Emerging drugs for pulmonary hypertension.
Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by structural narrowing of the small pulmonary arteries that often culminates in fatal right heart failure. PubMed was searched for PAH and treatment. Data from scientific meetings and pharmaceutical websites are also included. There are currently eight FDA approved drugs for PAH that fall into one of three classes: prostacyclins, endothelin-receptor antagonists and PDE-5 inhibitors. All have important limitations and morbidity and mortality remain high. Several new agents with similar mechanisms of action are in clinical development. Multiple novel therapeutic targets are being explored. New applications for PAH therapies, such as pulmonary hypertension due to left heart and lung disease, are also being investigated. An understanding of currently available drugs and those in clinical development for pulmonary hypertension. Drugs targeting the pulmonary vasculature have been an extremely active area of basic and clinical research for the past 20 years and will continue to be so for the foreseeable future. Considerable progress has been made, and yet there continues to be a great unmet medical need for developing more efficacious therapies.


[Network of international scientific collaboration on smoking: analysis of coauthorship through the Science Citation Index (1999-2003)].
The aim of this study was to analyze patterns of scientific collaboration and the visibility generated by coauthorship of articles on smoking among different countries on a world-wide basis through the Science Citation Index-Expanded (SCI-expanded) from 1999 to 2003. We selected articles on smoking resulting from collaboration among different countries in the SCI-Expanded (1999-2003). The underlying networks of collaboration among countries were analyzed by comparing production (number of articles published), visibility (number of citations received) and centrality (node degree, intermediation and proximity). A total of 3,484 articles were obtained, in which 5,008 institutions from 79 countries participated. The most productive country was the United Kingdom, with Germany and France in the second and third places. The United Kingdom also published the largest number of articles with inter-institutional collaboration (570 articles), with the USA and Germany in second and third places. The USA published the largest number of articles with international collaboration with the United Kingdom and France in the second and third places. All countries received a greater number of citations for articles resulting from international and inter-institutional collaboration than for those performed without collaboration. Networks of collaboration were completely connected through a single component and the annual increase in size of these inter-country networks was due to new countries joining the periphery of the network. We found a positive correlation between international and inter-institutional collaboration and the number of citations received by articles on smoking research. The number of citations per year remained constant throughout the 5-year study period.


Unsupervised learning of sequence-specific aggregation behavior for a model copolymer.
We apply a recently developed unsupervised machine learning scheme for local environments [Reinhart, Comput. Mater. Sci., 2021, 196, 110511] to characterize large-scale, disordered aggregates formed by sequence-defined macromolecules. This method provides new insight into the structure of these disordered, dilute aggregates, which has proven difficult to understand using collective variables manually derived from expert knowledge [Statt et al., J. Chem. Phys., 2020, 152, 075101]. In contrast to such conventional order parameters, we are able to classify the global aggregate structure directly using descriptions of the local environments. The resulting characterization provides a deeper understanding of the range of possible self-assembled structures and their relationships to each other. We also provide detailed analysis of the effects of finite system size, stochasticity, and kinetics of these aggregates based on the learned collective variables. Interestingly, we find that the spatiotemporal evolution of systems in the learned latent space is smooth and continuous, despite being derived from only a single snapshot from each of about 1000 monomer sequences. These results demonstrate the insight which can be gained by applying unsupervised machine learning to soft matter systems, especially when suitable order parameters are not known.


Integrative visual analysis of the effects of alternative splicing on protein domain interaction networks.
Proteins and their interactions are essential for the functioning of all organisms and for understanding biological processes. Alternative splicing is an important molecular mechanism for increasing the protein diversity in eukaryotic cells. Splicing events that alter the protein structure and the domain composition can be responsible for the regulation of protein interactions and the functional diversity of different tissues. Discovering the occurrence of splicing events and studying protein isoforms have become feasible using Affymetrix Exon Arrays. Therefore, we have developed the versatile Cytoscape plugin DomainGraph that allows for the visual analysis of protein domain interaction networks and their integration with exon expression data. Protein domains affected by alternative splicing are highlighted and splicing patterns can be compared.


New thinking on how to link executive pay with performance.
As the stock market began its ascent in the mid-1990s, executive pay--always the subject of heated debate--mounted along with it. That's because among the largest U.S. companies, stock options now account for more than half of total CEO compensation and about 30% of senior operating managers' pay. One problem became particularly clear during the bull market's astonishing run: even below-average performers reap huge gains from stock options when the market is rising rapidly. The author proposes steps to close the gap between existing compensation practices and those needed to promote higher levels of achievement at all levels of the corporation. For top managers, he recommends replacing conventional stock options with options that are tied to a market or peer index. Below-average performers would not be rewarded under such plans; superior performers could, depending on the way plans were structured, receive even more. He notes that managers at the business unit level should not be judged on the company's stock price--over which they have little control--and advocates an approach that accurately measures the value added by each unit. Finally, he suggests how certain indicators of value can be used to measure the contribution of frontline managers and employees. The concept of pay for performance has gained wide acceptance, but the link between incentive pay and superior performance is still too weak. Reforms must be adopted at all levels of the organization. Shareholders will applaud changes in pay schemes that motivate companies to deliver more value.


