multiple toxin-antitoxin (TA)-based addiction systems (i.e., PemI/PemK, VagC/VagD, CcdA/CcdB, and Hok/Sok) and a plasmid partitioning system, ParAB, and PsiAB, which are important for plasmid maintenance were also found. Comparative plasmid analysis revealed only one conserved gene, the repA1 as the core genome, showing that there is an extensive diversity among the IncFIIA plasmids. The phylogenetic relationship of 18 IncF plasmids based on the core regions revealed that ColV/ColBM-plasmids and non-ColV/ColBM plasmids were separated into two distinct groups. These plasmids, which carry highly diverse genetic contents, are also mosaic in nature. The atypical combination of genetic materials, i.e., the MDR- and ColV/ColBM-plasmid-virulence encoding regions in a single ExPEC plasmid is rare but of clinical importance. Such phenomenon is bothersome when the plasmids are transmissible, facilitating the spread of virulence and resistance plasmids among pathogenic bacteria. Notably, certain TA systems are more commonly found in particular ExPEC plasmid types, indicating the possible relationships between certain TA systems and ExPEC pathogenesis.


Still a puzzle: why is haem covalently attached in c-type cytochromes?
c-Type cytochromes are a group of proteins with diverse structures and functions. Their common feature is covalent attachment of haem to one or more CXXCH motifs. There does not seem to be a single advantageous reason for this covalent attachment.


Increase in Allergic Sensitization in Schoolchildren: Two Cohorts Compared 10 Years Apart.
Time trends of incidence of allergic sensitization are unknown and recent trends of prevalence and risk factors are lacking. To estimate the incidence, prevalence, remission, risk factors, and time trends for allergic sensitization among schoolchildren followed from age 7 to 8 years to age 11 to 12 years. In 2006, all children in grades 1 and 2 aged 7 to 8 years in 2 municipalities in northern Sweden were invited to a questionnaire survey and to skin prick testing to 10 common airborne allergens. The cohort was reexamined in 2010, with additional blood sampling for specific IgE. Participation rates were 90% (n = 1700) at age 7 to 8 years and 85% (n = 1657) at age 11 to 12 years. The results were compared with a cohort examined by identical methods 10 years earlier. The prevalence of positive skin prick test result to any allergen increased from 30% at age 7 to 8 years to 41% at age 11 to 12 years (P < .001). The cumulative 4-year incidence was 18%, while remission was low. Sensitization to pollen and furred animals was most common. A family history of allergy was significantly associated with incident sensitization, whereas the presence of furred animals at home was negatively associated. The prevalence at age 7 to 8 years and at age 11 to 12 years and the 4-year incidence were all significantly higher compared with the cohort examined 10 years earlier. The prevalence of allergic sensitization increased by age as a consequence of a high incidence and a low remission. The trends of increasing incidence and prevalence among schoolchildren imply future increases in the prevalence of allergic diseases.


Benefits and Risks of Clopidogrel vs. Aspirin Monotherapy after Recent Ischemic Stroke: A Systematic Review and Meta-Analysis.
Though combination of clopidogrel added to aspirin has been compared to aspirin alone in patients with stroke or transient ischemic attack, limited data exists on the relative efficacy and safety between clopidogrel and aspirin monotherapy in patients with a recent ischemic stroke. We aimed to compare clopidogrel versus aspirin monotherapy in this population. PubMed, Embase, and CENTRAL databases were searched from inception to May 2018 to identify clinical trials and observational studies comparing clopidogrel versus aspirin for secondary prevention in patients with recent ischemic stroke within 12 months. Pooled effect estimates were calculated using a random effects model and were reported as risk ratios with 95% confidence intervals. Five studies meeting eligibility criteria were included in the analysis. A total of 29,357 adult patients who had recent ischemic stroke received either clopidogrel (n = 14, 293) or aspirin (n = 15, 064) for secondary prevention. Pairwise meta-analysis showed a statistically significant risk reduction in the occurrence of major adverse cardiovascular and cerebrovascular events (risk ratio 0.72 [95% CI, 0.53-0.97]), any ischemic or hemorrhagic stroke (0.76 [0.58, 0.99), and recurrent ischemic stroke (0.72 [0.55, 0.94]) in patients who received clopidogrel versus aspirin. The risk of bleeding was also lower for clopidogrel versus aspirin (0.57 [0.45, 0.74]). There was no difference in the rate of all-cause mortality between the two groups. The analysis showed lower risks of major adverse cardiovascular or cerebrovascular events, recurrent stroke, and bleeding events for clopidogrel monotherapy compared to aspirin. These findings support clinical benefit for single antiplatelet therapy with clopidogrel over aspirin for secondary prevention in patients with recent ischemic stroke.


Carotid artery stiffness, high-density lipoprotein cholesterol and inflammation in men with pre-hypertension.
Low circulating levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk for cardiovascular events. HDL-C has a variety of poorly understood atheroprotective effects, including altering lipid metabolism and reducing inflammation. Increased arterial stiffness is an important predictor of subsequent cardiovascular risk. Therefore, in this study, we sought to determine whether HDL-C levels are associated with carotid arterial stiffness. In addition, we examined potential correlates of this association, such as inflammatory factors, cardiorespiratory fitness and body fat percentage. Carotid artery beta-stiffness was measured by ultrasound in 47 (23 years old) healthy pre-hypertensive men. Low HDL-C was defined as <1.0 mmol l(-1). Body fat was measured by air displacement plethysmography. Cardiorespiratory fitness was measured using a maximal exercise test, with metabolic gas analysis and inflammatory markers consisting of C-reactive protein (CRP), white blood cell (WBC) count and absolute neutrophil count. Men with a low HDL-C had significantly higher carotid artery stiffness, CRP, WBC count, neutrophil count, body fat, fasting glucose and lower cardiorespiratory fitness (P<0.05). Co-varying for cardiorespiratory fitness, % body fat and glucose had no effect on group differences in carotid artery stiffness. Co-varying for inflammatory markers resulted in groups having similar carotid artery stiffness. Pre-hypertensive men with low HDL-C have a higher carotid artery stiffness when compared with those with higher HDL-C. The detrimental effects of low HDL-C on large artery stiffness in pre-hypertensive men may be mediated by inflammation and not by cardiorespiratory fitness or body fat levels.


Diagnostic performance and system delay using telemedicine for prehospital diagnosis in triaging and treatment of STEMI.
European ST-segment elevation myocardial infarction (STEMI) guidelines recommend prehospital diagnosis to facilitate early reperfusion in patients with STEMI, and they provide recommendations regarding optimal system delay (time from first medical contact (FMC) to the primary percutaneous coronary intervention (PPCI)). There are limited data on achievable system delays in an optimal STEMI system of care using prehospital diagnosis to triage patients with STEMI directly to percutaneous coronary intervention (PCI) centres. We examined the proportion of tentative prehospital STEMI diagnoses established by telemedicine confirmed on hospital arrival, and we determined system delay in patients diagnosed before hospital arrival and triaged directly to the catheterisation laboratory. Population-based follow-up study. Central Denmark Region. 15 992 patients diagnosed using telemedicine. During the study period, a tentative diagnosis of STEMI was established in 1061 patients, of whom 919 were triaged directly to the PCI centre. In 771 (84%) patients, a diagnosis of STEMI was confirmed. Patients transported <10 km had a mean system delay of 82 min; this delay rose to 103 min for patients transported 50-75 km. Data on system delay was achievable in 682 patients in whom 553 (81%) were treated within 120 min of the FMC, and a system delay of <120 min was achievable in 89% of patients living up to 95 km from the PCI centre. Even for patients living <10 km from the PCI centre, only 16 (14%) had a system delay of 60 min or less. The use of telemedicine for prehospital diagnosis and triage of patients directly to the catheter laboratory is feasible and allows 89% of patients living up to 95 km from the invasive centre to be treated with PPCI within 120 min of the emergency medical service call. The study confirms that a recommendation of a system delay <60 min is unachievable if the FMC is the emergency medical call.


COMPUTED TOMOGRAPHIC FEATURES OF PHARYNGEAL NEOPLASIA IN 25 DOGS.
Computed tomography (CT) is commonly used to investigate head tumors in dogs, however little information is available for lesions of the pharyngeal area. The purpose of this multicentric, retrospective, cross-sectional study was to describe the CT findings in a sample of dogs with pathologically confirmed pharyngeal neoplasia and determine whether any CT features allowed differentiation of tumor type. Location of lesions, size and shape, margins, relationship with surrounding structures and vessels, attenuation characteristics and enhancement pattern, regional lymph node changes, and presence of metastasis were recorded by three observers (1 DECVDI). The effect of final diagnosis on each CT feature was tested. A total of 25 dogs were included: 15 with carcinomas, five sarcomas, four melanomas, and one lymphoma. The oropharynx and laryngopharynx were more frequently involved. Among tumor groups, lesions were of similar size, irregularly shaped, had ill-defined margins, and had moderate-to-marked heterogeneous contrast enhancement. Lysis of hyoid bones was recorded in two carcinomas and infiltration of the lingual artery occurred in one case. Marked medial retropharyngeal lymphoadenomegaly was recorded in 11 of 14 carcinomas, in all sarcomas and in two of four melanomas. The single lymphoma case showed ill-defined thickening of the oropharyngeal and laryngeal wall with retropharyngeal and mandibular lymphadenomegaly. Lung metastases were found in two of five sarcomas and two of four melanomas. Findings from the current study did not support the hypothesis that CT features could be used to predict pharyngeal tumor type in dogs. However, CT was helpful for determining mass extension, lymph node involvement, and distant metastatic spread.


