Constructing the angiome: a global angiogenesis protein interaction network.
Angiogenesis is the formation of new blood vessels from pre-existing microvessels. Excessive and insufficient angiogenesis have been associated with many diseases including cancer, age-related macular degeneration, ischemic heart, brain, and skeletal muscle diseases. A comprehensive understanding of angiogenesis regulatory processes is needed to improve treatment of these diseases. To identify proteins related to angiogenesis, we developed a novel integrative framework for diverse sources of high-throughput data. The system, called GeneHits, was used to expand on known angiogenesis pathways to construct the angiome, a protein-protein interaction network for angiogenesis. The network consists of 478 proteins and 1,488 interactions. The network was validated through cross validation and analysis of five gene expression datasets from in vitro angiogenesis assays. We calculated the topological properties of the angiome. We analyzed the functional enrichment of angiogenesis-annotated and associated proteins. We also constructed an extended angiome with 1,233 proteins and 5,726 interactions to derive a more complete map of protein-protein interactions in angiogenesis. Finally, the extended angiome was used to identify growth factor signaling networks that drive angiogenesis and antiangiogenic signaling networks. The results of this analysis can be used to identify genes and proteins in different disease conditions and putative targets for therapeutic interventions as high-ranked candidates for experimental validation.


Renal changes and apoptosis caused by subacute exposure to Aroclor 1254 in selenium-deficient and selenium-supplemented rats.
Aroclor 1254 (A1254), a mixture of polychlorinated biphenyls, exerts hepatic, renal, and reproductive toxicity in rodents. This study aimed to determine a protective role of selenium on histopathological changes, oxidative stress, and apoptosis caused by A1254 in rat kidney. It included a control group, which received regular diet containing 0.15 mg/kg Se (C), a Se-supplemented group (SeS) receiving 1 mg/kg Se, a Se-deficient group (SeD) receiving Se-deficient diet of ≤0.05 mg/kg Se, an A1254-treated group (A) receiving 10 mg/kg of Aroclor 1254 and regular diet, an A1254-treated group receiving Se-supplementation (ASeS), and an A1254-treated group receiving Se-deficient diet (ASeD). Treatments lasted 15 days. After 24 h of the last dose of A1254, the animals were decapitated under anaesthesia and their renal antioxidant enzyme activities, lipid peroxidation (LP), glutathione, protein oxidation, and total antioxidant capacity levels measured. Histopathological changes were evaluated by light and electron microscopy. Apoptosis was detected with the TUNEL assay. Kidney weights, CAT activities, and GSH levels decreased significantly in all A1254-treated groups. Renal atrophic changes and higher apoptotic cell counts were observed in the A and ASeD groups. Both groups also showed a significant drop in GPx1 activities (A - 34.92 % and ASeD - 86.46 %) and rise in LP (A - 30.45 % and ASeD - 20.44 %) vs control. In contrast, LP levels and apoptotic cell counts were significantly lower in the ASeS group vs the A group. Histopathological changes and renal apoptosis were particularly visible in the ASeD group. Our findings suggest that selenium supplementation provides partial protection against renal toxicity of Aroclor 1254.


Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations.
Hereditary angioedema with normal C1-INH may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or mutations in genes that are still unknown (HAE-unknown). To assess the differences in transmission and inheritance, clinical features, and laboratory parameters between patients with HAE-FXII and HAE-unknown. Sixty-nine patients with HAE-FXII from 23 unrelated families and 196 patients with HAE-unknown from 65 unrelated families were studied. Both HAE-FXII and HAE-unknown are inherited as autosomal-dominant traits with incomplete penetrance. The male to female ratio was 1 : 68 in HAE-FXII and 1 : 6.3 in HAE-unknown. The maternal to paternal transmission ratio was 35 : 14 for HAE-FXII and 109 : 12 for HAE-unknown. Mean age at onset of clinical symptoms was 20.3 years in patients with HAE-FXII and 29.6 years in patients with HAE-unknown. The incidence of asphyxiation due to angioedema was similar for HAE-FXII and HAE-unknown. Oral contraceptives and pregnancies had a significantly higher impact on HAE-FXII than on HAE-unknown. Slightly decreased C1-INH activity and C4 concentration were observed in more patients with HAE-FXII than HAE-unknown. Tests for FXI and FXII activity, plasminogen activator inhibitor 1, and activated partial thromboplastin time showed variability but no significant differences between the groups. No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin, antithrombin III, and angiotensin-converting enzyme. In families with HAE-FXII, the number of female offspring with F12 mutations was significantly increased and that of male offspring was significantly decreased. HAE-FXII and HAE-unknown differ in various respects, including gender distribution, genetics, symptoms, and estrogen impact.


Molecular characterisation of the colicin E2 operon and identification of its products.
The DNA sequence of the entire colicin E2 operon was determined. The operon comprises the colicin activity gene, ceaB, the colicin immunity gene, ceiB, and the lysis gene, celB, which is essential for colicin release from producing cells. A potential LexA binding site is located immediately upstream from ceaB, and a rho-independent terminator structure is located immediately downstream from celB. A comparison of the predicted amino acid sequences of colicin E2 and cloacin DF13 revealed extensive stretches of homology. These colicins have different modes of action and recognise different cell surface receptors; the two major regions of heterology at the carboxy terminus, and in the carboxy-terminal end of the central region probably correspond to the catalytic and receptor-recognition domains, respectively. Sequence homologies between colicins E2, A and E1 were less striking, and the colicin E2 immunity protein was not found to share extensive homology with the colicin E3 or cloacin DF13 immunity proteins. The lysis proteins of the ColE2, ColE1 and CloDF13 plasmids are almost identical except in the aminoterminal regions, which themselves have overall similarity with lipoprotein signal peptides. Processing of the ColE2 prolysis protein to the mature form was prevented by globomycin, a specific inhibitor of the lipoprotein signal peptidase. The mature ColE2 lysis protein was located in the cell envelope. The results are discussed in terms of the functional organisation of the colicin operons and the colicin proteins, and the way in which colicins are released from producing cells.


A novel nuclear-encoded mitochondrial poly(A) polymerase PAPD1 is a potential candidate gene for the extreme obesity related phenotypes in mammals.
People with obesity, especially extreme obesity, are at risk for many health problems. However, the responsible genes remain unknown in >95% of severe obesity cases. Our previous genome-wide scan of Wagyu x Limousin F2 cattle crosses with extreme phenotypes revealed a molecular marker significantly associated with intramuscular fat deposition. Characterization of this marker showed that it is orthologous to the human gene KIAA1462 located on HSA10p11.23, where a major quantitative trait locus for morbid obesity has been reported. The newly identified mitochondrial poly(A) polymerase associated domain containing 1 (PAPD1) gene, which is located near this marker, is particularly interesting because the polymerase is required for the polyadenylation and stabilization of mammalian mitochondrial mRNAs. In the present study, both cDNA and genomic DNA sequences were annotated for the bovine PAPD1 gene and ten genetic markers were detected in the promoter and exon 1 region. Among seven markers assayed on approximately 250 Wagyu x Limousin F2 animals, two single nucleotide polymorphisms (SNPs) in the promoter region were significantly associated with intramuscular fat (P<0.05). However, there was a significant interaction (P<0.05) between a third SNP, which causes an amino acid change in coding exon 1, and each of these two promoter SNPs on intramuscular fat deposition. In particular, the differences between double heterozygous animals at two polymorphic sites and the slim genotype animals exceeded 2.3 standard deviations for the trait in both cases. Our study provides evidence for a new mechanism--the involvement of compound heterosis in extreme obesity, which warrants further examination.


Silicosis due to Denim Sandblasting in Young People: MDCT Findings.
Occupational lung disease due to silica dust is one of the most common work-related injuries. In denim sandblasting, workers are exposed to silica that may cause immediate mortality, especially in young people. The aim of this study was to assess the multidetector computed tomography (MDCT) findings of silicosis in denim sandblasters and to better define the role of MDCT in the early detection of silicosis. The study included 12 consecutive male patients who were admitted to a pulmonary outpatient clinic between April 2009 and December 2009. All patients had been working as sandblasters for at least one year. All patients underwent chest CT examinations for suspected silicosis. Two radiologists independently assessed the images for the presence and distribution of airspace consolidation, ground-glass opacity, nodules, interlobular septal thickening, parenchymal bands, fibrosis, masses, traction bronchiectasis, honeycombing, lobular low-attenuation areas, emphysema, pleural effusion or thickening, and mediastinal or hilar adenopathy. MDCT detected parenchymal abnormalities in the lungs in eight (67%) of the twelve patients. The most common MDCT finding was ground glass opacity (58%). Other common findings were parencyhmal nodules and interlobular septal thickening, predominantly in the upper zones. Nodules were detected in six (50%) of the twelve patients. In four cases (67%), the nodules were numerous (>10), were predominantly smaller than 10 mm, and were centrilobular in distribution. In five (42%) of the 12 patients, interlobular septal thickening was detected. Only one (8%) patient presented with airspace consolidation; this was bilateral in the upper zones and associated with air bronchograms. In one (8%) patient there were several traction bronchiectases in the upper zones. None of the patients presented with pleural effusion, thickening, or honeycombing. Enlarged mediastinal nodes were identified in half of the patients, predominantly in the precarinal, paratracheal, and prevascular regions. No egg-shell calcification was detected. One (8%) patient presented with punctate calcification in the hilar region. Early detection of silicosis is important because it may cause immediate mortality, especially in young people. Enlarged mediastinal lymph nodes, centrilobular nodules, interlobular septal thickening, and patchy ground glass opacity may be early MDCT findings of silicosis. Thus, MDCT plays an important role in the early detection of silicosis in denim sandblasters.