Indirect sandwich enzyme-linked immunosorbent assay for rapid detection of Haemophilus influenzae type b infection.
We report the development and testing of an enzyme-linked immunosorbent assay with excellent sensitivity for the detection of Haemophilus influenzae type b (HI(b)) antigen in clinical specimens from patients with HI(b) meningitis. The assay, an indirect sandwich technique, uses polystyrene balls as a solid phase and an alkaline phosphatase-labeled goat anti-rabbit globulin conjugate. Specimens are incubated with polystyrene balls armed with burro anti-HI(b) antiserum, and recognition antibody is visualized by addition of alkaline phosphatase-labeled anti-globulin, together with the enzyme substrate p-nitrophenyl phosphate. Concentrations of antigen are determined from standard curves prepared by using purified HI(b) capsular antigen polyribophosphate. The assay reproducibly detects polyribophosphate at concentrations between 1 and 5 ng/ml. Cross-reactions have not as yet been encountered in simulated and authentic clinical specimens containing other species including Escherichia coli, Klebsiella pneumoniae, group B Streptococcus, Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis, and Listeria monocytogenes. In preliminary tests with 11 spinal fluid specimens, 2 serum specimens, and 5 urine specimens from patients with culture-proved HI(b) meningitis, antigen was detected in all specimens in concentrations ranging from 1 to 7,000 ng/ml. Antigen was not detected in any of 62 clinical specimens which were culture negative for HI(b), including 11 spinal fluid specimens from patients with bacterial meningitis caused by microorganisms other than HI(b). The enzyme-linked immunosorbent assay technique described here is considerably simpler than radioimmunoassay and, based on concurrent tests with 14 positive clinical specimens, may be more sensitive than counterimmunoelectrophoresis. It seems, therefore, to hold considerable promise for clinical use in rapid detection of systemic HI(b) infections.


When shape matters: strategies of different Antarctic ascidians morphotypes to deal with sedimentation.
Climate change leads to increased melting of tidewater glaciers in the Western Antarctic Peninsula region and sediment bearing glacial melt waters negatively affects filter feeding species as solitary ascidians. In previous work the erect-forms Molgula pedunculata and Cnemidocarpa verrucosa (Order Stolidobranchiata) appeared more sensitive than the flat form Ascidia challengeri (Order Phlebobranchiata). Sedimentation exposure is expected to induce up-regulation of anaerobic metabolism by obstructing the organs of gas exchange (environmental hypoxia) or causes enhanced squirting activity (functional hypoxia). In this study we evaluated the possible relationship between ascidian morphotype and their physiological response to sedimentation. Together with some behavioural observations, we analysed the response of anaerobic metabolic parameters (lactate formation and glycogen consumption) in different tissues of three Antarctic ascidians, exposed to high sediment concentrations (200 mgL(-1)). The results were compared to experimental hypoxia (10% pO2) and exercise (induced muscular contraction) effects, in order to discriminate the effect of sediment on each species and morpho-type (erect vs. flat forms). Our results suggest that the styled (erect) C. verrucosa increases muscular squirting activity in order to expulse excessive material, while the flat-form A. challengeri reacts more passively by down-regulating its aerobic metabolism under sediment exposure. Contrary, the erect ascidian M. pedunculata did not show any measurable response to the treatments, indicating that filtration and ingestion activities were not reduced or altered even under high sedimentation (low energetic material) which could be disadvantageous on the long-term and could explain why M. pedunculata densities decline in the study area.


Role of aminoglutethimide in male breast cancer.
Five men with advanced breast cancer were treated with aminoglutethimide (AG) plus replacement dose hydrocortisone. None of the 4 patients with intact testes responded, although 3 did so subsequently to tamoxifen. The previously orchidectomized patient responded to aminoglutethimide for 14 months. Oestrone and oestradiol were suppressed by AG in all patients, but not to the levels achieved by orchidectomy. AG produced substantial further oestrogen suppression in the orchidectomized patient and should only be used after orchidectomy.


The detection of fear-relevant stimuli: are guns noticed as quickly as snakes?
Potentially dangerous stimuli are important contenders for the capture of visual-spatial attention, and it has been suggested that an evolved fear module is preferentially activated by stimuli that are fear relevant in a phylogenetic sense (e.g., snakes, spiders, angry faces). In this study, a visual search task was used to test this hypothesis by directly contrasting phylogenetically (snakes) and ontogenetically (guns) fear-relevant stimuli. Results showed that the modern threat was detected as efficiently as the more ancient threat. Thus, both guns and snakes attracted attention more effectively than neutral stimuli (flowers, mushrooms, and toasters). These results support a threat superiority effect but not one that is preferentially accessed by threat-related stimuli of phylogenetic origin. The results are consistent with the view that faster detection of threat in visual search tasks may be more accurately characterized as relevance superiority effects rather than as threat superiority effects.


Human, mouse, and dog bone marrow show similar mesenchymal stromal cells within a distinctive microenvironment.
Bone marrow stromal cells (BMSCs) are a key part of the hematopoietic niche. Mouse and human BMSCs are recognized by different markers (LepR and NGFR/CD271, respectively). However, there has not been a detailed in situ comparison of both populations within the hematopoietic microenvironment. Moreover, dog BMSCs have not been characterized in situ by any of those markers. We conducted a systematic histopathological comparison of mouse, human, and dog BMSCs within their bone marrow architecture and microenvironment. Human and dog CD271+ BMSCs had a morphology, frequency, and distribution within trabecular bone marrow similar to those of mouse LepR+ BMSCs. However, mouse bone marrow had higher cellularity and megakaryocyte content. In conclusion, highly comparable bone marrow mesenchymal stromal cell distribution among the three species establishes the validity of using mouse and dog as a surrogate experimental model of hematopoietic stem cell-BMSC interactions. However, the distinct differences in adipocyte and megakaryocyte microenvironment content of mouse bone marrow and how they might influence hematopoietic stem cell interactions as compared with humans require further study.