Interaction of the antitumour antibiotic luzopeptin with the hexanucleotide duplex d(5'-GCATGC)2. One-dimensional and two-dimensional n.m.r. studies.
1H- and 31P-n.m.r. spectroscopy were used to characterize the solution structure of the 1:1 complex formed between the antitumour antibiotic luzopeptin and the self-complementary hexanucleotide d(5'-GCATGC)2. Eighteen nuclear Overhauser effects between antibiotic and nucleotide protons, together with ring-current-induced perturbations to base-pair and quinoline 1H resonances, define the position and orientation of the bound drug molecule. Luzopeptin binds in the minor groove of the DNA with full retention of dyad symmetry, its quinoline chromophores intercalating at the 5'-CpA and 5'-TpG steps and its depsipeptide ring spanning the central two A.T base-pairs. The chromophores stack principally on the adenine base with their carbocyclic rings pointing towards the deoxyribose of the cytosine. There is no evidence for Hoogsteen base-pairing in the complex, all glycosidic bond angles and sugar puckers being typical of B-DNA as found for the free hexanucleotide. The 'breathing' motions of the A.T and internal G.C base-pairs are substantially slowed in the complex compared with the free DNA, and the observation that two phosphate resonances are shifted downfield by at least 0.5 p.p.m. in the 31P-n.m.r. spectrum of the complex suggests pronounced local helix unwinding at the intercalation sites. The data are consistent with a model of the complex in which luzopeptin bisintercalates with its depsipeptide essentially in the conformation found in the crystal of the free antibiotic [Arnold & Clardy (1981) J. Am. Chem. Soc. 103, 1243-1244]. We postulate only one conformational change within the peptide ring, which involves rotation of the pyridazine-glycine amide group linkage by 90 degrees towards the DNA surface. This manoeuvre breaks the glycine-to-glycine transannular hydrogen bonds and enables the glycine NH groups to bond to the thymine O-2 atoms of the sandwiched A.T base-pairs. It also shortens the major axis of the depsipeptide so that the interchromophore distance is more suitable for spanning two base-pairs. The model further implies that the carboxy and hydroxy groups of the L-beta-hydroxyvaline residue are appropriately positioned for hydrogen-bonding to the 2-amino group of guanine and the O-2 atom of cytosine of the adjacent G.C base-pair.


Cat and dog allergen in mattresses and textile covered floors of homes which do or do not have pets, either in the past or currently.
The aim of this study was to measure the levels of cat and dog allergen in homes of families that had either never kept pets or kept or had kept cats or dogs. From a small residential area outside Stockholm consisting of 250 houses with similar exteriors 70 homes were included. Dust samples were collected from mattresses and textile-covered floors. The levels of cat and dog allergen were analysed by ELISA. Fel d1 was found in mattress dust in all 70 homes, median 0.5 micrograms/g [0.24-8.89 micrograms/g (quartiles)] and textile-covered floors 0.7 micrograms/g (0.20-2.52 micrograms/g). Can f1, was found in 98% of the collected samples, mattress dust 1.89 micrograms/g (0.70-9.20 micrograms/g) and textile-covered floor dust 2.5 micrograms/g (1.04-2.72 micrograms/g). There was a positive correlation (p < 0.001) between allergen levels in dust from mattresses and textile-covered floors for both Fel d1 (r = 0.68) and Can f1 (r = 0.78). The highest levels of cat and dog allergen were found in homes with furred pets (p < 0.001). A significant (p < 0.001) difference was seen in the levels of Fel d1 and Can f1 between the homes of former pet-owners and homes without pets. In summary; cat and dog allergens are present in homes regardless of whether such animals live in the house or not. Mattresses seem to be an underestimated reservoir for pet allergens even in homes without pets. It is important to note that the homes of former pet owners have much lower levels of allergen than current pet owners.


Measurement of the surface profile of an axicon lens with a polarization phase-shifting shearing interferometer.
We present a Twyman-Green interferometer (TGI)-based polarization phase-shifting shearing interferometric technique for testing the conical surface of an axicon (AX) lens. In this technique, the annular beam generated due to the passing of an expanded collimated laser beam traveling along the axis of revolution of the transparent glass AX element is split up into its reflected and transmitted components, having the plane of polarization in the orthogonal planes, by the polarization beam splitter (PBS) cube of the TGI-based optical setup. The split-up components are made to travel unequal paths along the two arms of the TGI and are recombined by the PBS. Because of the difference in path lengths traveled by the annular conical beams, a linear shear is introduced along the radial direction between the interfering components. Thus, the resulting interference pattern gives a map of the optical path difference (OPD) between two successive close points along a radial direction on the conical surface of the AX lens. The OPD map along radial directions, and hence the slopes/profiles of the conical surface, are obtained by applying polarization phase-shifting interferometry. Results obtained for an AX lens are presented.


Multi-trait genomic-enabled prediction enhances accuracy in multi-year wheat breeding trials.
Implementing genomic-based prediction models in genomic selection requires an understanding of the measures for evaluating prediction accuracy from different models and methods using multi-trait data. In this study, we compared prediction accuracy using six large multi-trait wheat data sets (quality and grain yield). The data were used to predict 1 year (testing) from the previous year (training) to assess prediction accuracy using four different prediction models. The results indicated that the conventional Pearson's correlation between observed and predicted values underestimated the true correlation value, whereas the corrected Pearson's correlation calculated by fitting a bivariate model was higher than the division of the Pearson's correlation by the squared root of the heritability across traits, by 2.53-11.46%. Across the datasets, the corrected Pearson's correlation was higher than the uncorrected by 5.80-14.01%. Overall, we found that for grain yield the prediction performance was highest using a multi-trait compared to a single-trait model. The higher the absolute genetic correlation between traits the greater the benefits of multi-trait models for increasing the genomic-enabled prediction accuracy of traits.


Dietary and stored iron as predictors of breast cancer risk: A nested case-control study in Shanghai.
Increases in risk of breast cancer in successive generations of migrants to the United States from China and rapid temporal changes in incidence rates in China following social and economic changes clearly implicate environmental factors in the etiology of this disease. Case-control and cohort studies have provided evidence that at least some of these factors may be dietary. Iron, an essential element necessary for cell function, has also been demonstrated to have potential carcinogenic and co-carcinogenic activities. Iron overload, which was previously uncommon, has become more common in the United States than iron deficiency and may be increasing in China concurrently with dramatic increases in meat consumption. A case-control study nested in a cohort of women in Shanghai, China, was conducted to evaluate possible associations between risk of proliferative and nonproliferative fibrocystic changes as well as breast cancer and dietary iron intake and plasma ferritin levels. Plasma ferritin levels and reported dietary iron intake were compared in 346 women with fibrocystic changes, 248 breast cancer cases and 1,040 controls. Increasing ferritin levels were significantly associated with increasing risk of nonproliferative fibrocystic changes (OR: 2.51, 95% CI: 1.16-5.45, p trend = 0.04). Similar, but weaker, trends were observed for proliferative changes and for breast cancer. Risk of breast cancer relative to the risk of fibrocystic changes was associated with dietary iron intake in women with nonproliferative fibrocystic changes (OR: 2.63, 95% CI: 1.04-6.68, p = 0.02). In conclusion, this study finds significant associations between iron (stored and dietary) and fibrocystic disease and breast cancer.


Work productivity in rhinitis using cell phones: The MASK pilot study.
Allergic rhinitis often impairs social life and performance. The aim of this cross-sectional study was to use cell phone data to assess the impact on work productivity of uncontrolled rhinitis assessed by visual analogue scale (VAS). A mobile phone app (Allergy Diary, Google Play Store and Apple App Store) collects data from daily visual analogue scales (VAS) for overall allergic symptoms (VAS-global measured), nasal (VAS-nasal), ocular (VAS-ocular) and asthma symptoms (VAS-asthma) as well as work (VAS-work). A combined nasal-ocular score is calculated. The Allergy Diary is available in 21 countries. The app includes the Work Productivity and Activity Impairment Allergic Specific Questionnaire (WPAI:AS) in six EU countries. All consecutive users who completed the VAS-work from 1 June to 31 October 2016 were included in the study. A total of 1136 users filled in 5818 days of VAS-work. Symptoms of allergic rhinitis were controlled (VAS-global <20) in approximately 60% of the days. In users with uncontrolled rhinitis, approximately 90% had some work impairment and over 50% had severe work impairment (VAS-work >50). There was a significant correlation between VAS-global calculated and VAS-work (Rho=0.83, P<0.00001, Spearman's rank test). In 144 users, there was a significant correlation between VAS-work and WPAI:AS (Rho=0.53, P<0.0001). This pilot study provides not only proof-of-concept data on the work impairment collected with the app but also data on the app itself, especially the distribution of responses for the VAS. This supports the interpretation that persons with rhinitis report both the presence and the absence of symptoms.