The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study.
Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD. 100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis. 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312). This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon. This study is publically registered on the United Kingdom Clinical Research Network Portfolio (9633).


The What-If Tool: Interactive Probing of Machine Learning Models.
A key challenge in developing and deploying Machine Learning (ML) systems is understanding their performance across a wide range of inputs. To address this challenge, we created the What-If Tool, an open-source application that allows practitioners to probe, visualize, and analyze ML systems, with minimal coding. The What-If Tool lets practitioners test performance in hypothetical situations, analyze the importance of different data features, and visualize model behavior across multiple models and subsets of input data. It also lets practitioners measure systems according to multiple ML fairness metrics. We describe the design of the tool, and report on real-life usage at different organizations.


Tracking of lung function parameters and the longitudinal relationship with lifestyle.
The purpose of this study was to analyse tracking (i.e. relative stability over time/predictability of future values by early measurements) of lung function parameters and their longitudinal relationship with lifestyle (smoking, alcohol consumption, daily physical activity, neuromotor and cardiopulmonary fitness, and dietary intake of retinol and polyunsaturated fatty acids (PUFA)). Data were obtained from the observational Amsterdam Growth and Health Study, a longitudinal study with six repeated measurements between ages 13-27 yrs (n=167). The statistical analyses were carried out with generalized estimating equations. The following "stability" coefficients were found: for forced vital capacity (FVC) in males 0.66 (95% confidence interval (CI): 0.54-0.77) and in females 0.51 (95% CI: 0.43-0.60); for forced expiratory volume in one second (FEV1) in males 0.65 (95% CI: 0.50-0.80), in females 0.53 (95% CI 0.46-0.60); for peak expiratory flow (PEF) in both males and females 0.41 (95% CI: 0.31-0.51). Positive relationships were found between alcohol consumption and FVC and FEV1 and between neuromotor fitness and PEF and (only for males) with FVC and FEV1. Physical activity was inversely related to PEF and the intake of PUFA positively related to FVC and FEV1. Smoking was related to a decrease in FVC and FEV1; changes in physical activity positively correlated to changes in FVC. In conclusion, high to moderate stability/tracking was observed for forced vital capacity and forced expiratory volume in one second; for peak expiratory flow it was slightly lower. Preventive strategies regarding improvements of lung function should focus on smoking cessation and improving daily physical activity.


Acute myocardial infarction in sickle cell disease: a systematic review.
Myocardial infarction in young adults is, in practice, a diagnosis of exclusion. Given the fact that most of the patients with sickle cell disease are young and have predisposition to painful crisis, they are often overlooked for myocardial infarction. These patients often have few or no traditional risk factors for coronary artery disease, and risk stratification tools such as the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) models place these patients at low risk. Nonspecific changes on electrocardiogram are of little diagnostic value. Myocardial infarction is very often a missed diagnosis in patients with sickle cell disease. Diagnostic criteria, potential mechanisms, and management for acute myocardial infarction in patients with sickle cell disease are discussed.


Recording thoughts while memorizing music: a case study.
Musicians generally believe that memory differs from one person to the next. As a result, memorizing strategies that could be useful to almost everyone are not widely taught. We describe how an 18-years old piano student (Grade 7, ABRSM), learned to memorize by recording her thoughts, a technique inspired by studies of how experienced soloists memorize. The student, who had previously ignored suggestions that she play from memory, decided to learn to memorize, selecting Schumann's "Der Dichter Spricht" for this purpose. Rather than explicitly teaching the student how to memorize, the teacher taught her to record her thoughts while playing by marking them on copies of the score, adapting an approach used previously in research with experienced performers. Over a 6½ week period, the student recorded her thoughts during practice (five times) and while performing from memory for the teacher (three times). The student also video-recorded 3 weeks of practice, three performances, and the reconstruction of the piece from memory after a 9½-weeks break. The thoughts that the student reported were prepared during practice, stable over time, and functioned as memory retrieval cues during reconstruction. This suggests that the student memorized in the same way as the more experienced musicians who have been studied previously and that teaching student musicians to record their thoughts may be an effective way to help them memorize. The speed and durability of her memorization surprised the student, inspiring her to perform in public and to use the same technique for new pieces.


Stigma management and gay identity development.
Disclosure of homosexuality is now generally viewed in the professional literature as more desirable than secrecy; disclosure is often seen as evidence of a healthy gay identity, whereas secrecy has come to be viewed as socially and psychologically problematic. By drawing on data from an interview study of 38 gay men in Montreal, this article shows that decisions concerning disclosure and secrecy are related to a variety of situational and relational factors that are largely distinct from gay identity development. It is argued that the new models of identity formation fail to recognize adequately the social factors that shape the ways gay men manage information concerning their sexual preferences. Conceptual and clinical implications of new normative views of disclosure and secrecy are discussed.


Preparation and evaluation of a molecularly imprinted sol-gel material for on-line solid-phase extraction coupled with high performance liquid chromatography for the determination of trace pentachlorophenol in water samples.
A highly selective imprinted amino-functionalized silica gel sorbent was prepared by combining a surface molecular imprinting technique with a sol-gel process for on-line solid-phase extraction-HPLC determination of trace pentachlorophenol (PCP) in water samples. The PCP-imprinted amino-functionalized silica sorbent was characterized by FT-IR, SEM, nitrogen adsorption and the static adsorption experiments. The imprinted functionalized silica gel sorbent exhibited high selectivity and offered a fast kinetics for the adsorption and desorption of PCP. The prepared sorbent was shown to be promising for on-line solid-phase extraction for HPLC determination of trace levels of PCP in environmental samples. With a sample loading flow rate of 5 ml min(-1) for 2 min, an enhancement factor of 670 and a detection limit (S/N = 3) of 6 ng l(-1) were achieved at a sample throughput of five samples h(-1). The precision (RSD) for nine replicate on-line sorbent extractions of 10 microgl(-1) PCP was 3.8%. The sorbent also offered good linearity (r = 0.9997) for on-line solid-phase extraction of trace levels of PCP. The method was applied to the determination of PCP in local lake water, river water and wastewater samples.


Biogeographical patterns in soil bacterial communities across the Arctic region.
The considerable microbial diversity of soils and key role in biogeochemical cycling have led to growing interest in their global distribution and the impact that environmental change might have at the regional level. In the broadest study of Arctic soil bacterial communities to date, we used high-throughput DNA sequencing to investigate the bacterial diversity from 200 independent Arctic soil samples from 43 sites. We quantified the impact of spatial and environmental factors on bacterial community structure using variation partitioning analysis, illustrating a nonrandom distribution across the region. pH was confirmed as the key environmental driver structuring Arctic soil bacterial communities, while total organic carbon (TOC), moisture and conductivity were shown to have little effect. Specialist taxa were more abundant in acidic and alkaline soils while generalist taxa were more abundant in acidoneutral soils. Of the 48 147 bacterial taxa, a core microbiome composed of only 13 taxa that were ubiquitously distributed and present within 95% of samples was identified, illustrating the high potential for endemism in the region. Overall, our results demonstrate the importance of spatial and edaphic factors on the structure of Arctic soil bacterial communities.


Listening to locals on payments for environmental services.
Payments for Environmental Services (PES) is gaining recognition worldwide as a serious option for conservation of ecosystems, as well as potentially improving the livelihoods of people providing environmental services. However, little attention has been paid to research on views of local people in their potential roles as service providers. In this research we explore perspectives of poor people living in a National Park in Vietnam, where introduction of PES is being considered. In-depth interviews and workshops were conducted - with strong emphasis on the use of visual techniques, to help facilitate learning processes and provide insight into local perspectives. From the research, two models were developed to indicate general factors that influence the likelihood of people adopting, and adhering to, PES schemes. We suggest these models can be used to guide the design of PES. Our findings also reveal three main requirements important in design of pro-poor PES: (1) Thorough scoping studies for ensuring that schemes are based on sound understanding of potential providers' perspectives and context. (2) Such studies should emphasise qualitative research and draw on participatory tools, to facilitate open dialogue and co-learning by researchers and participants. (3) Policy makers should consider designing hybridized schemes, i.e., in which PES concepts are combined with integrated conservation and development.


Panel 8: Report on Recent Advances in Molecular and Cellular Biochemistry.
Objectives To update the medical literature on recent cellular and molecular advances in otitis media disease models with a principal focus on developments in the past 5 years. We also aim to explain recent translational advances in cellular and molecular biology that have influenced our understanding and management of otitis media. Data Sources PubMed-indexed peer-reviewed articles. Review Methods A comprehensive review of the literature was conducted with the term otitis media and the following search terms: molecular biology, cell biology, innate immunity, oxidative stress, mucins, molecular diagnostics. Included articles were published in the English language from January 1, 2010, to July 31, 2015. Implications for Practice The molecular understanding of otitis media disease progression has rapidly advanced over the last 5 years. The roles of inflammation, mucins, and cell signaling mechanisms have been elucidated and defined. Advances in the field provide a plethora of opportunities for innovative molecular targeting in the development of novel therapeutic strategies for otitis media.