Health disparities: Understanding and promoting healthy communities.
This themed issue focuses on understanding and addressing several public health issues affecting communities today nationally and internationally. Health disparities, and global health in general, cover a large breadth of health concerns impossible to address in one issue. Here we provide a scope of some health disparities while focusing on health promotion and well-being of diverse populations, specifically within urban undeserved populations, rural communities in Peru, Roma minorities in Spain, and refugee communities. We focus on understanding contextual issue that affect health disparities as well as on examining the effectiveness of community-based interventions and community coalitions designed to address disparities.


Impact of increased authenticity in instructional format on preclerkship students' performance: a two-year, prospective, randomized study.
To address whether increasingly authentic instructional formats are more effective in improving preclerkship medical students' performance. From 2007 to 2009, the authors conducted a prospective, randomized, crossover study with second-year medical students in a clinical reasoning course at the Uniformed Services University of the Health Sciences. The authors randomly assigned students to one of three cohorts and used instructional formats of differing authenticity (paper, DVD, standardized patient) to teach three subject areas (abdominal pain, anemia, polyuria). Each cohort received one instructional format for each subject area. The authors collected outcome measures (objective structured clinical exam, video quiz, and essay exam scores) at the end of each academic year. They stratified the students into tertiles by first-year grade point average to investigate the impact of instructional formats on learners of different abilities. Outcomes for students in the top tertile improved with increased authenticity of the instructional format compared with outcomes for students in the middle and bottom tertiles (0.188 versus -0.038 and -0.201, P=.001 and .027, respectively). However, outcomes for students in the bottom tertile decreased when students were given only the paper case, compared with the middle and top tertiles (-0.374 versus 0.043 and 0.023, respectively, P=.001), but subsequently improved with more authentic instructional formats. The authors could not demonstrate that increased authenticity of the instructional format resulted in improved learner performance. However, they believe that there may be some benefit to tailoring preclerkship clinical education based on students' ability.


The effects of 5-fluorouracil on the proteome of colon cancer cells.
The pyrimidine analogue 5-fluorouracil (5FU) is used as a treatment for solid tumors, but its mechanism of action is not fully understood. We have used mass spectrometry to study the mechanism of action of 5FU, and we have measured the effects of this drug on the composition and on the turnover of the proteome of RKO cancer cells. We have identified novel potential targets of 5FU that are affected after very short exposure times. We have also shown that 5FU has a massive effect on the proteins involved in RNA metabolism. After only 1 h of treatment, 5FU causes a post-transcriptional reduction in the abundance of components of the translation machinery (mostly ribosomal proteins), and this reduction is accompanied by a down-regulation of the translational capacity of the cells. Neither rapamycin nor raltitrexed, two drugs that also block cell proliferation, reduce the abundances of ribosomal proteins as 5FU does, which suggests that the down-regulation of ribosomal proteins is coupled to the mechanism of action of 5FU. Some of our observations conflict with previous reports based on RNA quantification. This shows how important it is to complement RNA profiling studies with analyses of drug toxicity at the protein level.


Microfluidic CD4+ and CD8+ T lymphocyte counters for point-of-care HIV diagnostics using whole blood.
Roughly 33 million people worldwide are infected with HIV; disease burden is highest in resource-limited settings. One important diagnostic in HIV disease management is the absolute count of lymphocytes expressing the CD4(+) and CD8(+) receptors. The current diagnostic instruments and procedures require expensive equipment and trained technicians. In response, we have developed microfluidic biochips that count CD4(+) and CD8(+) lymphocytes in whole blood samples, without the need for off-chip sample preparation. The device is based on differential electrical counting and relies on five on-chip modules that, in sequence, chemically lyses erythrocytes, quenches lysis to preserve leukocytes, enumerates cells electrically, depletes the target cells (CD4 or CD8) with antibodies, and enumerates the remaining cells electrically. We demonstrate application of this chip using blood from healthy and HIV-infected subjects. Erythrocyte lysis and quenching durations were optimized to create pure leukocyte populations in less than 1 min. Target cell depletion was accomplished through shear stress-based immunocapture, using antibody-coated microposts to increase the contact surface area and enhance depletion efficiency. With the differential electrical counting method, device-based CD4(+) and CD8(+) T cell counts closely matched control counts obtained from flow cytometry, over a dynamic range of 40 to 1000 cells/μl. By providing accurate cell counts in less than 20 min, from samples obtained from one drop of whole blood, this approach has the potential to be realized as a handheld, battery-powered instrument that would deliver simple HIV diagnostics to patients anywhere in the world, regardless of geography or socioeconomic status.


Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: Results from the HCV-TARGET study.
Data outside of clinical trials with direct-acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct-acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. In a large prospective observational cohort study, direct-acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090-1101).