Effect of oxidation of carbon material on suspension electrodes for flow electrode capacitive deionization.
Flow electrode deionization (FCDI) is an emerging area for continuous and scalable deionization, but the electrochemical and flow properties of the flow electrode need to be improved to minimize energy consumption. Chemical oxidation of granular activated carbon (AC) was examined here to study the role of surface heteroatoms on rheology and electrochemical performance of a flow electrode (carbon slurry) for deionization processes. Moreover, it was demonstrated that higher mass densities could be used without increasing energy for pumping when using oxidized active material. High mass-loaded flow electrodes (28% carbon content) based on oxidized AC displayed similar viscosities (∼21 Pa s) to lower mass-loaded flow electrodes (20% carbon content) based on nonoxidized AC. The 40% increased mass loading (from 20% to 28%) resulted in a 25% increase in flow electrode gravimetric capacitance (from 65 to 83 F g(-1)) without sacrificing flowability (viscosity). The electrical energy required to remove ∼18% of the ions (desalt) from of the feed solution was observed to be significantly dependent on the mass loading and decreased (∼60%) from 92 ± 7 to 28 ± 2.7 J with increased mass densities from 5 to 23 wt %. It is shown that the surface chemistry of the active material in a flow electrode effects the electrical and pumping energy requirements of a FCDI system.


Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers: Findings from a prospective cohort study.
Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development.


High-quality rendering of quartic spline surfaces on the GPU.
We present a novel GPU-based algorithm for high-quality rendering of bivariate spline surfaces. An essential difference to the known methods for rendering graph surfaces is that we use quartic smooth splines on triangulations rather than triangular meshes. Our rendering approach is direct in the sense that since we do not use an intermediate tessellation but rather compute ray-surface intersections (by solving quartic equations numerically) as well as surface normals (by using Bernstein-Bézier techniques) for Phong illumination on the GPU. Inaccurate shading and artifacts appearing for triangular tesselated surfaces are completely avoided. Level of detail is automatic since all computations are done on a per fragment basis. We compare three different (quasi-) interpolating schemes for uniformly sampled gridded data, which differ in the smoothness and the approximation properties of the splines. The results show that our hardware based renderer leads to visualizations (including texturing, multiple light sources, environment mapping, etc.) of highest quality.


Glass Transition Temperature Regulates Mechanical Performance in Nacre-Mimetic Nanocomposites.
Although research in bioinspired nanocomposites is delivering mechanically superior nanocomposite materials, there remain gaps in understanding some fundamental design principles. This article discusses how the mechanical properties of nacre-mimetic polymer/nanoclay nanocomposites with nanoconfined polymer layers are controlled by the thermo-mechanical polymer properties, that is, glass transition temperature, Tg, using a series of poly(ethylene glycol methyl ether methacrylate-co-N,N-dimethylacrylamide) copolymers with tunable Tg from 130 to -55 °C. It is elucidated that both the type of copolymer and the nanoconfined polymer layer thickness control energy dissipation and inelastic deformation at high fractions of reinforcements in such bioinspired nanocomposites.


A pilot study assessing the value of 3D printed molecular modelling tools for pharmacy student education.
Medicinal chemistry and pharmacology are difficult topics to both teach and learn given the complex nature of drug mechanisms and drug-receptor interactions. This highlights the need for innovative teaching methods to deliver this information to students. One such method is through three-dimensional (3D) printing of enzymes and ligands in the teaching of molecular modelling concepts relating to drug-receptor and enzyme interactions be ligands. This type of printing has been shown to be beneficial in several educational settings; however, to our knowledge, its effectiveness in pharmacy, medicinal chemistry and pharmacology learning and teaching is largely unknown. Therefore, the aim of this study was to evaluate pharmacy student perceptions and the educational benefits of 3D printed molecules in molecular modelling with regards to engagement and learning outcomes when used in a drug-target interaction topic. This aim was achieved through administering students a short questionnaire designed to evaluate their engagement and learning outcomes with students also free to provide comments. This study found that nearly all (>90%) students found the activity was useful in improving both student engagement and learning outcomes. In conclusion, 3D printing may provide an alternative learning activity to help pharmacy students understand the drug-target interaction.


High-yield electro-oxidative preparation of graphene oxide.
Herein, we report a green electrochemical oxidative approach to convert large quantities of graphite into graphene oxide (GO). The resulted GO flakes have been characterized using various analytical techniques. It was possible to control the degree of oxidation of the produced GO via controlling the electrochemical parameters of the process.


Multifunctional role of ATM/Tel1 kinase in genome stability: from the DNA damage response to telomere maintenance.
The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, in Saccharomyces cerevisiae, haploid strains defective in the TEL1 gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.


Microglial P2Y12 receptor regulates ventral hippocampal CA1 neuronal excitability and innate fear in mice.
The P2Y12 receptor (P2Y12R) is a purinoceptor that is selectively expressed in microglia in the central nervous system. As a signature receptor, microglial P2Y12R mediates process chemotaxis towards ADP/ATP gradients and is engaged in several neurological diseases including chronic pain, stroke and seizures. However, the role of microglial P2Y12R in regulating neuronal excitability and innate behaviors is not fully understood. Here, we generated P2Y12-floxed mice to delete microglial P2Y12R beginning in development (CX3CR1Cre/+:P2Y12f/f; "constitutive knockout"), or after normal development in adult mice (CX3CR1CreER/+:P2Y12f/f; "induced knockout"). Using a battery of behavioral tests, we found that both constitutive and induced P2Y12R knockout mice exhibited innate fear but not learned fear behaviors. After mice were exposed to the elevated plus maze, the c-fos expression in ventral hippocampus CA1 neurons was robustly increased in P2Y12R knockout mice compared with wild-type mice. Consistently, using whole cell patch clamp recording, we found the excitability of ventral hippocampus CA1 neurons was increased in the P2Y12R knockout mice. The results suggest that microglial P2Y12R regulates neuronal excitability and innate fear behaviors in developing and adult mice.


The challenge of problem residents.
Internal medicine residency training is demanding and residents can experience a wide variety of professional and personal difficulties. Residency programs everywhere have had and will continue to have problem residents. Training programs should be equipped to effectively identify and manage residents who experience problems. Previous articles that have been published on the topic of problem residents primarily addressed concerns such as impairment due to depression and substance abuse. The content of this article is derived from a comprehensive review of the literature as well as other data sources such as interviews with program directors and workshops at national professional meetings. This article focuses primarily on four issues related to problem residents: their identification, underlying causes, management, and prevention. The study attempts to be evidence-based, wherever possible, highlighting what is known. Recommendations based on the synthesis of the data are also made. Future ongoing studies of problem residents will improve our understanding of the matters involved, and may ultimately lead to improved outcomes for these trainees.


Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4.
The epithelial-mesenchymal transition (EMT) is an important factor in lung cancer metastasis, and targeting EMT is a potential therapeutic strategy. Fucosyltransferase IV (FUT4) and its synthetic cancer sugar antigen Lewis Y (LeY) was abnormally elevated in many cancers. In this study, a traditional Chinese medicine ginsenoside Rg3 was used to investigate whether its inhibition to EMT and invasion of lung cancer is by the glycobiology mechanism. We found that Rg3 treatment (25, 50, 100 μg/ml) inhibited cell migration and invasion by wound-healing and transwell assays. Rg3 could significantly alter EMT marker proteins with increased E-cadherin, but decreased Snail, N-cadherin and Vimentin expression. Rg3 also down-regulated FUT4 gene and protein expression in lung cancer cells by qPCR, Western blot and immunofluorescence. After FUT4 down-regulated with shFUT4, EMT was obviously inhibited. Furthermore, the activation of EGFR through decreased LeY biosynthesis was inhibited, which blocked the downstream MAPK and NF-κB signal pathways. In addition, Rg3 reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. In conclusion, Rg3 inhibits EMT and invasion of lung cancer by down-regulating FUT4 mediated EGFR inactivation and blocking MAPK and NF-κB signal pathways. Rg3 may be a potentially effective agent for the treatment of lung cancer.


Approach to multiparticle parallel tracking in thick samples with three-dimensional nanoresolution.
This Letter proposes a method referred to as distorted grating (DG) and double-helix point spread function (DH-PSF) combination microscopy (DDCM), which is capable of multiparticle parallel localization and tracking in a transparent sample thicker than 10 μm, the thickness of cells. A special phase mask, combining the field depth extension capabilities of DG with the three-dimensional (3D) nanolocalization capabilities of the DH-PSF, is designed for multiparticle parallel localization. Time-lapse tracking of one particle moving along the z axis and parallel tracking of two particles are simulated. Results demonstrate that, with only a single snapshot, particles can be localized, tracking with 3D nanoresolution wherever they are. The theoretical localization precisions of DDCM, DH-PSF, and multifocus microscopy are compared. DDCM results in almost constant localization precisions in all three dimensions for a depth of field larger than 10 μm. DDCM is expected to become a tool in investigations of important dynamic events in living cells.


Aquatic insects of New York salt marsh associated with mosquito larval habitat and their potential utility as bioindicators.
The aquatic insect fauna of salt marshes is poorly characterized, with the possible exception of biting Diptera. Aquatic insects play a vital role in salt marsh ecology, and have great potential importance as biological indicators for assessing marsh health. In addition, they may be impacted by measures to control mosquitoes such as changes to the marsh habitat, altered hydrology, or the application of pesticides. Given these concerns, the goals of this study were to conduct the first taxonomic survey of salt marsh aquatic insects on Long Island, New York, USA and to evaluate their utility for non-target pesticide impacts and environmental biomonitoring. A total of 18 species from 11 families and five orders were collected repeatedly during the five month study period. Diptera was the most diverse order with nine species from four families, followed by Coleoptera with four species from two families, Heteroptera with three species from three families, then Odonata and the hexapod Collembola with one species each. Water boatmen, Trichocorixa verticalis Fieber (Heteroptera: Corixidae) and a shore fly, Ephydra subopaca Loew (Diptera: Ephydridae), were the two most commonly encountered species. An additional six species; Anurida maritima Guérin-Méneville (Collembola: Neanuridae), Mesovelia mulsanti White (Heteroptera: Mesovelidae), Enochrus hamiltoni Horn (Coleoptera: Hydrophilidae), Tropisternus quadristriatus Horn (Coleoptera: Hydrophilidae), Dasyhelea pseudocincta Waugh and Wirth (Diptera: Ceratopogonidae), and Brachydeutera argentata Walker (Diptera: Ephydridae), were found regularly. Together with the less common Erythrodiplax berenice Drury (Odonata: Libellulidae), these nine species were identified as the most suitable candidates for pesticide and environmental impact monitoring due to abundance, position in the food chain, and extended seasonal occurrence. This study represents a first step towards developing an insect-based index of biological integrity for salt marsh health assessment.