Plasma membrane aquaporin AqpZ protein is essential for glucose metabolism during photomixotrophic growth of Synechocystis sp. PCC 6803.
The genome of Synechocystis PCC 6803 contains a single gene encoding an aquaporin, aqpZ. The AqpZ protein functioned as a water-permeable channel in the plasma membrane. However, the physiological importance of AqpZ in Synechocystis remains unclear. We found that growth in glucose-containing medium inhibited proper division of ΔaqpZ cells and led to cell death. Deletion of a gene encoding a glucose transporter in the ΔaqpZ background alleviated the glucose-mediated growth inhibition of the ΔaqpZ cells. The ΔaqpZ cells swelled more than the wild type after the addition of glucose, suggesting an increase in cytosolic osmolarity. This was accompanied by a down-regulation of the pentose phosphate pathway and concurrent glycogen accumulation. Metabolite profiling by GC/TOF-MS of wild-type and ΔaqpZ cells revealed a relative decrease of intermediates of the tricarboxylic acid cycle and certain amino acids in the mutant. The changed levels of metabolites may have been the cause for the observed decrease in growth rate of the ΔaqpZ cells along with decreased PSII activity at pH values ranging from 7.5 to 8.5. A mutant in sll1961, encoding a putative transcription factor, and a Δhik31 mutant, lacking a putative glucose-sensing kinase, both exhibited higher glucose sensitivity than the ΔaqpZ cells. Examination of protein expression indicated that sll1961 functioned as a positive regulator of aqpZ gene expression but not as the only regulator. Overall, the ΔaqpZ cells showed defects in macronutrient metabolism, pH homeostasis, and cell division under photomixotrophic conditions, consistent with an essential role of AqpZ in glucose metabolism.


Relationship between shoulder abduction strength and rotator cuff tear in elderly women: a general population study.
To investigate the effect of age-related rotator cuff tears on shoulder strength in a general population cohort. Cross sectional observational study. This study was set in an outpatient clinic setting in Chingford, North East London, and was a component of the 20 year visit of the Chingford 1000 women cohort. Individuals were part of the Chingford 1000 women cohort, a 20-year-old longitudinal population study. This cohort has been extensively characterised as representative of the population of the UK. At the 20 year visit, 446 attended for shoulder assessment and were aged between 64 and 87. Isometric shoulder abduction strength measured using a Nottingham Mecmesin Myometer and the presence of rotator cuff pathology, determined via ultrasound examination (GE voluson i portable ultrasound machine with a 10-16MHz linear probe). Shoulders were classified into normal, abnormal tendon/partial tear, full-thickness tears (>0 and ≤2.5 cm) and full-thickness tears (>2.5 cm). Symptoms were defined using the Oxford Shoulder Score, where an abnormal score was defined as symptomatic. 446 women (891 shoulders) aged 71 (range 65-84) were included in the study. Age, the presence of pain and the non-dominant arm were demonstrated to reduce strength. Rotator cuff tears and pathology had no isolated effect on shoulder strength in those aged under 70. However, in the over 70s full-thickness tears>0 and ≤2.5 cm, and >2.5 cm had mean reductions of 6.3 and 12.7 N, respectively (p<0.001). Rotator cuff tears of all sizes in those aged under 70 were not associated with a loss of shoulder strength. In those aged over 70, strength was reduced by 30% with small and 40% with large full thickness tears. Loss in strength was associated a loss of ability to perform activities of daily living but only for large tears.


Computerized cognitive training in prostate cancer patients on androgen deprivation therapy: a pilot study.
Prostate cancer patients who have undergone androgen deprivation therapy (ADT) may experience cognitive impairment, yet there is an unmet need for nonpharmacological interventions to address cognitive impairment in this population. This study examines the feasibility, acceptability, and preliminary efficacy of a home-based computerized cognitive training (CCT) program to treat cancer-related cognitive impairment. Sixty men who had received ≥ 3 months of ADT were screened for at least mild cognitive or neurobehavioral impairment and randomized to 8 weeks of CCT or usual care. Follow-up assessments occurred immediately post-intervention or equivalent (T2) and 8 weeks later (T3). The acceptability of CCT was also assessed. Feasibility:A priori feasibility thresholds were partially met (i.e., randomization rate > 50%, retention rate > 70% excluding CCT drop-outs, but < 70% for intent-to-treat). Acceptability: Participants were mostly satisfied with CCT and found it somewhat enjoyable, though barriers to uptake existed. Preliminary efficacy: Linear mixed models indicated significant time by group effects favorable to CCT in reaction time (p = .01), but unfavorable to CCT in verbal and visual memory (ps < .05). Memory was temporarily suppressed in the CCT group at T2, but normalized by T3. There was no effect of CCT on self-reported cognitive functioning, neurobehavioral functioning, nor quality of life. This study provides tentative support for the feasibility and acceptability of CCT to treat mild cognitive impairment in ADT patients. CCT had a beneficial effect on reaction time, but temporarily suppressed memory. CCT's benefits may be limited to a narrow area of functioning. Larger-scale studies are needed.


A method of active case detection to target reservoirs of asymptomatic malaria and gametocyte carriers in a rural area in Southern Province, Zambia.
Asymptomatic reservoirs of malaria parasites are common yet are difficult to detect, posing a problem for malaria control. If control programmes focus on mosquito control and treatment of symptomatic individuals only, malaria can quickly resurge if interventions are scaled back. Foci of parasite populations must be identified and treated. Therefore, an active case detection system that facilitates detection of asymptomatic parasitaemia and gametocyte carriers was developed and tested in the Macha region in southern Zambia. Each week, nurses at participating rural health centres (RHC) communicated the number of rapid diagnostic test (RDT) positive malaria cases to a central research team. During the dry season when malaria transmission was lowest, the research team followed up each positive case reported by the RHC by a visit to the homestead. The coordinates of the location were obtained by GPS and all consenting residents completed a questionnaire and were screened for malaria using thick blood film, RDT, nested-PCR, and RT-PCR for asexual and sexual stage parasites. Persons who tested positive by RDT were treated with artemether/lumefantrine (Coartem). Data were compared with a community-based study of randomly selected households to assess the prevalence of asymptomatic parasitaemia in the same localities in September 2009. In total, 186 and 141 participants residing in 23 case and 24 control homesteads, respectively, were screened. In the case homesteads for which a control population was available (10 of the 23), household members of clinically diagnosed cases had a 8.0% prevalence of malaria using PCR compared to 0.7% PCR positive individuals in the control group (p = 0.006). The case and control groups had a gametocyte prevalence of 2.3% and 0%, respectively but the difference was not significant (p = 0.145). This pilot project showed that active case detection is feasible and can identify reservoirs of asymptomatic infection. A larger sample size, data over multiple low transmission seasons, and in areas with different transmission dynamics are needed to further validate this approach.


CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages.
Persistent high fever is one of the most typical clinical symptoms in dengue virus (DV)-infected patients. However, the source of endogenous pyrogen (eg, IL-1β) and the signaling cascade leading to the activation of inflammasome and caspase-1, which are essential for IL-1β and IL-18 secretion, during dengue infection have not been elucidated yet. Macrophages can be polarized into distinct phenotypes under the influence of GM-CSF or M-CSF, denoted as GM-Mϕ and M-Mϕ, respectively. We found that DV induced high levels of IL-1β and IL-18 from GM-Mϕ (inflammatory macrophage) and caused cell death (pyroptosis), whereas M-Mϕ (resting macrophage) did not produce IL-1β and IL-18 on DV infection even with lipopolysaccharide priming. This observation demonstrates the distinct responses of GM-Mϕ and M-Mϕ to DV infection. Moreover, up-regulation of pro-IL-1β, pro-IL-18, and NLRP3 associated with caspase-1 activation was observed in DV-infected GM-Mϕ, whereas blockade of CLEC5A/MDL-1, a C-type lectin critical for dengue hemorrhagic fever and Japanese encephalitis virus infection, inhibits NLRP3 inflammasome activation and pyrotopsis in GM-Mϕ. Thus, DV can activate NLRP3 inflammasome via CLEC5A, and GM-Mϕ plays a more important role than M-Mϕ in the pathogenesis of DV infection.


Abiraterone and increased survival in metastatic prostate cancer.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).


Nested polymerase chain reaction with sequence-specific primers typing for HLA-A, -B, and -C alleles: detection of microchimerism in DR-matched individuals.
It is widely accepted that donor leukocytes survive within the recipient periphery after blood transfusion or solid organ transplantation. The significance of this microchimerism remains unclear, partially because of the insecurity of assays used to detect the donor-derived material. The techniques used to detect donor-derived DNA within recipient peripheral blood rely largely on major histocompatibility complex class II polymorphism. We and others have shown that the sensitivity of polymerase chain reaction with sequence-specific primers (PCR-SSP) typing for HLA class II alleles can be increased 100-fold by the addition of a primary amplification step (nested PCR-SSP). We have now extended this technique to encompass typing for HLA class I alleles, thereby adding flexibility to microchimerism testing by enabling testing of recipients HLA-DR matched with their donors. However, the high level of sensitivity achieved with the technique (1:100,000) leads to a concomitant decrease in the specificity that results in the amplification of unexpected products, a phenomenon we encountered in the development of our nested PCR-SSP typing system for HLA class II alleles. We describe here how it is possible to compensate for these anomalies by including multiple testing of a pretransfusion sample that acts as a specificity control, establishing a rigorous baseline for subsequent analysis.