Change in uptake, transport and accumulation of ions in Nerium oleander (rosebay) as affected by different nitrogen sources and salinity.
The source of nitrogen plays an important role in salt tolerance of plants. In this study, the effects of NaCl on net uptake, accumulation and transport of ions were investigated in Nerium oleander with ammonium or nitrate as the nitrogen source in order to analyse differences in uptake and cycling of ions within plants. Plants were grown in a greenhouse in hydroponics under different salt treatments (control vs. 100 mm NaCl) with ammonium or nitrate as the nitrogen source, and changes in ion concentration in plants, xylem sap exuded from roots and stems, and phloem sap were determined. Plant weight, leaf area and photosynthetic rate showed a higher salt tolerance of nitrate-fed plants compared with that of ammonium-fed plants. The total amount of Na+ transported in the xylem in roots, accumulated in the shoot and retranslocated in the phloem of ammonium-fed plants under salt treatment was 1.8, 1.9 and 2.7 times more, respectively, than that of nitrate-treated plants. However, the amount of Na+ accumulated in roots in nitrate-fed plants was about 1.5 times higher than that in ammonium-fed plants. Similarly, Cl- transport via the xylem to the shoot and its retranslocation via the phloem (Cl- cycling) were far greater with ammonium treatment than with nitrate treatment under conditions of salinity. The uptake and accumulation of K+ in shoots decreased more due to salinity in ammonium-fed plants compared with nitrate-fed plants. In contrast, K+ cycling in shoots increased due to salinity, with higher rates in the ammonium-treated plants. The faster growth of nitrate-fed plants under conditions of salinity was associated with a lower transport and accumulation of Na+ and Cl- in the shoot, whereas in ammonium-fed plants accumulation and cycling of Na+ and Cl- in shoots probably caused harmful effects and reduced growth of plants.


Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug.
Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.


Electropharmacogram of Sceletium tortuosum extract based on spectral local field power in conscious freely moving rats.
The endemic succulent South African plant, Sceletium tortuosum (L.) N.E. Br. (synonym Mesembryanthemum tortuosum L.), of the family Mesembryathemaceae, has an ancient oral tradition history of use by San and Khoikhoi people as an integral part of the indigenous culture and materia medica. A special standardized extract of Sceletium tortuosum (Zembrin®) has been developed and tested pre-clinically in rats, and clinically in healthy subjects. The present investigation aimed at the construction of electropharmacograms of Zembrin® in the presence of three dosages (2.5, 5.0 and 10.0 mg/kg), and comparative electropharmacograms and discriminatory analyses for other herbal extracts, citicoline and rolipram. Seventeen adult Fischer rats were each implanted with a set consisting of four bipolar concentric steel electrodes fixed by dental cement and three screws driven into the scalp. After two weeks of recovery from surgery the animals were adapted to oral administration by gavage and to experimental conditions (45 min pre-drug period and 5h of recording after a rest of 5 min for calming down). Data were transmitted wirelessly and processed using a Fast Fourier Transformation (FFT). Spectral power was evaluated for 8 frequency ranges, namely delta, theta, alpha1, alpha2, beta1a, beta1b, beta2 and gamma power. Zembrin® dose dependently attenuated all frequency ranges, to varying degrees. The most prominent was the statistically significant reduction in alpha2 and beta1a waves, correlated with activation of the dopaminergic and glutamatergic transmitter systems respectively. This feature is common to all synthetic and herbal stimulants tested to date. The second strongest effects were reduction in both the delta and the theta frequency ranges, correlated with changes in the cholinergic and norepinephrine systems respectively, a pattern seen in preparations prescribed for neurodegenerative diseases. Theta wave reduction in common with the delta, alpha2 and beta1 attenuation has been noted for analgesic drugs. Attenuation of alpha1 waves emerged during the highest dosage in all brain areas, a feature seen in all antidepressants. The electropharmacogram of Zembrin® was compared to the electropharmacograms of herbal extracts archived in our database. Extracts of Oenothera biennis and Cimicifuga racemosa gave a very similar electropharmacograms to that of Zembrin®, and extracts of Ginkgo biloba and Rhodiola rosea gave rather similar electropharmacograms to Zembrin®. Linear discriminant analysis confirmed these similarities and demonstrated that all three dosages of Zembrin® plotted in close neighbourhood to each other. Citocoline, a synthetic compound originally developed for cognitive enhancement, had a similar electropharmacogram to Zembrin®. Similarity to the electropharmacograms of the synthetic phosphodiesterase-4 inhibitor, rolipram, suggests Zembrin® has antidepressant and cognitive function enhancing potential. The combined results from the electropharmacograms and comparative discriminatory analyses suggest that Zembrin® has dose dependent activity, with potential applications as a cognitive function enhancer, as an antidepressant, and as an analgesic.


Fluoro-silsesquioxane-urethane hybrid for thin film applications.
New fluoropolyurethane hybrids containing fluorinated polyhedral oligomeric silsesquioxane were synthesized for thin film applications using fluoro(13) disilanol isobutyl-POSS (FluoroPOSS) and a short chain fluorodiol and diisocyanate. The kinetics of the urethane reaction was monitored using Fourier transform infrared spectroscopy (FTIR) and the formation of urethane was confirmed using (29)Si Nuclear magnetic resonance spectroscopy (NMR). The effect of addition of FluoroPOSS either in the I step or II step of the two step polymerization reaction is evaluated using various spectroscopic, thermal, microscopic, and diffraction techniques. In general, the major shortcoming of the lack of flexibility of fluoropolyurethane from short chain diol and diisocyanate has been overcome by the use of tethered FluoroPOSS. X-ray photoelectron spectroscopy (XPS), atomic force microscpopy (AFM), and contact angle measurements on the hybrid thin films on silicon wafer demonstrate the migration of FluoroPOSS segment to the air-thin film interface when FluoroPOSS is used in I stage reaction, and it resides at the interface when used as a chain extender. However, in both cases, the formed thin film exhibits ultrahydrophobicity with water contact angle of approximately 107 degrees and low contact angle hysteresis and solvent resistance, which are preferable for protective thin film applications.