Medical student web-based formative assessment tool for renal pathology.
Web-based formative assessment tools have become widely recognized in medical education as valuable resources for self-directed learning. To explore the educational value of formative assessment using online quizzes for kidney pathology learning in our renal pathophysiology course. Students were given unrestricted and optional access to quizzes. Performance on quizzed and non-quizzed materials of those who used ('quizzers') and did not use the tool ('non-quizzers') was compared. Frequency of tool usage was analyzed and satisfaction surveys were utilized at the end of the course. In total, 82.6% of the students used quizzes. The greatest usage was observed on the day before the final exam. Students repeated interactive and more challenging quizzes more often. Average means between final exam scores for quizzed and unrelated materials were almost equal for 'quizzers' and 'non-quizzers', but 'quizzers' performed statistically better than 'non-quizzers' on both, quizzed (p=0.001) and non-quizzed (p=0.024) topics. In total, 89% of surveyed students thought quizzes improved their learning experience in this course. Our new computer-assisted learning tool is popular, and although its use can predict the final exam outcome, it does not provide strong evidence for direct improvement in academic performance. Students who chose to use quizzes did well on all aspects of the final exam and most commonly used quizzes to practice for final exam. Our efforts to revitalize the course material and promote learning by adding interactive online formative assessments improved students' learning experience overall.


Individualized antithrombotic therapy.
Clot formation in the circulation is a physiological mechanism preventing bleeding at sites of loss of vascular integrity. Clot formation may also occur intravascularly under pathological conditions, e.g. leading to myocardial infarction, stroke, and critical limb ischaemia. Clot formation involves activation of the coagulation cascade and of platelets eventually leading to an occlusive clot. In the venous circulation, clots are rich in erythrocytes and fibrin, while in the arterial circulation platelets predominate. Accordingly, drugs have been developed to interfere with the activation of the coagulation and/or platelets. As several coagulation factors such as factor VII, VIIII, X and thrombin (factor II) are vitamin K-dependent, drugs interfering with the effects of the vitamin (VKAs), i.e. warfarin, marcoumar or sintrom have been used for decades to prevent thromboembolism and embolic stroke. With the advent of selective inhibitors of factor X (apixaban, edoxaban and rivaroxaban) or factor II (dabigratan) the therapeutic spectrum of anti-thrombotic therapy has been expanded. On the other hand, platelet inhibitors such as aspirin and thienopyridines, i.e. clopidogrel, prasugrel, and ticagrelor have extensively been used to treat arterial disease in the coronary, cerebrovascular and peripheral circulation. Individualized antithrombotic therapy considers (1) characteristics of the disease and (2) those of the patient. Such a decision tree first separates "arterial" and "venous" thrombi. For the prevention of arterial thrombi that occur in acute myocardial infarction and certain forms of stroke and critical limb ischemia, platelet inhibitors are indicated. The first line drug is aspirin which interferes with thromboxane A2 (TXA2) formation and partially inhibits platelet activation. In patients receiving a stent or in acute coronary syndromes (ACS), the combination of aspirin with a thienopyridine is indicated. On the other hand, patients with venous clots should be treated with anticoagulants interfering with the activation of the coagulation cascade. While the longest experiences exist with vitamin K antagonists, the novel oral anticoagulants (NOACs) are at least as effective, but associated with less intracerebral and life-threatening bleeding. VKAs remain the treatment of choice in patients receiving artificial heart valves or with renal failure (in general a GFR of 30 ml/min/KG or less). In the remaining patients, current evidence suggests that NOACs should be preferred. The NOACs are well documented in patients with thromboembolism and atrial fibrillation. Whether patients with an acute ACS should receive dual antiplatelet drugs plus a low dose NOAC is a matter of debate, although conceptually it is an attractive concept. In patients after stent implantation with atrial fibrillation, in which a triple therapy with dual antiplatelet drugs and an anticoagulant is indicated, bleeding is an issue. Recent data suggest that administering a thienopyridine plus warfarin (or possibly a NOAC), while at the same time skipping aspirin may be an alternative to avoid severe bleeding and to maintain antithrombotic efficacy. An extensive therapeutic arsenal to interfere with clot formation requires an individualized approach considering the disease condition and co-morbidities of the patient, the anticoagulants' and patient characteristics. This review builds on and extends previous publications of the authors on this topic.


A follow-up study of childhood psychosis.
A cohort of 227 children having attended the same day treatment facility during their childhood was followed-up in adult life. A questionnaire was designed to collect data on various aspects of social and personal adjustment. The length of the follow-up period is 17 years. Information was obtained on 99 subjects whose mean age was 27-years. Of these, 55 had been admitted to the facility for childhood psychosis, and the remaining 44 subjects served as a comparison group. The results show that, in adulthood, the psychotic children fare significantly worse than the controls for employment, autonomy, marriage and the need for continuing medical care. Although non significant, a trend is found in the same direction for educational attainment and medication consumption. We then looked at the clinical and therapeutic variables in the childhood of the psychotic group which were the strongest predictors of adjustment in adulthood. We found that those children who had been admitted at a younger age, whose length of stay in the day treatment hospital had been longer, who scored lower on IQ tests and who had been discharged towards other specialised institutions, were less well adjusted. The results of this study must be interpreted with caution in light of the important attrition during the follow-up period. The discussion then focuses on case definition issues. Emphasis is placed on the need for careful diagnostic assessment and for the use of precise diagnostic assessment and for the use of precise diagnostic criteria. Further, our result on the prognostic significance of IQ level suggests that the assessment of cognitive functioning in autistic and psychotic children is key information which should be more systematically taken into account both in clinical practice and in future research projects.


Transition state analogues for enzymes of nucleic acid metabolism.
Knowledge of enzymatic transition states permits the logical design of transition state analogues. Kinetic isotope effects have been used to solve transition state structures for several N-ribosyltransferases. Nucleoside hydrolases from protozoan parasites show ribooxacarbenium ion character at their transition states, but with different extents of activation at the leaving group and the oxacarbenium ion. Transition state analogues are designed to capture these interactions and provide isozyme-specific inhibitors. Ricin A-chain is an RNA N-ribohydrolase for a single site on 28S rRNA. Its transition state resembles a fully dissociated ribooxacarbenium ion. A transition state analogue for ricin A-chain mimics the fully dissociated purine and cationic ribosyl transition state. The transition state for human purine nucleoside phosphorylase (PNP) is more dissociated than for the bovine enzyme. Immucillin-H, a powerful transition state inhibitor for human PNP, has entered clinical trials as an anti T-cell agent.


Small-world human brain networks: Perspectives and challenges.
Modelling the human brain as a complex network has provided a powerful mathematical framework to characterize the structural and functional architectures of the brain. In the past decade, the combination of non-invasive neuroimaging techniques and graph theoretical approaches enable us to map human structural and functional connectivity patterns (i.e., connectome) at the macroscopic level. One of the most influential findings is that human brain networks exhibit prominent small-world organization. Such a network architecture in the human brain facilitates efficient information segregation and integration at low wiring and energy costs, which presumably results from natural selection under the pressure of a cost-efficiency balance. Moreover, the small-world organization undergoes continuous changes during normal development and ageing and exhibits dramatic alterations in neurological and psychiatric disorders. In this review, we survey recent advances regarding the small-world architecture in human brain networks and highlight the potential implications and applications in multidisciplinary fields, including cognitive neuroscience, medicine and engineering. Finally, we highlight several challenging issues and areas for future research in this rapidly growing field.