Rates of radiologically confirmed pneumonia as defined by the World Health Organization in Northern Territory Indigenous children.
To determine the burden of hospitalised, radiologically confirmed pneumonia (World Health Organization protocol) in Northern Territory Indigenous children. Historical, observational study of all hospital admissions for any diagnosis of NT resident Indigenous children, aged between > or = 29 days and < 5 years, 1 April 1997 to 31 March 2005. All chest radiographs taken during these admissions, regardless of diagnosis, were assessed for pneumonia in accordance with the WHO protocol. The primary outcome was endpoint consolidation (dense fluffy consolidation [alveolar infiltrate] of a portion of a lobe or the entire lung) present on a chest radiograph within 3 days of hospitalisation. We analysed data on 24,115 hospitalised episodes of care for 9492 children and 13,683 chest radiographs. The average annual cumulative incidence of endpoint consolidation was 26.6 per 1000 population per year (95% CI, 25.3-27.9); 57.5 per 1000 per year in infants aged 1-11 months, 38.3 per 1000 per year in those aged 12-23 months, and 13.3 per 1000 per year in those aged 24-59 months. In all age groups, rates of endpoint consolidation in children in the arid southern region of NT were about twice that of children in the tropical northern region. The rates of severe pneumonia in hospitalised NT Indigenous children are among the highest reported in the world. Reducing this unacceptable burden of disease should be a national health priority.


Multisensory integration: the case of a time window of gesture-speech integration.
This experiment investigates the integration of gesture and speech from a multisensory perspective. In a disambiguation paradigm, participants were presented with short videos of an actress uttering sentences like "She was impressed by the BALL, because the GAME/DANCE...." The ambiguous noun (BALL) was accompanied by an iconic gesture fragment containing information to disambiguate the noun toward its dominant or subordinate meaning. We used four different temporal alignments between noun and gesture fragment: the identification point (IP) of the noun was either prior to (+120 msec), synchronous with (0 msec), or lagging behind the end of the gesture fragment (-200 and -600 msec). ERPs triggered to the IP of the noun showed significant differences for the integration of dominant and subordinate gesture fragments in the -200, 0, and +120 msec conditions. The outcome of this integration was revealed at the target words. These data suggest a time window for direct semantic gesture-speech integration ranging from at least -200 up to +120 msec. Although the -600 msec condition did not show any signs of direct integration at the homonym, significant disambiguation was found at the target word. An explorative analysis suggested that gesture information was directly integrated at the verb, indicating that there are multiple positions in a sentence where direct gesture-speech integration takes place. Ultimately, this would implicate that in natural communication, where a gesture lasts for some time, several aspects of that gesture will have their specific and possibly distinct impact on different positions in an utterance.


Synthesis of the fungus metabolite cladosin C.
Cladosin C is one of the few known enaminotetramic acids, isolated from extracts of the deep sea fungus Cladosporium sphaerospermum. It was synthesised in ten steps and 14% overall yield by a late-stage amination of the corresponding 3-acyltetramic acid. This was obtained by a Dieckmann condensation of an N-β-ketoacylaminoester derived from dehydrovalinate and the thioester-terminated side chain containing the stereogenic centre which stemmed from poly-(R)-3-hydroxybutyrate.


An analysis of children with brucellosis associated with pancytopenia.
Brucellosis produces a variety of nonspecific hematologic abnormalities. Hematologic complications of mild anemia and leukopenia have been frequently associated with acute brucellosis, but pancytopenia is less frequently seen. In this study, records of children with brucellosis aged under or equal to 16 years, admitted to Yuzuncu Yil University Hospital between 2004 and 2010, were analyzed retrospectively. Over this time period, 187 patients with brucellosis were diagnosed. Twenty-five (13.3%) of 187 patients had pancytopenia during admission to hospital. The diagnosis of brucellosis was confirmed by standard tube agglutination test in all patients; titers were 1:320 in 1 patient and 1:1280 in 24 patients. Blood culture was positive for Brucella melitensis in 3 patients (12%). Fever was the most common manifestation, followed by malaise, anorexia, sweating, and weight loss. Fever and splenomegaly were the common signs in most patients. In addition, arthritis was observed in 5 patients, and epistaxis, headache, and abdominal pain were observed in 3 patients. The common bone marrow aspiration findings consisted of increased megakaryocytes and hyperplasia of erythroid series, with a shift to the left of the granulocytic series. Histiocytic hyperplasia was observed in the bone marrow smear of 2 patients. Mild hemophagocytosis was observed in the bone marrow of 3 patients. All patients recovered completely, and their peripheral blood counts returned to normal by 2 to 6 weeks after antibiotic treatment of brucellosis. In conclusion, the authors would like to emphasize that brucellosis should be considered in the differential diagnosis of children with pancytopenia.


Loss of nuclear receptor RXRα in epidermal keratinocytes promotes the formation of Cdk4-activated invasive melanomas.
Keratinocytes contribute to melanocyte transformation by affecting their microenvironment, in part through the secretion of paracrine factors. Here we report a loss of expression of nuclear receptor RXRα in epidermal keratinocytes during human melanoma progression. In the absence of keratinocytic RXRα, in combination with mutant Cdk4, cutaneous melanoma was generated that metastasized to lymph nodes in a bigenic mouse model. Expression of several keratinocyte-derived mitogenic growth factors (Et-1, Hgf, Scf, α-MSH and Fgf 2 ) was elevated in skin of bigenic mice, whereas Fas, E-cadherin and Pten, implicated in apoptosis, cellular invasion and melanomagenesis, respectively, were downregulated within the microdissected melanocytic tumors. We demonstrated that RXRα is recruited on the proximal promoter of both Et-1 and Hgf, possibly directly regulating their transcription in keratinocytes. These studies demonstrate the contribution of keratinocytic paracrine signaling during the cellular transformation and malignant conversion of melanocytes.


Fatty acids linked to cardiovascular mortality are associated with risk factors.
Although saturated fatty acids (FAs) have been linked to cardiovascular mortality, it is not clear whether this outcome is attributable solely to their effects on low-density lipoprotein cholesterol (LDL-C) or whether other risk factors are also associated with FAs. The Western Alaskan Native population, with its rapidly changing lifestyles, shift in diet from unsaturated to saturated fatty acids and dramatic increase in cardiovascular disease (CVD), presents an opportunity to elucidate any associations between specific FAs and known CVD risk factors. We tested the hypothesis that the specific FAs previously identified as related to CVD mortality are also associated with individual CVD risk factors. In this community-based, cross-sectional study, relative proportions of FAs in plasma and red blood cell membranes were compared with CVD risk factors in a sample of 758 men and women aged ≥35 years. Linear regression analyses were used to analyze relations between specific FAs and CVD risk factors (LDL-C, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, fasting glucose and fasting insulin, 2-hour glucose and 2-hour insulin). The specific saturated FAs previously identified as related to CVD mortality, the palmitic and myristic acids, were adversely associated with most CVD risk factors, whereas unsaturated linoleic acid (18:2n-6) and the marine n-3 FAs were not associated or were beneficially associated with CVD risk factors. The results suggest that CVD risk factors are more extensively affected by individual FAs than hitherto recognized, and that risk for CVD, MI and stroke can be reduced by reducing the intake of palmitate, myristic acid and simple carbohydrates and improved by greater intake of linoleic acid and marine n-3 FAs.


Cancer risk among patients with myotonic muscular dystrophy.
Myotonic muscular dystrophy (MMD) is an autosomal-dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks that have never been quantified. To quantitatively evaluate cancer risk in patients with MMD, overall and by sex and age. We identified 1658 patients with an MMD discharge diagnosis in the Swedish Hospital Discharge Register or Danish National Patient Registry between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed up from date of first MMD-related inpatient or outpatient contact to first cancer diagnosis, death, emigration, or completion of cancer registration. Risks of all cancers combined and by anatomic site, stratified by sex and age. One hundred four patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during postdischarge follow-up. This corresponds to an observed cancer rate of 73.4 per 10,000 person-years in MMD vs an expected rate of 36.9 per 10,000 person-years in the general Swedish and Danish populations combined (standardized incidence ratio [SIR], 2.0; 95% CI, 1.6-2.4). Specifically, we observed significant excess risks of cancers of the endometrium (n = 11; observed rate, 16.1/10,000 person-years; SIR, 7.6; 95% CI, 4.0-13.2), brain (n = 7; observed rate, 4.9/10,000 person-years; SIR, 5.3; 95% CI, 2.3-10.4), ovary (n = 7; observed rate, 10.3/10,000 person-years; SIR, 5.2; 95% CI, 2.3-10.2), and colon (n = 10; observed rate, 7.1/10,000 person-years; SIR, 2.9; 95% CI, 1.5-5.1). Cancer risks were similar in women and men after excluding genital organ tumors (SIR, 1.9; 95% CI, 1.4-2.5, vs SIR, 1.8; 95% CI, 1.3-2.5, respectively; P = .81 for heterogeneity; observed rates, 64.5 and 47.7 per 10,000 person-years in women and men, respectively). The same pattern of cancer excess was observed first in the Swedish and then in the Danish cohorts, which were studied sequentially and initially analyzed independently. Patients with MMD identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.