The long noncoding RNA KTN1-AS1 promotes bladder cancer tumorigenesis via KTN1 cis-activation and the consequent initiation of Rho GTPase-mediated signaling.
Accumulating evidence support the hypothesis that long noncoding RNAs (lncRNAs) are involved in several physiological and pathological conditions, including cancer. Here, we investigated the potential role of lncRNAs in bladder cancer. We first looked at available datasets retrieved from the TCGA database and discovered that the lncRNA KTN 1 antisense RNA 1 (KTN1-AS1) was significantly up-regulated in several cancer types including bladder cancer, but was decreased in some other tumors. Therefore, we focused our attention on KTN1-AS1. Using both in vitro and in vivo systems that allowed the modulation of KTN1-AS1 and expression of other relevant proteins, we investigated in-depth the role of KTN1-AS1 in bladder cancer (and the mechanism behind). We further investigated the potential KTN1-AS1-interacting proteins using RNA immunoprecipitation, and explored the KTN1-AS1-related epigenetic landscape (with a particular emphasis on acetylation) using chromatin immunoprecipitation (ChIP) assays. KTN1-AS1 silencing inhibited the proliferation, invasion, and migration of bladder cancer cells, while KTN1-AS1 overexpression had the obvious opposite effects. Mechanistically, KTN1-AS1 promoted the recruitment of EP300, a histone acetyltransferase that enriched acetylation of histone H3 at lysine 27 (H3K27Ac) in the KTN1 promoter region. This epigenetic modulation contributed to the up-regulation of KTN1, which affected bladder cancer growth and progression via the regulation of Rho GTPase (RAC1, RHOA, and CDC42)-mediated signaling. Overall, our data support the idea that the lncRNA KTN1-AS1 promotes bladder cancer tumorigenesis via modulation of the KTN1/Rho GTPase axis and is a promising new therapeutic target for the treatment of bladder cancer.


Do burnout and work engagement predict depressive symptoms and life satisfaction? A three-wave seven-year prospective study.
Burnout and work engagement have been viewed as opposite, yet distinct states of employee well-being. We investigated whether work-related indicators of well-being (i.e. burnout and work engagement) spill-over and generalize to context-free well-being (i.e. depressive symptoms and life satisfaction). More specifically, we examined the causal direction: does burnout/work engagement lead to depressive symptoms/life satisfaction, or the other way around? Three surveys were conducted. In 2003, 71% of all Finnish dentists were surveyed (n=3255), and the response rate of the 3-year follow-up was 84% (n=2555). The second follow-up was conducted four years later with a response rate of 86% (n=1964). Structural equation modeling was used to investigate the cross-lagged associations between the study variables across time. Burnout predicted depressive symptoms and life dissatisfaction from T1 to T2 and from T2 to T3. Conversely, work engagement had a negative effect on depressive symptoms and a positive effect on life satisfaction, both from T1 to T2 and from T2 to T3, even after adjusting for the impact of burnout at every occasion. The study was conducted among one occupational group, which limits its generalizability. Work-related well-being predicts general wellbeing in the long-term. For example, burnout predicts depressive symptoms and not vice versa. In addition, burnout and work engagement are not direct opposites. Instead, both have unique, incremental impacts on life satisfaction and depressive symptoms.


Analysis of the Phlebiopsis gigantea genome, transcriptome and secretome provides insight into its pioneer colonization strategies of wood.
Collectively classified as white-rot fungi, certain basidiomycetes efficiently degrade the major structural polymers of wood cell walls. A small subset of these Agaricomycetes, exemplified by Phlebiopsis gigantea, is capable of colonizing freshly exposed conifer sapwood despite its high content of extractives, which retards the establishment of other fungal species. The mechanism(s) by which P. gigantea tolerates and metabolizes resinous compounds have not been explored. Here, we report the annotated P. gigantea genome and compare profiles of its transcriptome and secretome when cultured on fresh-cut versus solvent-extracted loblolly pine wood. The P. gigantea genome contains a conventional repertoire of hydrolase genes involved in cellulose/hemicellulose degradation, whose patterns of expression were relatively unperturbed by the absence of extractives. The expression of genes typically ascribed to lignin degradation was also largely unaffected. In contrast, genes likely involved in the transformation and detoxification of wood extractives were highly induced in its presence. Their products included an ABC transporter, lipases, cytochrome P450s, glutathione S-transferase and aldehyde dehydrogenase. Other regulated genes of unknown function and several constitutively expressed genes are also likely involved in P. gigantea's extractives metabolism. These results contribute to our fundamental understanding of pioneer colonization of conifer wood and provide insight into the diverse chemistries employed by fungi in carbon cycling processes.