Scavenger properties of cultivated pig liver endothelial cells.
BACKGROUND: The liver sinusoidal endothelial cells (LSEC) and Kupffer cells constitute the most powerful scavenger system in the body. Various waste macromolecules, continuously released from tissues in large quantities as a consequence of normal catabolic processes are cleared by the LSEC. In spite of the fact that pig livers are used in a wide range of experimental settings, the scavenger properties of pig LSEC has not been investigated until now. Therefore, we studied the endocytosis and intracellular transport of ligands for the five categories of endocytic receptors in LSEC. RESULTS: Endocytosis of five 125I-labelled molecules: collagen alpha-chains, FITC-biotin-hyaluronan, mannan, formaldehyde-treated serum albumin (FSA), and aggregated gamma globulin (AGG) was substantial in cultured LSEC. The endocytosis was mediated via the collagen-, hyaluronan-, mannose-, scavenger-, or IgG Fc-receptors, respectively, as judged by the ability of unlabelled ligands to compete with labelled ligands for uptake. Intracellular transport was studied employing a morphological pulse-chase technique. Ninety minutes following administration of red TRITC-FSA via the jugular vein of pigs to tag LSEC lysosomes, cultures of the cells were established, and pulsed with green FITC-labelled collagen, -mannan, and -FSA. By 10 min, the FITC-ligands was located in small vesicles scattered throughout the cytoplasm, with no co-localization with the red lysosomes. By 2 h, the FITC-ligands co-localized with red lysosomes. When LSEC were pulsed with FITC-AGG and TRITC-FSA together, co-localization of the two ligands was observed following a 10 min chase. By 2 h, only partial co-localization was observed; TRITC-FSA was transported to lysosomes, whereas FITC-AGG only slowly left the endosomes. Enzyme assays showed that LSEC and Kupffer cells contained equal specific activities of hexosaminidase, aryl sulphates, acid phosphatase and acid lipase, whereas the specific activities of alpha-mannosidase, and glucuronidase were higher in LSEC. All enzymes measured showed considerably higher specific activities in LSEC compared to parenchymal cells. CONCLUSION: Pig LSEC express the five following categories of high capacity endocytic receptors: scavenger-, mannose-, hyaluronan-, collagen-, and IgG Fc-receptors. In the liver, soluble ligands for these five receptors are endocytosed exclusively by LSEC. Furthermore, LSEC contains high specific activity of lysosomal enzymes needed for degradation of endocytosed material. Our observations suggest that pig LSEC have the same clearance activity as earlier described in rat LSEC.


Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity.
Non-alcoholic fatty liver disease (NAFLD) represents a key feature of obesity-related type 2 diabetes with increasing prevalence worldwide. To our knowledge, no treatment options are available to date, paving the way for more severe liver damage, including cirrhosis and hepatocellular carcinoma. Here, we show an unexpected function for an intracellular trafficking regulator, the small Rab GTPase Rab24, in mitochondrial fission and activation, which has an immediate impact on hepatic and systemic energy homeostasis. RAB24 is highly upregulated in the livers of obese patients with NAFLD and positively correlates with increased body fat in humans. Liver-selective inhibition of Rab24 increases autophagic flux and mitochondrial connectivity, leading to a strong improvement in hepatic steatosis and a reduction in serum glucose and cholesterol levels in obese mice. Our study highlights a potential therapeutic application of trafficking regulators, such as RAB24, for NAFLD and establishes a conceptual functional connection between intracellular transport and systemic metabolic dysfunction.


Phase asymmetry ultrasound despeckling with fractional anisotropic diffusion and total variation.
We propose an ultrasound speckle filtering method for not only preserving various edge features but also filtering tissue-dependent complex speckle noises in ultrasound images. The key idea is to detect these various edges using a phase congruence-based edge significance measure called phase asymmetry (PAS), which is invariant to the intensity amplitude of edges and takes 0 in non-edge smooth regions and 1 at the idea step edge, while also taking intermediate values at slowly varying ramp edges. By leveraging the PAS metric in designing weighting coefficients to maintain a balance between fractional-order anisotropic diffusion and total variation (TV) filters in TV cost function, we propose a new fractional TV framework to not only achieve the best despeckling performance with ramp edge preservation but also reduce the staircase effect produced by integral-order filters. Then, we exploit the PAS metric in designing a new fractional-order diffusion coefficient to properly preserve low-contrast edges in diffusion filtering. Finally, different from fixed fractional-order diffusion filters, an adaptive fractional order is introduced based on the PAS metric to enhance various weak edges in the spatially transitional areas between objects. The proposed fractional TV model is minimized using the gradient descent method to obtain the final denoised image. The experimental results and real application of ultrasound breast image segmentation show that the proposed method outperforms other state-of-the-art ultrasound despeckling filters for both speckle reduction and feature preservation in terms of visual evaluation and quantitative indices. The best scores on feature similarity indices have achieved 0.867, 0.844 and 0.834 under three different levels of noise, while the best breast ultrasound segmentation accuracy in terms of the mean and median dice similarity coefficient are 96.25% and 96.15%, respectively.


Three-dimensional ultrasound for assessing women with gynecological cancer: a systematic review.
Three-dimensional ultrasound (3D-US) is a new imaging technique that has become available in clinical practice. It is being increasingly used in women with gynecological cancer. The goal of this article is to review critically current evidence of the role of this technique in this clinical setting. Through Medline search (2001-2010) 46 studies using 3D-US in women with gynecological cancer were identified (28 studies involving ovarian cancer, 15 studies involving endometrial cancer and 6 studies involving cervical cancer). A systematic review of these studies was performed. Most studies were prospective and observational. Series were small in most of them. Ten studies addressed to technical and reproducibility issues. All of them demonstrate that 3D-US is a reproducible technique among examiners. Studies involving ovarian cancer showed that gray-scale 3D-US is not superior to conventional 2D-US for predicting ovarian cancer. Tumor vascular assessment by 3D power Doppler showed that this method might be useful in a selected subset of adnexal masses. Studies involving endometrial cancer showed that endometrial volume estimation is more specific than endometrial thickness measurement for predicting endometrial cancer. This method is useful for determining myometrial infiltration in women with endometrial cancer. The role of 3D power Doppler in endometrial cancer is controversial. Studies involving cervical cancer showed that tumor vascularity as assessed by 3D power Doppler correlates with prognostic tumor features. Three-dimensional ultrasound is a new imaging technique that offers unique ways for assessing women with gynecologic cancer. Current evidence shows that it is reproducible. It might be useful in some clinical circumstances. Further studies are needed to establish its role in clinical practice in gynecologic oncology.


User experiences and acceptability attributes of the diaphragm and lubricant gel in an HIV prevention trial in southern Africa.
Methods for Improving Reproductive Health in Africa (MIRA), a phase III HIV prevention trial, was conducted among 5039 Zimbabwean and South African women to test the Ortho All-Flex diaphragm and Replens(®) lubricant gel. Among the 2418 intervention group participants, 105 women who had completed the trial and 41 male partners participated in focus group discussions and in-depth interviews about the acceptability of the diaphragm and gel and their experiences using the study products. Women who participated in the qualitative study had exited the trial in the prior nine months, were HIV negative, and used the diaphragm and gel for 12-24 months. The comprehensive and flexible conceptual framework was applied to investigate the salient attributes for acceptability of the products as potential HIV prevention methods, and emerging themes for acceptability were framed within three categories of attributes (product, relationship, and sexual intercourse attributes). Both diaphragm and gel were found to be highly acceptable in the study group, and the gel was popular due to its effect of enhancing sexual pleasure. Some of the important product attributes influencing acceptability as reported by users were convenience, ease of use, dual use potential for contraception and disease prevention, and being female-initiated. It was also noted that some elements (such as sexual pleasure, couple communication, and the necessity of diaphragm negotiation) could be more important than others in terms of influencing product acceptability and use. Acceptability attributes reflective of the broader contextual environment (beliefs generated in the trial community suggesting preventive efficacy - preventive method optimism - and gendered norms favoring male superiority in sexual decision making) also emerged as important themes. The high level of acceptability of the diaphragm and gel among MIRA trial participants and their male partners is an indicator of the continued need for an effective female-initiated product.


Alcohol accelerates loss of muscle and impairs recovery of muscle mass resulting from disuse atrophy.
Muscle disuse atrophy is observed in patients recovering from trauma and there is an increased risk and severity of injury in patients abusing alcohol (EtOH). However, the interaction of EtOH and disuse on muscle protein balance has not been examined. Therefore, the present study addressed the hypothesis that EtOH accelerates the disuse atrophy and/or impairs the accretion of muscle protein during muscle recovery. To address this aim, disuse atrophy was induced in rats by 3 days of unilateral hindlimb immobilization (casting), using the contralateral leg as control, with EtOH or saline being orally gavaged twice, each day during this period. In a separate study, EtOH-treated rats received Velcade to inhibit proteasomal degradation. Finally, in the last study, rats had 1 limb casted for 5 days, the cast removed, and EtOH or saline gavaged twice daily during a 5-day recovery period. Muscle protein metabolism was assessed using surrogate markers of protein synthesis [i.e., phosphorylation of 4E-binding protein 1 (BP1) and S6 kinase 1 (S6K1)] and protein degradation (i.e., mRNA content of the ubiquitin E3 ligases atrogin-1 and MuRF1). Ethanol alone did not decrease muscle weight in the uncasted muscle. However, the loss of mass of immobilized muscle from EtOH-gavaged rats was 80% greater than in the animals not receiving EtOH. This atrophic response was not associated with a change in Akt, 4E-BP1 or S6K1 phosphorylation among groups. In contrast, immobilization alone increased both atrogin-1 and MuRF1 mRNA, and EtOH further increased their expression in immobilized muscle. The proteasome inhibitor Velcade attenuated atrophy produced by EtOH + disuse. When administered during the recovery period, EtOH prevented the normal accretion of muscle mass. This EtOH effect was associated with increased atrogin-1 mRNA, a reduction in 4E-BP1 and S6 phosphorylation, and an increased AMP-activated kinase phosphorylation. Based on the changes in these surrogate markers, our data suggest that EtOH accelerates disuse atrophy by stimulating ubiquitin-mediated proteolysis, and blunts repletion of muscle protein during recovery from disuse by increasing proteolysis and decreasing protein synthesis.