An approach to automated particle picking from electron micrographs based on reduced representation templates.
Reduced representation templates are used in a real-space pattern matching framework to facilitate automatic particle picking from electron micrographs. The procedure consists of five parts. First, reduced templates are constructed either from models or directly from the data. Second, a real-space pattern matching algorithm is applied using the reduced representations as templates. Third, peaks are selected from the resulting score map using peak-shape characteristics. Fourth, the surviving peaks are tested for distance constraints. Fifth, a correlation-based outlier screening is applied. Test applications to a data set of keyhole limpet hemocyanin particles indicate that the method is robust and reliable.


Adenine Radical Cation Formation by a Ligand-Centered Excited State of an Intercalated Chromium Polypyridyl Complex Leads to Enhanced DNA Photo-oxidation.
Assessment of the DNA photo-oxidation and synthetic photocatalytic activity of chromium polypyridyl complexes is dominated by consideration of their long-lived metal-centered excited states. Here we report the participation of the excited states of [Cr(TMP)2dppz]3+ (1) (TMP = 3,4,7,8-tetramethyl-1,10-phenanthroline; dppz = dipyrido[3,2-a:2',3'-c]phenazine) in DNA photoreactions. The interactions of enantiomers of 1 with natural DNA or with oligodeoxynucleotides with varying AT content (0-100%) have been studied by steady state UV/visible absorption and luminescence spectroscopic methods, and the emission of 1 is found to be quenched in all systems. The time-resolved infrared (TRIR) and visible absorption spectra (TA) of 1 following excitation in the region between 350 to 400 nm reveal the presence of relatively long-lived dppz-centered states which eventually yield the emissive metal-centered state. The dppz-localized states are fully quenched when bound by GC base pairs and partially so in the presence of an AT base-pair system to generate purine radical cations. The sensitized formation of the adenine radical cation species (A•+T) is identified by assigning the TRIR spectra with help of DFT calculations. In natural DNA and oligodeoxynucleotides containing a mixture of AT and GC of base pairs, the observed time-resolved spectra are consistent with eventual photo-oxidation occurring predominantly at guanine through hole migration between base pairs. The combined targeting of purines leads to enhanced photo-oxidation of guanine. These results show that DNA photo-oxidation by the intercalated 1, which locates the dppz in contact with the target purines, is dominated by the LC centered excited state. This work has implications for future phototherapeutics and photocatalysis.


Quantitative-phase-contrast imaging of a two-level surface described as a 2D linear filtering process.
The paper deals with quantitative phase imaging of two-height-level surface reliefs. The imaging is considered to be a linear system and, consequently, the Fourier transform of the image is the product of the Fourier transform of a 2D function characterizing the surface and a specific 2D coherent transfer function. The Fourier transform of functions specifying periodic surface reliefs is factorized into two functions similar to lattice and structure amplitudes in crystal structure analysis. The approach to the imaging process described in the paper enables us to examine the dependence of the phase image on the surface geometry. Theoretical results are verified experimentally by means of a digital holographic microscope.


RGS4 RNA Secondary Structure Mediates Staufen2 RNP Assembly in Neurons.
RNA-binding proteins (RBPs) act as posttranscriptional regulators controlling the fate of target mRNAs. Unraveling how RNAs are recognized by RBPs and in turn are assembled into neuronal RNA granules is therefore key to understanding the underlying mechanism. While RNA sequence elements have been extensively characterized, the functional impact of RNA secondary structures is only recently being explored. Here, we show that Staufen2 binds complex, long-ranged RNA hairpins in the 3'-untranslated region (UTR) of its targets. These structures are involved in the assembly of Staufen2 into RNA granules. Furthermore, we provide direct evidence that a defined Rgs4 RNA duplex regulates Staufen2-dependent RNA localization to distal dendrites. Importantly, disrupting the RNA hairpin impairs the observed effects. Finally, we show that these secondary structures differently affect protein expression in neurons. In conclusion, our data reveal the importance of RNA secondary structure in regulating RNA granule assembly, localization and eventually translation. It is therefore tempting to speculate that secondary structures represent an important code for cells to control the intracellular fate of their mRNAs.


Perceptions of isolation during facility births in Haiti - a qualitative study.
Haiti's maternal mortality, stillbirth, and neonatal mortality rates are the highest in Latin America and the Caribbean. Despite inherent risks, the majority of women still deliver at home without supervision from a skilled birth attendant. The purpose of this study was to elucidate factors driving this decision. We conducted six focus group discussions with women living in urban (N = 14) or rural (N = 17) areas and asked them questions pertaining to their reasons for delivering at a facility or at home, perceptions of staff at the health facility, experiences with or knowledge of facility or home deliveries, and prior pregnancy experiences (if relevant). We also included currently pregnant women to learn about their plans for delivery, if any. All of the women interviewed acknowledged similar perceived benefits of a facility birth, which were a reduced risk of complications during pregnancy and access to emergency care. However, many women also reported unfavorable birthing experiences at facilities. We identified four key thematic concerns that underpinned women's negative assessments of a facility birth: being left alone, feeling ignored, being subject to physical immobility, and lack of compassionate touch/care. Taken together, these concerns articulated an overarching sense of what we term "isolation," which encompasses feelings of being isolated in the hospital during delivery. Although Haitian women recognized that a facility was a safer place for birthing than the home, an overarching stigma of patient neglect and isolation in facilities was a major determining factor in choosing to deliver at home. The Haitian maternal mortality rate is high and will not be lowered if women continue to feel that they will not receive comfort and compassionate touch/care at a facility compared to their experience of delivering with traditional birth attendants at home. Based on these results, we recommend that all secondary and tertiary facilities offering labor and delivery services develop patient support programs, where women are better supported from admission through the labor and delivery process, including but not limited to improvements in communication, privacy, companionship (if deemed safe), respectful care, attention to pain during vaginal exams, and choice of birth position.


Early life exposure to PCB126 results in delayed mortality and growth impairment in the zebrafish larvae.
The occurrence of chronic or delayed toxicity resulting from the exposure to sublethal chemical concentrations is an increasing concern in environmental risk assessment. The Fish Embryo Toxicity (FET) test with zebrafish provides a reliable prediction of acute toxicity in adult fish, but it cannot yet be applied to predict the occurrence of chronic or delayed toxicity. Identification of sublethal FET endpoints that can assist in predicting the occurrence of chronic or delayed toxicity would be advantageous. The present study characterized the occurrence of delayed toxicity in zebrafish larvae following early exposure to PCB126, previously described to cause delayed effects in the common sole. The first aim was to investigate the occurrence and temporal profiles of delayed toxicity during zebrafish larval development and compare them to those previously described for sole to evaluate the suitability of zebrafish as a model fish species for delayed toxicity assessment. The second aim was to examine the correlation between the sublethal endpoints assessed during embryonal and early larval development and the delayed effects observed during later larval development. After exposure to PCB126 (3-3000ng/L) until 5 days post fertilization (dpf), larvae were reared in clean water until 14 or 28 dpf. Mortality and sublethal morphological and behavioural endpoints were recorded daily, and growth was assessed at 28 dpf. Early life exposure to PCB126 caused delayed mortality (300 ng/L and 3000 ng/L) as well as growth impairment and delayed development (100 ng/L) during the clean water period. Effects on swim bladder inflation and cartilaginous tissues within 5 dpf were the most promising for predicting delayed mortality and sublethal effects, such as decreased standard length, delayed metamorphosis, reduced inflation of swim bladder and column malformations. The EC50 value for swim bladder inflation at 5 dpf (169 ng/L) was similar to the LC50 value at 8 dpf (188 and 202 ng/L in two experiments). Interestingly, the patterns of delayed mortality and delayed effects on growth and development were similar between sole and zebrafish. This indicates the comparability of critical developmental stages across divergent fish species such as a cold water marine flatfish and a tropical freshwater cyprinid. Additionally, sublethal effects in early embryo-larval stages were found promising for predicting delayed lethal and sublethal effects of PCB126. Therefore, the proposed method with zebrafish is expected to provide valuable information on delayed mortality and delayed sublethal effects of chemicals and environmental samples that may be extrapolated to other species.


Studies of polaritonic gaps in photonic crystals.
In a photonic band structure two kinds of gaps with different origins can be observed. Photonic gaps are determined by the symmetry of the photonic crystal, the lattice constant, and the contrast of the dielectric functions for the two components. Polaritonic gaps originate from the bulk optical properties of one of the components. Excitation of ionic components in the lattice results in a photon energy interval in which the dielectric function is negative. Here we investigate the interaction between photonic gaps and polaritonic gaps in one-dimensional and two-dimensional photonic structures. In particular, we show that by such interactions the polaritonic gap can be made wider and stronger, be left unchanged, or be made to vanish.


The neurodynamics of emotion: delineating typical and atypical emotional processes during adolescence.
The study of development is, in and of itself, the study of change over time, but emotions, particularly emotional reactivity and emotional regulation, also unfold over time, albeit over briefer time-scales. Adolescence is a period of development characterized by marked changes in emotional processes and rewiring of the underlying neural circuitry, making this time of life formative. Yet this period is also a time of increased risk for anxiety and mood disorders. Changes in the temporal dynamics of emotional processes (e.g. magnitude, time-to-peak and duration) occur during this developmental period and have been associated with risk for mood and anxiety disorders. In this article, we describe how the temporal dynamics of emotions change during adolescence and how they may increase risk for these psychopathologies. We highlight studies that illustrate how formalizing temporal neurodynamics of emotion may enhance links among levels of analyses from neurobiological to real-world, moment-to-moment experiences.