Effects of Exposure to Methyl Parathion on Egg Hatchability and Eggshell Chemical Composition in Podocnemis expansa (Testudines, Podocnemididae).
Eggshell evaluation may serve as an indicator of the effect of substances released in the environment, which may change eggshell shape, size, structure, and/or chemical composition. Additionally, exposure may interfere with hatching rates in contaminated eggs. The objective of this study was to better understand how exposure to the insecticide methyl parathion interferes with chemical changes in eggshells of Podocnemis expansa throughout their artificial incubation, as well as with egg hatchability. A total of 343 P. expansa eggs were collected in a natural reproduction area for the species. These eggs were transferred to and artificially incubated in the Wild Animal Teaching and Research Laboratory at Universidade Federal de Uberlândia. On the first day of artificial incubation, 0, 35, 350, and 3500 ppb of methyl parathion were incorporated to the substrate. Eggs were collected every three days for chemical analysis of eggshells. Hatchability was evaluated as the number of hatchlings in each treatment, for the eggs that were not used in the chemical analysis. Student's T-test was used for data on eggshell chemical composition, and the Binomial Test for Two Proportions was used in the hatchability analysis, at a 5% significance level. It was observed that the incorporation of methyl parathion to the substrate on the first day of artificial incubation of P. expansa eggs reduced the levels of total fat in the shells throughout their incubation, besides reducing egg hatchability.


Diversity within the genus Elymus (Poaceae: Triticeae) II: analyses of variation within 5S nrDNA restrict membership in the genus to species with StH genomes.
The genus Elymus is a repository for a large number of species that have been difficult to classify by traditional techniques due to their remarkable levels of polymorphism. Following the genome analyses of Yen and Yang (Genus Elymus 5:58-362, 2013), we used sequences of the nr5SDNA to investigate diversity within those 24 species having St and H haplomes (Baum et al. Mol Genet Genomics 290:329-42, 2015) and for which the genome status was known. The present work extends this analysis to include eight species for which there was no information on genomic status. Our results show that these eight have nr5SDNA sequences that can be assigned to unit classes of orthologous sequences found in St and H haplomes, suggesting that the presence of St and H haplomes is characteristic of the genus. We then carried out a set of canonical discriminant analyses based on 247 DNA new sequences from these 8 species plus the 1054 sequences previously identified from 24 Elymus species. Sequences were analyzed to answer the following questions: Do the species integrate or are they different? Are the tetraploids different from the higher-ploid species? Are the species united within sections, or the same within regions? How do the species fare when divided according to sections? The main results of the canonical discriminant analyses are that the species are united within the tetraploids and within the hexaploids, within each region and within each section. In addition, a series of classificatory discriminant analyses showed that the identification tests are different, although not sufficiently useful for the discrimination of all the species. We also demonstrate the power of our approach by showing that the voucher for Elymus mobilis is not Elymus at all, but Leymus.


Modeling the adaptive potential of isolated populations: experimental simulations using Drosophila.
The genetic variability underlying many morphological and stress resistance traits may largely depend on the effects of genetic drift balanced by polygenic mutation. This model of adaptive potential has played a central role in the minimum viable population size concept and has been used to predict the effective population size necessary to prevent extinction within changing environments. However, there have been few long-term experimental studies of adaptive potential within isolated populations, and no study has thus far provided an experimental test of the drift-mutation model of quantitative genetic variation. Using the sternopleural bristle number of Drosophila melanogaster as a model quantitative trait, we performed repeated measurements of adaptive potential on 15 replicate populations of two and 10 male-female pairs over 30 and 77 generations, respectively. Declines in adaptive potential were analyzed by comparing observed and expected changes in realized heritability over time. The only significant model deviation occurred immediately after bottlenecks of two pairs, in which greater than expected declines in realized heritability were observed. This result suggests that changes in allelic diversity during bottleneck events may be as important as changes in heterozygosity in determining adaptive potential. Drift-mutation model expectations were otherwise realized over all generations. Our results validate the use of the drift-mutation model as a tool for understanding the dynamics of adaptive potential for peripheral fitness characters, but suggest caution in applying this model to recently bottlenecked populations.


Ocular Surface Erosion after Suspected Exposure to Evaporated COVID-19 Vaccine.
The purpose is to report ocular surface erosion of health personnel who were exposed to evaporated CoronaVac during a vaccination campaign. A campaign for CoronaVac vaccination was conducted in a closed space of 11.04 × 5.96 m, partially divided into 6 rooms with interconnected area among the rooms. A total of 20 health personnel worked in the vaccination rooms. On the third day of campaign, a vial, containing a single dose of 0.5 mL, of the vaccine was dropped accidentally onto the floor and broken by an administering nurse. A total of 15 personnel had symptoms and signs of ocular surface erosion at the average time from the accident to the onset of 10.2 ± 7.1 h; 4 personnel also had skin rash. These personnel included all 13 persons who already worked in the rooms when the accident occurred and continued for additional 4-6 h and 2 personnel who presented in the rooms 1-2 h after the accident and stayed for 2-3 h. Proximity and timing suggest CoronaVac correlation with the ocular and skin reactions. Cautions should be taken to avoid broken vials, spills, and aerosolization of CoronaVac during the vaccination.