Dynamics and stability of icosahedral Fe-Pt nanoparticles.
The structure, dynamics and stability of Fe-Pt nanoparticles have been investigated using DFT-based techniques: total energy calculations and molecular dynamics. The investigated systems included multi-shell and disordered nanoparticles of iron and platinum. The study concerns icosahedral particles with the magic number of atoms (55): iron-terminated Fe43Pt12, platinum-terminated Fe12Pt43, and disordered Fe27Pt28. Additionally, the Fe6Pt7 cluster has been investigated to probe the behaviour of extremely small Fe-Pt particles. Molecular dynamics simulations have been performed for a few temperatures between T = 150-1000 K. The calculations revealed high structural instability of the Fe-terminated nanoparticles and a strong stabilising effect of the Pt-termination in the shell-type icosahedral particles. The platinum termination prevented disordering of the particle even at T = 1000 K indicating very high melting temperatures of these Fe-Pt icosahedral structures. The analysis of evolution of the radial distribution function has shown a significant tendency of Pt atoms to move to the outside layer of the particles - even in the platinum deficient cases.


Improving the Long-Term Stability of Perovskite Solar Cells with a Porous Al2O3 Buffer Layer.
Hybrid perovskites represent a new paradigm for photovoltaics, which have the potential to overcome the performance limits of current technologies and achieve low cost and high versatility. However, an efficiency drop is often observed within the first few hundred hours of device operation, which could become an important issue. Here, we demonstrate that the electrode's metal migrating through the hole transporting material (HTM) layer and eventually contacting the perovskite is in part responsible for this early device degradation. We show that depositing the HTM within an insulating mesoporous "buffer layer" comprised of Al2O3 nanoparticles prevents the metal electrode migration while allowing for precise control of the HTM thickness. This enables an improvement in the solar cell fill factor and prevents degradation of the device after 350 h of operation.


Epithelial organisation revealed by a network of cellular contacts.
The emergence of differences in the arrangement of cells is the first step towards the establishment of many organs. Understanding this process is limited by the lack of systematic characterization of epithelial organisation. Here we apply network theory at the scale of individual cells to uncover patterns in cell-to-cell contacts that govern epithelial organisation. We provide an objective characterisation of epithelia using network representation, where cells are nodes and cell contacts are links. The features of individual cells, together with attributes of the cellular network, produce a defining signature that distinguishes epithelia from different organs, species, developmental stages and genetic conditions. The approach permits characterization, quantification and classification of normal and perturbed epithelia, and establishes a framework for understanding molecular mechanisms that underpin the architecture of complex tissues.


Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission.
The understanding of the fixation of mutations within human tissues and their subsequent clonal expansion is a considerable problem, of which little is known. We have previously shown that nononcogenic mutations in the mitochondrial genome occur in one of a number of morphologically normal colonic crypt stem cells, the progeny of which later occupy the whole crypt. We propose that these wholly mutated crypts then clonally expand by crypt fission, where each crypt divides into two mutated daughter crypts. Here we show that (i) mutated crypts in the process of fission share the same mutated mitochondrial genotype not present in neighboring cytochrome c oxidase-positive crypts (the odds of this being a random event are >or=2.48 x 10(9):1); (ii) neighboring mutated crypts have the same genotype, which is different from adjacent cytochrome c oxidase-positive crypts; (iii) mutated crypts are clustered together throughout the colon; and (iv) patches of cytochrome c oxidase-deficient crypts increase in size with age. We thus demonstrate definitively that crypt fission is the mechanism by which mutations spread in the normal human colon. This has important implications for the biology of the normal adult human colon and possibly for the growth and spread of colorectal neoplasms.


A TOG:αβ-tubulin complex structure reveals conformation-based mechanisms for a microtubule polymerase.
Stu2p/XMAP215/Dis1 family proteins are evolutionarily conserved regulatory factors that use αβ-tubulin-interacting tumor overexpressed gene (TOG) domains to catalyze fast microtubule growth. Catalysis requires that these polymerases discriminate between unpolymerized and polymerized forms of αβ-tubulin, but the mechanism by which they do so has remained unclear. Here, we report the structure of the TOG1 domain from Stu2p bound to yeast αβ-tubulin. TOG1 binds αβ-tubulin in a way that excludes equivalent binding of a second TOG domain. Furthermore, TOG1 preferentially binds a curved conformation of αβ-tubulin that cannot be incorporated into microtubules, contacting α- and β-tubulin surfaces that do not participate in microtubule assembly. Conformation-selective interactions with αβ-tubulin explain how TOG-containing polymerases discriminate between unpolymerized and polymerized forms of αβ-tubulin and how they selectively recognize the growing end of the microtubule.


A two-dimensional electrophoretic analysis of the proteins and glycoproteins of liver plasma membrane domains and endosomes. Implications for endocytosis and transcytosis.
1. Polypeptides of liver plasma membrane fractions enriched in three surface domains of hepatocytes, blood-sinusoidal, lateral and bile canalicular, were analysed by isoelectric focusing (IEF) and non-equilibrium pH gel electrophoresis (NEPHGE) across a wide pH range, followed by SDS/PAGE. The overall Coomassie Blue-stained polypeptide patterns in the fractions were different. lateral plasma membrane fractions contained a characteristically higher number of polypeptides focusing at the basic pH range, whereas few basic polypeptides were present in sinusoidal plasma membrane fractions. The glycoproteins in these plasma membrane fractions stained by a lectin overlay technique with radio-iodinated concanavalin A, wheat-germ agglutinin and a slug lectin, were also different. 2. The polypeptides and glycoproteins of 'early' and 'late' endosome fractions were also compared by two-dimensional electrophoresis. Their composition was shown by Coomassie Blue staining, lectin overlay staining and in membranes metabolically labelled with [35S]methionine to be generally similar. The glycoproteins of sinusoidal plasma membranes and early and late endosomes were generally similar, but major differences in polypeptides of molecular mass 20-50 kDa, pI 7.5-8.5, in plasma membranes and endosomes were demonstrated, with a specific population of basic (pI 8-9) low-molecular-mass polypeptides being present at highest levels in 'late' endosomal fractions (shown by Coomassie Blue staining). 3. Analysis of the distribution of three specific membrane glycoproteins identified by using immunoblotting techniques showed that the asialoglycoprotein and the divalent-cation-sensitive mannose 6-phosphate receptors were present in sinusoidal plasma membrane and in early and late endocytic fractions: they were not detected in canalicular plasma membrane fractions. In contrast, 5'-nucleotidase was detected in all fractions examined. The role of the endocytic compartment in regulating trafficking pathways between the plasma membrane domains of the hepatocyte is discussed.


Superiority of end-to-end versus telescoped bronchial anastomosis in single lung transplantation for pulmonary emphysema.
To assess the influence of surgical technique (telescoped versus end-to-end anastomosis) on the incidence of bronchial anastomotic complications in patients who underwent single lung transplantation for pulmonary emphysema. Seventy-six adult recipients of single lung transplants for pulmonary emphysema were evaluated for the presence of 3 types of major bronchial anastomotic complications: ischemia, dehiscence, and severe stenosis. Surgical technique, clinical course, and mortality were reviewed retrospectively. The 3 major complications were observed in 11 (34%; ischemia), 8 (25%; dehiscence), and 11 (34%; severe stenosis) of 32 telescoped bronchial anastomoses. In contrast, ischemia, dehiscence, and severe stenosis occurred in only 4 (9%), 1 (2%), and 2 (5%) of 44 end-to-end anastomoses (P =.0087, P =.0034, and P =.0012, respectively). The relative risk of ischemia, dehiscence, and severe stenosis in telescoped anastomoses was 2.1, 2.5, and 2.5, respectively, compared with end-to-end anastomoses. Five (13%) telescoped anastomoses required stent placement as compared with only 2 (5%) end-to-end anastomoses (P =.1244). Early postoperative pneumonia was more common in the telescoped anastomosis group (56%) than in the end-to-end group (32%; P =.0380). There was a trend toward shorter survival in the telescoped anastomosis group (mean survival 1045 +/- 145 days) as compared with the end-to-end group (mean survival 1289 +/- 156 days), but these differences did not achieve statistical significance (P =.2410). In patients who underwent single lung transplantation for pulmonary emphysema, telescoped anastomoses were associated with a higher incidence of bronchial anastomotic complications than end-to-end anastomoses.


Sludge treatment wetlands: a review on the state of the art.
Sludge management has become a key issue in wastewater treatment, representing some 20-60% of the operational costs of conventional wastewater treatment plants. The high water content of the sludge results in large daily flow rates to be handled and treated. Thus, the search for methods to improve sludge volume reduction continues to be of major interest. The technology known as sludge treatment wetlands has been used for sludge dewatering since the late 1980s. Major advantages include its low energy requirements, reduced operating and maintenance costs, and a reasonable integration in the environment. However, the number of plants in operation is still low in comparison with conventional technologies. This study represents a review of the state of the art of sludge treatment wetlands. The main characteristics and operational aspects of the technology are described, including a summary of the main results reported in the literature. Finally, the efficiency of sludge treatment wetlands versus conventional treatments is compared.


Addressing the needs of Nicaraguan older adults living on the edge: A university-community partnership in international service-learning.
Nicaragua is a very low-income country entering a period of rapid aging with limited geriatric training for health care professionals. To help build capacity and to enhance student learning, a short-term international service-learning program was implemented in 2004 in partnership with the Jessie F. Richardson Foundation and Nicaraguan community stakeholders. Graduate and undergraduate students at Portland State University complete coursework for one term in the United States then travel to Nicaragua for about two weeks to participate in educational, research, and service activities, primarily in group homes for older Nicaraguans. Students learn about global aging, gerontology, community development, service learning, and Nicaraguan history and culture, then apply their gerontology-related knowledge by training direct care staff, older adults and their family members, and students. The authors describe the impetus for and evolution of the program, students' evaluation of the program, faculty observations on program benefits and challenges, lessons learned, and future plans.