The urinary microbiome in women with mixed urinary incontinence compared to similarly aged controls.
Previous studies have suggested that women with urinary incontinence have an altered urinary microbiome. We hypothesized that the microbiome in women with mixed urinary incontinence (MUI) differed from controls and tested this hypothesis using bacterial gene sequencing techniques. This multicenter study compared the urinary microbiome in women with MUI and similarly aged controls. Catheterized urine samples were obtained; v4-6 regions of the 16S rRNA gene were sequenced to identify bacteria. Bacterial predominance (> 50% of an individual's genera) was compared between MUI and controls. Bacterial sequences were categorized into "community types" using Dirichlet multinomial mixture (DMM) methods. Generalized linear mixed models predicted MUI/control status based on clinical characteristics and community type. Post-hoc analyses were performed in women < 51 and ≥ 51 years. Sample size estimates required 200 samples to detect a 20% difference in Lactobacillus predominance with P < 0.05. Of 212 samples, 97.6% were analyzed (123 MUI/84 controls, mean age 53 ± 11 years). Overall Lactobacillus predominance did not differ between MUI and controls (45/123 = 36.6% vs. 36/84 = 42.9%, P = 0.36). DMM analyses revealed six community types; communities differed by age (P = 0.001). A High-Lactobacillus (89.2% Lactobacillus) community had a greater proportion of controls (19/84 = 22.6%, MUI 11/123 = 8.9%). Overall, bacterial community types did not differ in MUI and controls. However, post-hoc analysis of women < 51 years found that bacterial community types distinguished MUI from controls (P = 0.041); Moderate-Lactobacillus (aOR 7.78, CI 1.85-32.62) and Mixed (aOR 7.10, CI 1.32-38.10) community types were associated with MUI. Community types did not differentiate MUI and controls in women ≥ 51 years (P = 0.94). Women with MUI and controls did not differ in overall Lactobacillus predominance. In younger women, urinary bacterial community types differentiated MUI from controls.


Intravascular membrane oxygenation and carbon dioxide removal with IVOX: can improved design and permissive hypercapnia achieve adequate respiratory support during severe respiratory failure?
The intravenacaval oxygenator and carbon dioxide removal device (IVOX) conceived by Mortensen at CardioPulmonics is a diffusion-limited device capable of removing 30% of CO2 production of an adult at normocapnia with minimal reduction in ventilator requirements. Through mathematical modeling, an ex vivo venovenous bypass circuit to model the vena cava and animal models of severe smoke inhalation injury, the practice of permissive hypercapnia has been established to enhance CO2 removal by IVOX. By allowing the blood PCO2 to rise gradually, the CO2 excretion by IVOX can be linearly increased in a 1:1 relationship. Experimental and clinical studies have shown that CO2 removal by IVOX increased from 30-40 ml/min at normal blood PCO2 to 80-90 ml/min at PCO2 of 90 mm Hg. In addition, IVOX with permissive hypercapnia allowed a significant reduction in minute ventilation and peak airway pressure. Design changes could also improve the performance of IVOX. Increased surface area and mixing with more fibers and crimping in new prototypes of IVOX significantly increased CO2 removal and oxygen transfer. Active mixing in the blood to decrease the boundary layer resistance can further enhance gas exchange of IVOX. In conclusion, gas exchange by the current design of IVOX is limited, and improvements in design are needed for it to become a more clinically applicable device. Permissive hypercapnia can significantly enhance CO2 removal by IVOX as well as significantly reduce ventilator requirements.


Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells.
The anti-VEGF humanized antibody bevacizumab suppresses various malignancies, but tumors can acquire drug resistance. Preclinical studies suggest myeloid-derived suppressor cells (MDSCs) may be associated with tumor refractoriness to anti-VEGF treatment. Here we report a novel mechanism of tumor escape from anti-VEGF therapy. Anti-VEGF treatment enhanced intratumoral recruitment of CD11bhigh/Gr-1high polymorphonuclear (PMN)-MDSCs in anti-VEGF-resistant Lewis lung carcinoma tumors. This effect was diminished by the anticancer agent capecitabine, a pro-drug converted to 5-fluorouracil, but not by 5-fluorouracil itself. This process was mediated by enhanced intratumoral granulocyte-colony stimulating factor expression, as previously demonstrated. However, neither interleukin-17 nor Bv8, which were previously identified as key contributors to anti-VEGF resistance, was involved in this model. Capecitabine eliminated PyNPase-expressing MDSCs from both tumors and peripheral blood. Capecitabine treatment also reversed inhibition of both antitumor angiogenesis and tumor growth under anti-VEGF antibody treatment, and this effect partially inhibited in tumors implanted in mice deficient in both PyNPases. These results indicate that intratumoral granulocyte-colony stimulating factor expression and CD11bhigh/Gr-1high PMN-MDSC recruitment underlie tumor resistance to anti-VEGF therapy, and suggest PyNPases are potentially useful targets during anti-angiogenic therapy.


ACR Appropriateness Criteria on colorectal cancer screening.
Colorectal cancer remains one of the most common causes of cancer death in this country. This malignancy is ideally suited for screening because the detection and removal of the precursor adenomatous polyp can prevent most colorectal cancers from ever forming. The choice of a test for screening involves consideration of various individual parameters, including patient age and the presence of risk factors for the development of colorectal cancer. Computed tomographic colonography (CTC) has emerged as the leading imaging technique for colorectal cancer screening in average-risk individuals on the basis of the evidence presented in this paper. The double-contrast barium enema is an alternative imaging test that is appropriate particularly when CTC is not available. In 2008, the American Cancer Society guideline for colorectal cancer screening was revised jointly with the US Multi-Society Task Force on Colorectal Cancer and the ACR to include CTC every 5 years as an option for average-risk individuals. Computed tomographic colonography is also the preferred test for colon evaluation after an incomplete colonoscopy. Imaging tests including CTC and the double-contrast barium enema are usually not indicated for colorectal cancer screening in high-risk patients with polyposis syndromes or inflammatory bowel disease. This paper presents the new colorectal cancer imaging test ratings and is the result of evidence-based consensus by the ACR Appropriateness Criteria Expert Panel on Gastrointestinal Imaging.


Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality and has an increasing incidence worldwide. Locoregional therapies, defined as imaging-guided liver tumour-directed procedures, play a leading part in the management of 50-60% of HCCs. Radiofrequency is the mainstay for local ablation at early stages and transarterial chemoembolization (TACE) remains the standard treatment for intermediate-stage HCC. Other local ablative techniques (microwave ablation, cryoablation and irreversible electroporation) or locoregional therapies (for example, radioembolization and sterotactic body radiation therapy) have been explored, but have not yet modified the standard therapies established decades ago. This understanding is currently changing, and several drugs have been approved for the management of advanced HCC. Molecular therapies dominate the adjuvant trials after curative therapies and combination strategies with TACE for intermediate stages. The rationale for these combinations is sound. Local therapies induce antigen and proinflammatory cytokine release, whereas VEGF inhibitors and tyrosine kinase inhibitors boost immunity and prime tumours for checkpoint inhibition. In this Review, we analyse data from randomized and uncontrolled studies reported with ablative and locoregional techniques and examine the expected effects of combinations with systemic treatments. We also discuss trial design and benchmarks to be used as a reference for future investigations in the dawn of a promising new era for HCC treatment.


The epidemiology and hotspots of road traffic injuries in Moshi, Tanzania: An observational study.
Road traffic injuries (RTIs) continue to increase with the proliferation of motor vehicles, especially in low-income countries where safe road infrastructure is lacking. Knowing where and why RTIs occur would allow for increased safety and prevention planning. In this study, police records of 300 motor vehicle collisions which occurred between February 2013 and January 2014 in Moshi, Tanzania were reviewed. Analysis of variables including victim age, gender, type of collision, conditions, and use of safety equipment were analyzed. Geographic information system (GIS) analysis was performed to identify areas with the most collisions. Most injuries occurred at four intersections on two main corridor. Car crashes represented 48% of reports while motorcycle collisions were 35% of reports. Victims were predominantly male. The majority (64%) of RTI victims in cars used seatbelts while only 43% of motorcyclists wore helmets; none of those who used the helmet or seatbelt suffered a grievous injury. These data demonstrate that RTIs in Moshi occur in predictable high traffic locations. RTIs injure victims of all backgrounds and safety equipment is not universally utilized. More investment is needed in improved data collection methods, and a greater emphasis on intersection safety is needed to reduce these preventable injuries.


Platelet Function Determined by Flow Cytometry: New Perspectives?
Flow cytometry enables studies of several different aspects of platelet function in response to a variety of platelet agonists. This can be done using only a small volume of whole blood, and also in blood with low platelet counts. These properties, together with the increasing number of flow cytometers available in hospitals worldwide, make flow cytometry an interesting option for laboratories interested in studies of platelet function in different clinical settings. This review focuses on practical issues regarding the use of flow cytometry for platelet function testing. It provides an overview of available activation markers, platelet agonists, and experimental setup issues. The review summarizes previous experience and factors important to consider to perform high-quality platelet function testing by flow cytometry. It also discusses its current use and possibilities and challenges for future use of flow cytometry in clinical settings.