Fair regression for health care spending.
The distribution of health care payments to insurance plans has substantial consequences for social policy. Risk adjustment formulas predict spending in health insurance markets in order to provide fair benefits and health care coverage for all enrollees, regardless of their health status. Unfortunately, current risk adjustment formulas are known to underpredict spending for specific groups of enrollees leading to undercompensated payments to health insurers. This incentivizes insurers to design their plans such that individuals in undercompensated groups will be less likely to enroll, impacting access to health care for these groups. To improve risk adjustment formulas for undercompensated groups, we expand on concepts from the statistics, computer science, and health economics literature to develop new fair regression methods for continuous outcomes by building fairness considerations directly into the objective function. We additionally propose a novel measure of fairness while asserting that a suite of metrics is necessary in order to evaluate risk adjustment formulas more fully. Our data application using the IBM MarketScan Research Databases and simulation studies demonstrates that these new fair regression methods may lead to massive improvements in group fairness (eg, 98%) with only small reductions in overall fit (eg, 4%).


Large-Scale Analysis of Auditory Segregation Behavior Crowdsourced via a Smartphone App.
The human auditory system is adept at detecting sound sources of interest from a complex mixture of several other simultaneous sounds. The ability to selectively attend to the speech of one speaker whilst ignoring other speakers and background noise is of vital biological significance-the capacity to make sense of complex 'auditory scenes' is significantly impaired in aging populations as well as those with hearing loss. We investigated this problem by designing a synthetic signal, termed the 'stochastic figure-ground' stimulus that captures essential aspects of complex sounds in the natural environment. Previously, we showed that under controlled laboratory conditions, young listeners sampled from the university subject pool (n = 10) performed very well in detecting targets embedded in the stochastic figure-ground signal. Here, we presented a modified version of this cocktail party paradigm as a 'game' featured in a smartphone app (The Great Brain Experiment) and obtained data from a large population with diverse demographical patterns (n = 5148). Despite differences in paradigms and experimental settings, the observed target-detection performance by users of the app was robust and consistent with our previous results from the psychophysical study. Our results highlight the potential use of smartphone apps in capturing robust large-scale auditory behavioral data from normal healthy volunteers, which can also be extended to study auditory deficits in clinical populations with hearing impairments and central auditory disorders.


ADP-ribosylation in in vitro systems synthesizing adenovirus DNA.
Two systems utilizing extracts derived from nuclei of adenovirus-infected cells which synthesize adenovirus DNA in vitro were analysed for indications of ADP-ribosylation of virus proteins. On incubation with [32P]NAD or [14C]NAD, modification of the adenovirus T antigen could be demonstrated in one of these systems. ADP-ribosylation of adenovirus core proteins V and VII could also be demonstrated with both nuclear extracts. However, using 3-aminobenzamide, a specific inhibitor of poly(ADP-ribose) polymerase, there was no evidence either in vivo or in vitro that ADP-ribosylation played a critical role in the replication process.


A mesh generation and machine learning framework for Drosophila gene expression pattern image analysis.
Multicellular organisms consist of cells of many different types that are established during development. Each type of cell is characterized by the unique combination of expressed gene products as a result of spatiotemporal gene regulation. Currently, a fundamental challenge in regulatory biology is to elucidate the gene expression controls that generate the complex body plans during development. Recent advances in high-throughput biotechnologies have generated spatiotemporal expression patterns for thousands of genes in the model organism fruit fly Drosophila melanogaster. Existing qualitative methods enhanced by a quantitative analysis based on computational tools we present in this paper would provide promising ways for addressing key scientific questions. We develop a set of computational methods and open source tools for identifying co-expressed embryonic domains and the associated genes simultaneously. To map the expression patterns of many genes into the same coordinate space and account for the embryonic shape variations, we develop a mesh generation method to deform a meshed generic ellipse to each individual embryo. We then develop a co-clustering formulation to cluster the genes and the mesh elements, thereby identifying co-expressed embryonic domains and the associated genes simultaneously. Experimental results indicate that the gene and mesh co-clusters can be correlated to key developmental events during the stages of embryogenesis we study. The open source software tool has been made available at http://compbio.cs.odu.edu/fly/. Our mesh generation and machine learning methods and tools improve upon the flexibility, ease-of-use and accuracy of existing methods.


MRI in neurofibromatosis 1. The nature and evolution of increased intensity T2 weighted lesions and their relationship to intellectual impairment.
Thirty eight patients with neurofibromatosis 1 (NF1) had neurological examinations, intellectual assessments and MRI scans. Increased intensity lesions on T2 weighted images were found in 13 patients. These abnormalities were more common in patients aged under 18 years. The lesions occurred predominantly in the basal ganglia, brainstem and cerebellum, and were multiple in 11 patients. They did not produce symptoms or neurological deficit in any patient and did not enhance with gadolinium-meglumine-triamine-pentaacetic acid contrast medium (Gd-DTPA). In 2 patients, however, the abnormalities exerted mass effect distorting the brain and in 3 patients they occurred in conjunction with known gliomas. The lesions remained unchanged over a three year follow up period. The nature of the lesions is uncertain but the fact that they may produce mass effect and occur in association with gliomas suggests that they have malignant potential. There was no correlation between the presence of these abnormalities and intellectual impairment.