Varied presentation of celiac disease in Pakistani adults.
The objective of this retrospective study was to evaluate presentation of celiac disease in adults. It included 77 patients, 41 (53.2%) males with median age 26 years and median body mass index of 18 (16 - 22) kg/m². Typical presentation with gastrointestinal symptoms was seen in 76.6%. Atypical presentation with extra intestinal complaints in 7.8% and silent presentation in 15.6%. Major symptoms were diarrhea in 64.9%, weight loss 36.4%, abdominal pain 35.1%, vomiting 32.5%, pallor 24.7%, and weakness 13%. Iron deficiency was documented in 20.8%, B12 deficiency in 9.1%, folic acid deficiency in 6.5% and vitamin D deficiency in 10.4%. Half of the patients had haemoglobin less than 11 g/dl. Osteoporosis and osteomalacia, hypothyroidism, diabetes and atrophic gastritis were seen in 2.6% each. Raised alanine aminotransferase was documented in 23.4%. Duodenal biopsy, done in 39 patients, revealed increased intraepithelial lymphocytes in 11, along with crypt hyperplasia in 3, partial villous atrophy in 15 and sub-total villous atrophy in 10. In conclusion, celiac disease in adults should be looked for in patients with chronic diarrhea or irritable bowel syndrome like symptoms, underweight, anaemic, or having nutritional deficiencies.


Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review.
With a political debate about the potential risks and benefits of cannabis use as a backdrop, the wave of legalization and liberalization initiatives continues to spread. Four states (Colorado, Washington, Oregon, and Alaska) and the District of Columbia have passed laws that legalized cannabis for recreational use by adults, and 23 others plus the District of Columbia now regulate cannabis use for medical purposes. These policy changes could trigger a broad range of unintended consequences, with profound and lasting implications for the health and social systems in our country. Cannabis use is emerging as one among many interacting factors that can affect brain development and mental function. To inform the political discourse with scientific evidence, the literature was reviewed to identify what is known and not known about the effects of cannabis use on human behavior, including cognition, motivation, and psychosis.


Oxidative stability of DHA phenolic ester.
Docosahexaenoic acid vanillyl ester (DHA-VE) was synthesized from docosahexaenoic acid ethyl ester (DHA-EE) and vanillyl alcohol by a solvent-free alcoholysis process catalysed by Candida antarctica lipase B. Oxidative stability of pure DHA-VE and the crude reaction medium consisting of 45% DHA-VE and 55% DHA-EE were compared with that of DHA-EE under various storage conditions. Oxidation progress was followed by determination of conjugated dienes and FTIR measurements. Analyses showed that DHA-EE was rapidly oxidised under all storage conditions in comparison with DHA-VE and crude reaction medium, whatever the temperature and the storage time. The grafting of vanillyl alcohol appeared as a powerful way to stabilize DHA against oxidation. Thanks to their stability, both DHA-VE and the crude reaction medium, allowing the production of the ester, offer huge potential as functional ingredients.


Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B.
Efficacy trials have shown that antiviral therapy improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, prospective data regarding the effect of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), especially among patients without cirrhosis, are limited. The authors examined the impact of tenofovir disoproxil fumarate (TDF) on the incidence of HCC using a validated prediction model. The incidence of HCC in patients treated with TDF was obtained in the pivotal TDF registration studies after 384 weeks of follow-up. The predicted risk of HCC in individual patients was calculated using the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model, which estimates HCC incidence for up to 10 years based on age, sex, alanine aminotransferase level, hepatitis B e antigen status, and HBV-DNA. Standardized incidence ratios (SIRs) were calculated comparing the observed and predicted numbers of HCC cases in the study cohort. Among 634 patients with evaluable baseline biopsies, 152 had cirrhosis (Ishak fibrosis score of 5 or 6) and 482 did not. During the 384 weeks of study, 14 cases of HCC were reported, with 4 occurring within the first year. The incidence of HCC was 0.37% per year in the study as a whole (0.28% among patients without cirrhosis and 0.65% among patients with cirrhosis). Among patients without cirrhosis, the observed incidence of HCC was significantly lower than predicted (SIR, 0.40; 95% confidence interval, 0.199-0.795). The last HCC case in a patient with cirrhosis occurred around week 192 with an SIR of 0.51 (95% confidence interval, 0.231-1.144) reported at week 384. Based on the REACH-B risk calculator, long-term therapy with TDF was associated with a reduced incidence of HCC among patients without cirrhosis who met treatment criteria.


Varying demographic impacts of different fisheries on three Mediterranean seabird species.
Fisheries have an enormous economic importance, but reconciling their socio-economic features with the conservation and sustainability of marine ecosystems presents major challenges. Bycatch mortality from fisheries is clearly among the most serious global threats for marine ecosystems, affecting a wide range of top predators. Recent estimates report ca. 200,000 seabirds killed annually by bycatch in European waters. However, there is an urgent need to rigorously estimate actual mortality rates and quantify effects of bycatch on populations. The Mediterranean Sea is one of the most impacted regions. Here, we estimate for the first time both bycatch mortality rates and their population-level effects on three endemic and vulnerable Mediterranean taxa: Scopoli's shearwater, Mediterranean shag, and Audouin's gull, that die in different types of fishing gears: longlines, gillnets and sport trolling, respectively. We use multi-event capture-recapture modelling to estimate crucial demographic parameters, including the probabilities of dying in different fishing gears. We then build stochastic demography models to forecast the viability of the populations under different management scenarios. Longline bycatch was particularly severe for adults of Scopoli's shearwaters and Audouin's gulls (ca. 28% and 23% of total mortality, respectively) and also for immature gulls (ca. 90% of mortality). Gillnets had a lower impact, but were still responsible for ca. 9% of juvenile mortality on shags, whereas sport trolling only slightly influenced total mortality in gulls. Bycatch mortality has high population-level impacts in all three species, with shearwaters having the highest extinction risk under current mortality rates. Different life-history traits and compensatory demographic mechanisms between the three species are probably influencing the different bycatch impact: for shearwaters, urgent conservation actions are required to ensure the viability of their populations. Results will be very useful for guiding future seabird conservation policies and moving towards an ecosystem-based approach to sustainable fisheries management.


Pericardial patch reconstruction of the congenitally diseased aortic valve.
Congenital aortic valve disease manifests itself either in the course of its natural history or as a consequence of an intervention (balloon dilatation or surgery). In infancy, a congenital aortic valve presents with stenosis, in childhood and adolescence as slowly evolving regurgitation after primary intervention/surgery and in late adulthood, they re-emerge as stenosis due to natural degeneration and calcification of the fused leaflets. The surgical approach to a congenital aortic valve disease differs depending on whether it is a malformed or a normally laid down (tri-sinusoidal tricuspid) valve; it also differs depending on the type of deformity, dysfunction and valve tissue presenting at surgery. Acutely regurgitant aortic valve in a neonate or an infant after balloon dilatation of congenital aortic stenosis is an infrequently occurring difficult problem with few available options. This video presentation demonstrates a xenopericardial patch repair of the torn fused leaflet (fusion between the right and the noncoronary cusp) of a congenitally stenotic valve, followed by height augmentation of all the three leaflets. Because of the relative hypoplasia of the aortic annulus and the ascending aorta, the aortic root and proximal ascending aorta were enlarged by an oblong xenopericardial patch. The following text includes additional technical issues involved in congenital aortic valve repair. A brief summary of literature is presented.


Controversial beliefs about diabetes and its care.
The purpose of this study was to identify specific beliefs that differentiate health-care professionals whose attitudes toward diabetes agreed most strongly with a group of national diabetes experts from those whose attitudes disagreed most strongly. The sample for this study included 271 physicians, 834 nurses, and 546 dietitians who completed a Diabetes Attitudes Survey. The sample included specialists in diabetes care and nonspecialists. Controversial beliefs about diabetes and its care were determined by comparing the beliefs of the 10% of the sample whose attitudes were most concordant (with the national panel) with the beliefs of the 10% of the sample whose attitudes were the most discordant. Ten beliefs met the criteria for being defined as controversial. The most controversial beliefs concerned whether the patient or the physician should be the primary decision maker in diabetes care, the meaning of patient noncompliance, and the seriousness of non-insulin-dependent diabetes mellitus. The 10% of the sample with the most discordant attitudes contained a disproportionately large number of physicians, nonspecialists in diabetes, and health-care professionals who had been in practice longer than the other members of the sample. This study identifies some important differences in beliefs between younger health-care professionals who specialize in diabetes and older nonspecialists. Such beliefs should be addressed in continuing education programs with the aim being to foster the widespread adoption of a contemporary approach to diabetes care.