Control of DNMT1 abundance in epigenetic inheritance by acetylation, ubiquitylation, and the histone code.
Inheritance of DNA methylation patterns is a key mechanism involved in epigenetic cell memory transmission from mother cell to daughter cell. This occurs due to cooperation between the DNA methyltransferase DNMT1 and the ubiquitin ligase UHRF1 (ubiquitin-like, containing plant homeo domain and RING finger 1) in a macromolecular complex. Newly identified members of this complex are the acetyltransferase Tip60 (Tat-interactive protein) and the deubiquitinase HAUSP (herpes virus-associated ubiquitin specific protease), which exert tight regulation of DNMT1 abundance through a ubiquitylation-dependent process. It is important to determine how all of these actors communicate with each other and what signals coordinate their communication. In the case of DNMT1, the balance of UHRF1 and HAUSP activities might be influenced by the local environment, such as histone code, cell-cycle status, and local DNA methylation status.


The molecular basis for biological inactivation of nucleic acids. The action of methylating agents on the ribonucleic acid-containing bacteriophage R17.
1. The inactivation of an RNA-containing bacteriophage after reaction with four methylating agents was studied. Measurements of the extent of methylation of the RNA and of the nature and amounts of the various reaction products were made. In experiments with dimethyl sulphate and methyl methanesulphonate inactivation can be quantitatively accounted for by methylation at two of the positions involved in hydrogen bonding: N-1 of adenine and N-3 of cytosine. In experiments with N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine methylation at N-1 of adenine and N-3 of cytosine accounts for only about one-half of the observed inactivation. Scission of the RNA chain during reaction accounts for a further 20% of the inactivation. To account for the remainder it seems necessary to postulate that formation of O(6)-methylguanine constitutes a lethal lesion. 2. Breaks in the RNA chain formed on reaction with the nitroso derivatives presumably result from methylation of the phosphate diester group followed by hydrolysis of the unstable triester thus formed.


Effect of Performance Deficiencies on Graduation and Board Certification Rates: A 10-yr Multicenter Study of Anesthesiology Residents.
This multicenter, retrospective study was conducted to determine how resident performance deficiencies affect graduation and board certification. Primary documents pertaining to resident performance were examined over a 10-yr period at four academic anesthesiology residencies. Residents entering training between 2000 and 2009 were included, with follow-up through February 2016. Residents receiving actions by the programs' Clinical Competency Committee were categorized by the area of deficiency and compared to peers without deficiencies. A total of 865 residents were studied (range: 127 to 275 per program). Of these, 215 residents received a total of 405 actions from their respective Clinical Competency Committee. Among those who received an action compared to those who did not, the proportion graduating differed (93 vs. 99%, respectively, P < 0.001), as did the proportion achieving board certification (89 vs. 99%, respectively, P < 0.001). When a single deficiency in an Essential Attribute (e.g., ethical, honest, respectful behavior; absence of impairment) was identified, the proportion graduating dropped to 55%. When more than three Accreditation Council for Graduate Medical Education Core Competencies were deficient, the proportion graduating also dropped significantly. Overall graduation and board certification rates were consistently high in residents with no, or isolated, deficiencies. Residents deficient in an Essential Attribute, or multiple competencies, are at high risk of not graduating or achieving board certification. More research is needed on the effectiveness and selective deployment of remediation efforts, particularly for high-risk groups.


Improvement of long-term outcomes in hepatitis C virus antibody-positive patients with hepatocellular carcinoma after hepatectomy in the modern era.
The present study was conducted to clarify the causes of recent improvement of outcomes after hepatectomy in patients with hepatitis C (HC)-related hepatocellular carcinoma (HCC). From 1990 to 2006, 323 curative liver resections for HC-HCC were performed in our department. The patients were divided into two groups: early period (1990-1999: n=221) and the late period (2000-2006: n=102). Prognostic factors were determined to clarify the cause of the survival improvement in the modern era. The overall survival rates for the patients in the early and late periods were 54.9 and 70.3% at 5 years, respectively (P=0.0005). There was no difference in the recurrence-free survival rates between the two groups, although both survival without recurrence (P=0.0003) and survival after recurrence (P=0.0063) were significantly better in the late period than in the early period. Patients with better liver function, patients with interferon (IFN) therapy and patients with subsegmentectomy were selected more frequently, and the incidence of blood transfusion was decreased in the late period below the level recorded in the early period. For recurrent HCC, lipiodolization decreased and local ablation therapy increased in the late period. The independent prognostic factors for overall survival were preoperative serum levels of albumin and alanine aminotransferase, histological liver cirrhosis, tumor size, intrahepatic metastasis, histological grade, blood transfusion, and IFN therapy. In HC-HCC, survival was improved in the late period of the present study. Selection of patients with good liver function, no blood transfusion with reduction of blood loss, anti-hepatitis C virus therapy with IFN, and introduction of local ablation therapy for HCC recurrence may be related to the improved survival.


Meta-Prediction of MTHFR Gene Polymorphism and Air Pollution on the Risks of Congenital Heart Defects Worldwide: A Transgenerational Analysis.
Congenital heart disease (CHD) is the leading cause of death in children, and is affected by genetic and environmental factors. To investigate the association of air pollution with methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and the risk of CHD, we included 58 study groups of children and parents, with 12,347 cases and 18,106 controls worldwide. Both MTHFR C677T (rs 1801133) and A1298C (rs 1801131) gene polymorphisms were risks for CHD in children with transgenerational effects from their parents. Countries with greater risks of CHD with a pooled risk ratio (RR) > 2 from MTHFR 677 polymorphisms included Germany, Portugal, China, and Egypt for children; and Brazil, Puerto Rico, Mexico, China, and Egypt for mothers. Whereas, countries with greater risk of CHD with RR > 2 from MTHFR 1298 polymorphisms included Taiwan, Turkey, and Egypt for children; and Brazil, China, and Egypt for mothers. Additionally, meta-prediction analysis revealed that the percentages of MTHFR 677TT and TT plus CT polymorphisms together were increased in countries with higher levels of air pollution, with a trend of increased CHD risks with higher levels of air pollution for children (p = 0.07). Our findings may have significant implications for inflammatory pathways in association with MTHFR polymorphisms and future intervention studies to correct for folate-related enzyme deficits resultied from MTHFR polymorphisms to prevent CHDs for future generations.


Epidemiology and causation of coronary heart disease and stroke in India.
Cardiovascular diseases are major causes of mortality and disease in the Indian subcontinent, causing more than 25% of deaths. It has been predicted that these diseases will increase rapidly in India and this country will be host to more than half the cases of heart disease in the world within the next 15 years. Coronary heart disease and stroke have increased in both urban and rural areas. Case-control studies indicate that tobacco use, obesity with high waist:hip ratio, high blood pressure, high LDL cholesterol, low HDL cholesterol, abnormal apolipoprotein A-1:B ratio, diabetes, low consumption of fruits and vegetables, sedentary lifestyles and psychosocial stress are important determinants of cardiovascular diseases in India. These risk factors have increased substantially over the past 50 years and to control further escalation it is important to prevent them. National interventions such as increasing tobacco taxes, labelling unhealthy foods and trans fats, reduction of salt in processed foods and better urban design to promote physical activity may have a wide short-term impact.


Imported chikungunya cases in an area newly colonised by Aedes albopictus: mathematical assessment of the best public health strategy.
We aimed to identify the optimal strategy that should be used by public health authorities against transmission of chikungunya virus in mainland France. The theoretical model we developed, which mimics the current surveillance system, predicted that without vector control (VC), the probability of local transmission after introduction of viraemic patients was around 2%, and the number of autochthonous cases between five and 15 persons per hectare, depending on the number of imported cases. Compared with this baseline, we considered different strategies (VC after clinical suspicion of a case or after laboratory confirmation, for imported or autochthonous cases): Awaiting laboratory confirmation for suspected imported cases to implement VC had no significant impact on the epidemiological outcomes analysed, mainly because of the delay before entering into the surveillance system. However, waiting for laboratory confirmation of autochthonous cases before implementing VC resulted in more frequent outbreaks. After analysing the economic cost of such strategies, our study suggested implementing VC immediately after the notification of a suspected autochthonous case as the most efficient strategy in settings where local transmission has been proven. Nevertheless, we identified that decreasing reporting time for imported cases should remain a priority.


Combining phylogenomic and supermatrix approaches, and a time-calibrated phylogeny for squamate reptiles (lizards and snakes) based on 52 genes and 4162 species.
Two common approaches for estimating phylogenies in species-rich groups are to: (i) sample many loci for few species (e.g. phylogenomic approach), or (ii) sample many species for fewer loci (e.g. supermatrix approach). In theory, these approaches can be combined to simultaneously resolve both higher-level relationships (with many genes) and species-level relationships (with many taxa). However, fundamental questions remain unanswered about this combined approach. First, will higher-level relationships more closely resemble those estimated from many genes or those from many taxa? Second, will branch support increase for higher-level relationships (relative to the estimate from many taxa)? Here, we address these questions in squamate reptiles. We combined two recently published datasets, one based on 44 genes for 161 species, and one based on 12 genes for 4161 species. The likelihood-based tree from the combined matrix (52 genes, 4162 species) shared more higher-level clades with the 44-gene tree (90% vs. 77% shared). Branch support for higher level-relationships was marginally higher than in the 12-gene tree, but lower than in the 44-gene tree. Relationships were apparently not obscured by the abundant missing data (92% overall). We provide a time-calibrated phylogeny based on extensive sampling of genes and taxa as a resource for comparative studies.


Using differential ratings of perceived exertion to assess agreement between coach and player perceptions of soccer training intensity: An exploratory investigation.
We aimed to assess the coach-player agreement of subjective soccer training loads via differential ratings of perceived exertion (dRPE). The coach initially underwent quantifiable familiarisation (blackness test) with the Borg CR100 scale. Data were collected from 16 semi-professional soccer players across seven consecutive training sessions. For the measurement of subjective training load, the coach and players provided dRPE (CR100) for legs (RPE-L), breathlessness (RPE-B) and technical exertion (RPE-T). Coach-prescribed dRPE were recorded prior to training, with coach observed and player reported dRPE collected post training. Statistical equivalence bounds for agreement between coach (prescribed and observed) and player reported dRPE scores were 4 arbitrary units on the CR100 and we used a probability outcome of likely (≥75%) to infer realistic equivalence. Following three familiarisation sessions, the coach improved their blackness test score from 39% to 83%. Coach observed and player reported RPE-T scores were likely equivalent, with all other comparisons not realistically equivalent. Since training prescription is coach-led, our data highlight the importance of accurate internal load measurement and feedback in soccer. The improved accuracy and precision of coach intensity estimation after three attempts at the blackness test suggests that this method could be worthwhile to researchers and practitioners employing dRPE.


Effect of low dose oral contraceptives on exercise performance.
to examine the effect of cycle phase or a low dose oral contraceptive on exercise performance in young women. As controls, 15 men were tested twice by a maximal treadmill test (Vo2 max) and by an endurance run 14 d apart to determine performance variability from causes other than hormonal fluctuations. Ten women ages 18-30 were then tested for Vo2 max and endurance in the same way in both the follicular and the luteal phase (random order, ovulation assessed by sonography). They were then randomly assigned to placebo (n = 3) or oral contraceptive (1 mg norethindrone and 35 micrograms ethinyl oestradiol) (n = 7) for 21 days. Tests were repeated during the first and third weeks of treatment. Vo2 max and endurance tests were compared in the men and control cycle of the women by using independent t tests on percent change. The data for both cycles in the women were analysed by repeated measures ANOVA. There was no difference in per cent change in total test time, Vo2 max, or breathing frequency between the men and women in either test. Data obtained during the Vo2 max test revealed no difference between the follicular and luteal phases of the menstrual cycle for total test time [11.8 (SD 2.3) v 12.6 (2.3) min], Vo2 [41.6 (12.1) v 39.7 (11.4) ml.kg-1.min-1], or breathing frequency [26.8 (3.5) v 27.3 (9.9) breaths.min-1] respectively, or during the first and third weeks of treatment [total test time 12.0 (2.5) v 12.8 (2.4) min; Vo2 37.3 (7.4) v 41.0 (12.4) ml.kg-1.min-1; breathing frequency 27.8 (4.2) v 27.7 (3.4) breaths.min-1, respectively]. Data obtained during the endurance test revealed no difference between the follicular and luteal phase of the menstrual cycle for total test time [20.5 (15.7) v 16.2 (8.5) min], Vo2 [37.5 (9.4) v 32.9 (8.1) ml.kg-1.min-1], or breathing frequency [32.0 (6.0) v 33.2 (5.1) breaths.min-1, respectively], or during the first and third weeks of treatment [total test time 32.3 (34.9) v 30.6 (30.1) min; Vo2 33.9 (10.1) v 35.2 (8.6) ml.kg-1.min-1; breathing frequency 34.0 (5.9) v 34.8 (5.3) breaths.min-1, respectively]. Neither cycle phase nor a low dose oral contraceptive containing 1 mg norethindrone adversely affects performance during a maximal treadmill test or endurance run.


Developing a Patient-Centered Benefit-Risk Survey: A Community-Engaged Process.
To provide a community-engaged process to inform the design of a stated-preferences experiment. The process involved integrating patients and caregivers of people with Duchenne/Becker muscular dystrophy, advocates, clinicians, and the sponsor in conceptualizing and developing a benefit-risk survey on the basis of phase III trial results. Our community-engagement process for the development of a stated-preference survey included a set of five guiding principles with a foundation in the principles of community-engaged research. Engagement efforts were carried out through an informal network of three committees. Members of the leadership, stakeholder, and review committees comprised patients, caregivers, clinicians, advocacy leadership, and industry representatives. Committee members participated in 15 hours of formal engagement including interviews and conference calls that ranged from 45 to 90 minutes, plus additional less-formal ad hoc communication. Committees comprised 20 individuals across three committees including adults with DMD (n = 6), parents of children with DMD (n = 6), clinicians (n = 3), members of research and advocacy organizations (n = 4), and an industry representative (n = 1). Community engagement informed attribute selection, survey length, word choice, and eligibility criteria. Challenges in the process included managing diverse stakeholder perspectives, time requirements, and the inherent tension between outcomes used in clinical trials versus attributes that correspond to patient- and family-relevant outcomes. We demonstrated how community engagement can successfully influence study design to support the design of a relevant survey instrument that is ethical, acceptable, meaningful to the community, and enhances patient-centered benefit-risk assessment for regulatory decision making.


Molecular dynamics simulations of the formation of 1D spin-valves from stretched Au-Co and Pt-Co nanowires.
We have performed molecular dynamics (MD) simulations of stretched Aux-Co1 - x and Ptx-Co1 - x nanowires to investigate the formation of bimetallic monoatomic wires between two electrodes. We have considered nanowires with two concentrations x = 0.2 and 0.8, aspect ratio of 13, a cross section of 1 nm(2) and a wide range of temperatures (from 10 to 400 K). For the MD simulations we have used a semi-empirical interatomic potential based on the second moment approximation (SMA) of the density of states to the tight-binding Hamiltonian.For Au-Co alloys, Au atoms tends to migrate towards the narrowed region to form almost pure Au wires. In the PtCo case the formed chains usually consist of Pt enriched alternating structures. The most striking result is probably the Au(0.2)-Co(0.8) alloy where pure monoatomic Au chains form between two Co electrodes constituting a potential 1D spin valve. Despite the known ease with which the 5d metals (Pt, Ir, and Au) form monoatomic chains (MACS), our results show that in the presence of Co (x = 0.2), the percentage of chain formation is higher than in the Pt and Au rich cases (x = 0.8).


Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors.
NaV1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of NaV1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a NaV1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including NaV1.7 potency, selectivity over NaV1.5, aqueous solubility, and microsomal stability.


CRISPR/Cas9-based generation of knockdown mice by intronic insertion of artificial microRNA using longer single-stranded DNA.
Knockdown mouse models, where gene dosages can be modulated, provide valuable insights into gene function. Typically, such models are generated by embryonic stem (ES) cell-based targeted insertion, or pronuclear injection, of the knockdown expression cassette. However, these methods are associated with laborious and time-consuming steps, such as the generation of large constructs with elements needed for expression of a functional RNAi-cassette, ES-cell handling, or screening for mice with the desired knockdown effect. Here, we demonstrate that reliable knockdown models can be generated by targeted insertion of artificial microRNA (amiRNA) sequences into a specific locus in the genome [such as intronic regions of endogenous eukaryotic translation elongation factor 2 (eEF-2) gene] using the Clustered Regularly Interspaced Short Palindromic Repeats/Crispr associated 9 (CRISPR/Cas9) system. We used in vitro synthesized single-stranded DNAs (about 0.5-kb long) that code for amiRNA sequences as repair templates in CRISPR/Cas9 mutagenesis. Using this approach we demonstrate that amiRNA cassettes against exogenous (eGFP) or endogenous [orthodenticle homeobox 2 (Otx2)] genes can be efficiently targeted to a predetermined locus in the genome and result in knockdown of gene expression. We also provide a strategy to establish conditional knockdown models with this method.


Care satisfaction, hope, and life functioning among adults with bipolar disorder: data from the first 1000 participants in the Systematic Treatment Enhancement Program.
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is designed to evaluate the longitudinal outcome of patients with bipolar disorder. The STEP-BD disease-management model is built on evidence-based practices and a collaborative care approach designed to maximize specific and nonspecific treatment mechanisms. This prospective study examined the longitudinal relationships between patients' satisfaction with care, levels of hope, and life functioning in the first 1000 patients to enter STEP-BD. The study used scores from the Care Satisfaction Questionnaire, Beck Hopelessness Scale, Range of Impaired Functioning Tool, Young Mania Rating Scale, and Montgomery-Asberg Depression Rating Scale at 5 time points during a 1-year interval. Analyses tested mediational pathways between care satisfaction, hope, and life functioning, depression, and mania using mixed-effects (random and fixed) regression models. Increases in care satisfaction were associated with decreased hopelessness (P < .01) but not related to symptoms of depression or mania. Similarly, decreased hopelessness was associated with better life functioning (P < .01) but not related to symptoms of depression or mania. Depression was independently associated with poorer life functioning (P < .0001). This study provided support for the hypothesized mediational pathway between care satisfaction, hopelessness, and life functioning. Findings suggest that providing care that maximizes patient hope may be important. By so doing, patients might overcome the learned helplessness/hopelessness that often accompanies a cyclical illness and build a realistic illness-management strategy.