A Mucin1 C-terminal Subunit-directed Monoclonal Antibody Targets Overexpressed Mucin1 in Breast Cancer.
Background: Mucin1 (MUC1) is a highly glycosylated transmembrane protein that has gained attention because of its overexpression in various cancers. However, MUC1-targeted therapeutic antibodies have not yet been approved for cancer therapy. MUC1 is cleaved to two subunits, MUC1-N and MCU1-C. MUC1-N is released from the cell surface, making MUC1-C a more reasonable target for cancer therapy. Therefore, we produced a monoclonal antibody (anti-hMUC1) specific to the extracellular region of MUC1-C and evaluated its effects in vitro and in vivo. Methods: We produced a monoclonal antibody (anti-hMUC1) using a purified recombinant human MUC1 polypeptide and our novel immunization protocol. The reactivity of anti-hMUC1 was characterized by ELISA, western blotting and immunoprecipitation analyses. The localization of the antibody in the breast cancer cells after binding was determined by confocal image analysis. The effects of the antibody on the growth of cells were also investigated. We injected anti-hMUC1 and performed in vivo tracing analysis in xenograft mouse models. In addition, expression of MUC1 in tissue sections from patients with breast cancer was assessed by immunohistochemistry with anti-hMUC1. Results: The anti-hMUC1 antibody recognized recombinant MUC1 as well as native MUC1-C protein in breast cancer cells. Anti-hMUC1 binds to the membrane surface of cells that express MUC1 and is internalized in some cancer cell lines. Treatment with anti-hMUC1 significantly reduced proliferation of cells in which anti-hMUC1 antibody is internalized. Furthermore, the anti-hMUC1 antibody was specifically localized in the MUC1-expressing breast cancer cell-derived tumors in xenograft mouse models. Based on immunohistochemistry analysis, we detected significantly higher expression of MUC1 in cancer tissues than in normal control tissues. Conclusion: Our results reveal that the anti-hMUC1 antibody targets the extracellular region of MUC1-C subunit and may have utility in future applications as an anti-breast cancer agent.


Atypical mechanism of NF-κB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis.
The NF-κB transcription factor has a central role in diverse processes, including inflammation, proliferation and cell survival, and its activity is dysregulated in diseases such as autoimmunity and cancer. We recently identified the TRE17/ubiquitin-specific protease 6 (USP6) oncogene as the first de-ubiquitinating enzyme to activate NF-κB. TRE17/USP6 is translocated and overexpressed in aneurysmal bone cyst (ABC), a pediatric tumor characterized by extensive bone degradation and inflammatory recruitment. In the current study, we explore the mechanism by which TRE17 induces activation of NF-κB, and find that it activates the classical NF-κB pathway through an atypical mechanism that does not involve IκB degradation. TRE17 co-precipitates with IκB kinase (IKK), and IKK activity is augmented in stable cell lines overexpressing TRE17, in a USP-dependent manner. Optimal activation of NF-κB by TRE17 requires both catalytic subunits of IKK, distinguishing its mechanism from the classical and non-canonical pathways, which require either IKKβ or IKKα, respectively. TRE17 stimulates phosphorylation of p65 at serine 536, a modification that has been associated with enhanced transcriptional activity and nuclear retention. Induction of S536 phosphorylation by TRE17 requires both IKKα and IKKβ, as well as the IKKγ/NEMO regulatory subunit of IKK. We further demonstrate that TRE17(long) is highly tumorigenic when overexpressed in NIH3T3 fibroblasts, and that inhibition of NF-κB significantly attenuates tumor formation. In summary, these studies uncover an unexpected signaling mechanism for activation of classical NF-κB by TRE17. They further reveal a critical role for NF-κB in TRE17-mediated tumorigenesis, and suggest that NF-κB inhibitors may function as effective therapeutic agents in the treatment of ABC.


Percutaneous disc decompression with nucleoplasty-volumetry of the nucleus pulposus using ultrahigh-field MRI.
To evaluate changes in nucleus pulposus volume as a potential parameter for the effects of disc decompression. Fifty-two discs (T8 to L1) were extracted from 26 pigs and separated into thoracic (T8 to T11) and thoracolumbar discs (T12 to L1). The discs were imaged using 7.1 Tesla ultrahigh-field magnetic resonance imaging (MRI) with acquisition of axial T2-weighted turbo spin-echo sequences for determination of baseline and postinterventional nucleus pulposus volumes. Volumes were calculated using OsiriX® (http://www.osirix-viewer.com). After randomization, one group was treated with nucleoplasty, while the placebo group was treated with an identical procedure but without coblation current. The readers analyzing the MR images were blinded to the kind of procedure performed. Baseline and postinterventional volumes were compared between the nucleoplasty and placebo group. Average preinterventional nucleus volume was 0.799 (SD: 0.212) ml. Postinterventional volume reduction in the nucleoplasty group was significant at 0.052 (SD: 0.035) ml or 6.30% (p<0.0001) (thoracic discs) and 0.082 (SD: 0.042) ml or 7.25% (p = 0.0078) (thoracolumbar discs). Nucleoplasty achieved volume reductions of 0.114 (SD: 0.054) ml or 14.72% (thoracic) and 0.093 (SD: 0.081) ml or 11.61% (thoracolumbar) compared with the placebo group. Nucleoplasty significantly reduces thoracic and thoracolumbar nucleus pulposus volumes in porcine discs.


BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis.
Critical issues in apoptosis include the importance of caspases versus organelle dysfunction, dominance of anti- versus proapoptotic BCL-2 members, and whether commitment occurs upstream or downstream of mitochondria. Here, we show cells deficient for the downstream effectors Apaf-1, Caspase-9, or Caspase-3 display only transient protection from "BH3 domain-only" molecules and die a caspase-independent death by mitochondrial dysfunction. Cells with an upstream defect, lacking "multidomain" BAX, BAK demonstrate long-term resistance to all BH3 domain-only members, including BAD, BIM, and NOXA. Comparison of wild-type versus mutant BCL-2, BCL-X(L) indicates these antiapoptotics sequester BH3 domain-only molecules in stable mitochondrial complexes, preventing the activation of BAX, BAK. Thus, in mammals, BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.


Pituitary stalk Langerhans cell histiocytosis treated with CyberKnife radiosurgery.
Langerhans cell histiocytosis (LCH) is a rare idiopathic disease that is characterized by clonal proliferation of Langerhans histiocytes in various parts of the body. These atypical cells have been found to infiltrate single or multiple organs, including bone, lungs, liver, spleen, lymph nodes, and skin. Central nervous system invasion in LCH patients has rarely been reported, especially in the adult population. We describe three histopathologically confirmed cases of adult LCH that involves both the pituitary stalk and hypothalamus, and report our limited experience of such cases in this location that has been treated with CyberKnife radio surgery. The treatment goal of controlling lesion growth is achieved by CyberKnife radiosurgery in this case series. All patients tolerated the treatment well without obvious complications.


Risk and Resiliency in the Relationship Between Widowhood and Depressive Symptoms Among Older Mexican Americans.
This study examined the association between widowhood and depressive symptoms and the extent to which the association is contingent upon risk and resiliency, including immigration status, functional limitations, financial strains, and intergenerational support, among older Mexican Americans. The sample included 344 parent-child pairs reported by 83 respondents. Clustered regression analysis showed that widowhood elevated risks for depressive symptoms. We found that having some functional limitations, having more children and living in the same city with children exacerbated the adverse effects of widowhood on depressive symptoms. We also found that living in the same city with children increased the detrimental effects of widowhood on the depressive symptoms in men, whereas we did not find this pattern in women. The findings highlight the heterogeneity within the widowed Mexican American older adults. Implications for future research and practice are discussed.


Active linking in evolutionary games.
In the traditional approach to evolutionary game theory, the individuals of a population meet each other at random, and they have no control over the frequency or duration of interactions. Here we remove these simplifying assumptions. We introduce a new model, where individuals differ in the rate at which they seek new interactions. Once a link between two individuals has formed, the productivity of this link is evaluated. Links can be broken off at different rates. In a limiting case, the linking dynamics introduces a simple transformation of the payoff matrix. We outline conditions for evolutionary stability. As a specific example, we study the interaction between cooperators and defectors. We find a simple relationship that characterizes those linking dynamics which allow natural selection to favour cooperation over defection.


Defining and Measuring Vulnerability in Young People.
Adolescents and youth, together addressed as "young people", form the future building blocks of any society. They being most energetic and dynamic, tend to get involved in high-risk behaviors making themselves susceptible to criminal offences, accidents, physical injuries, emotional trauma, and medical problems - some of them extremely serious like transmission of human immunodeficiency virus (HIV). The concept of vulnerability is applicable to all the people who are more exposed to risks than their peers like the young people. In order to deal with social evils like criminal offences, domestic violence, sexual abuse, HIV, etc. we need to define vulnerability and understand the factors that influence it. This review also attempts to summarize the indicators of vulnerability and the data currently available to estimate its burden in India. Measuring the magnitude of vulnerability by means of certain indicators/variables might help us in devising tools to assess this poorly defined entity. This may also evolve a conceptual framework on which targeted remedial interventions can be devised and implemented.


Identification of a receptor mediating absorption of dietary cholesterol in the intestine.
Here we show that scavenger receptor class B type I is present in the small-intestine brush border membrane where it facilitates the uptake of dietary cholesterol from either bile salt micelles or phospholipid vesicles. This receptor can also function as a port for several additional classes of lipids, including cholesteryl esters, triacylglycerols, and phospholipids. It is the first receptor demonstrated to be involved in the absorption of dietary lipids in the intestine. In liver and steroidogenic tissues, the physiological ligand of this receptor is high-density lipoprotein. We show that binding of high-density lipoprotein and apolipoprotein A-I to the brush border membrane-resident receptor inhibits uptake of cholesterol (sterol) into the brush border membrane from lipid donor particles. This finding lends further support to the conclusion that scavenger receptor BI catalyzes intestinal cholesterol uptake. Our findings suggest new therapeutic approaches for limiting the absorption of dietary cholesterol and reducing hypercholesterolemia and the risk of atherosclerosis.