Prevalence and incidence of liver dysfunction and assessment of biomarkers of liver disease in HIV-infected Asian children.
We determined the prevalence and incidence of liver dysfunction before and after initiation of combination antiretroviral therapy (cART) in the TREAT Asia Pediatric HIV Observational Database. Data from children initiated on cART between 2 and 18 years of age with baseline alanine aminotransferase (ALT) available before and at least once after cART initiation in TREAT Asia Pediatric HIV Observational Database between 2008 and 2012 were analyzed. Prevalence and incidence of liver dysfunction and biomarkers including the aspartate aminotransferase to platelet ratio index and FIB4 index (a noninvasive panel to stage liver disease) were assessed. Data from 1930 children were included. Their median age was 6.9 years; 49% were male; 98% were perinatally infected and 94% were initiated on non-nucleoside reverse transcriptase-based cART regimens. Before cART, the prevalence of ALT ≥3 times the upper limit of normal (×ULN) was 5.8%. There were 8.5% of children with aspartate aminotransferase to platelet ratio index >1.5 (suggestive of liver fibrosis) and 2.7% with FIB4 index >1.3 (predictive of possible cirrhosis). Among the 1143 cases with normal baseline ALT (≤1×ULN), the incidence of ALT 3×ULN after cART was 1.19 of 1000 person-months (95% confidence interval: 0.93-1.51). Two of 350 with available tests (0.6%) met Hy's law (ALT >3×ULN and total bilirubin >2×ULN). By multivariate analysis, baseline hemoglobin <7.5 g/dL was a predictor of ALT >3×ULN, whereas age 5-9 years at cART initiation was protective for liver dysfunction. We demonstrated a low prevalence and incidence of liver dysfunction before and after cART initiation in children with normal baseline chemistries. In this population facing life-long cART, prospective surveillance for emergence of liver disease is warranted.


The effect of air thinning on dentin adhesive bond strength.
The purpose of this study was to determine if air thinning three dentin adhesives would affect bond strength to dentin. Ninety human molars were mounted in acrylic and the occlusal surfaces ground to expose a flat dentin surface. Thirty teeth were randomly assigned to one of the following dentin bonding agent/composite combinations: A) Universal Bond 3/TPH (Caulk), B) All-Bond 2/Bis-Fil-P (Bisco), and C) Scotchbond Multi-Purpose/Z-100 (3m). The primers were applied following the manufacturers' instructions. The adhesives were applied by two methods. A thin layer of adhesive was applied with a brush to 15 specimens in each group and light cured. Adhesive was brushed on to the remaining 15 teeth in the group, air thinned for 3 seconds, and then polymerized. The appropriate composite was applied in 2 mm increments and light cured utilizing a 5 mm-in-diameter split Teflon mold. Following 3 months of water storage, all groups were shear tested to failure on an Instron Universal Testing Machine. Bond strength was significantly higher in all groups when the dentin bonding agent was painted on without being air thinned. Scotchbond Multi-Purpose had significantly higher bond strength than All-Bond 2, which had significantly higher bond strength than Universal Bond 3.


Reverse chromatic aberration and its numerical optimization in a metamaterial lens.
In planar metamaterial lenses, the focal point moves with the frequency. Here it is shown numerically that this movement can be controlled by properly engineering the dimensions of the metamaterial-based phase shifters that constitute the lens. In particular, such lenses can be designed to exhibit unusual chromatic aberration with the focal length increasing, rather than decreasing, with the frequency. It is proposed that such an artificial "reverse" chromatic aberration may optimize the transverse resolution of millimeter wave diagnostics of plasmas and be useful in compensating for the natural "ordinary" chromatic aberration of other components in an optical system. More generally, optimized chromatic aberration will allow for simultaneous focusing of several objects located at different distances and emitting or reflecting at different frequencies.


Dissociation of centrosome replication events from cycles of DNA synthesis and mitotic division in hydroxyurea-arrested Chinese hamster ovary cells.
Relatively little is known about the mechanisms used by somatic cells to regulate the replication of the centrosome complex. Centrosome doubling was studied in CHO cells by electron microscopy and immunofluorescence microscopy using human autoimmune anticentrosome antiserum, and by Northern blotting using the cDNA encoding portion of the centrosome autoantigen pericentriolar material (PCM)-1. Centrosome doubling could be dissociated from cycles of DNA synthesis and mitotic division by arresting cells at the G1/S boundary of the cell cycle using either hydroxyurea or aphidicolin. Immunofluorescence micros-copy using SPJ human autoimmune anticentrosome antiserum demonstrated that arrested cells were able to undergo numerous rounds of centrosome replication in the absence of cycles of DNA synthesis and mitosis. Northern blot analysis demonstrated that the synthesis and degradation of the mRNA encoding PCM-1 occurred in a cell cycle-dependent fashion in CHO cells with peak levels of PCM-1 mRNA being present in G1 and S phase cells before mRNA amounts dropped to undetectable levels in G2 and M phases. Conversely, cells arrested at the G1/S boundary of the cell cycle maintained PCM-1 mRNA at artificially elevated levels, providing a possible molecular mechanism for explaining the multiple rounds of centrosome replication that occurred in CHO cells during prolonged hydroxyurea-induced arrest. The capacity to replicate centrosomes could be abolished in hydroxyurea-arrested CHO cells by culturing the cells in dialyzed serum. However, the ability to replicate centrosomes and to synthesize PCM-1 mRNA could be re-initiated by adding EGF to the dialyzed serum. This experimental system should be useful for investigating the positive and negative molecular mechanisms used by somatic cells to regulate the replication of centrosomes and for studying and the methods used by somatic cells for coordinating centrosome duplication with other cell cycle progression events.


A comparison of the pharmacokinetic and pharmacodynamic properties of quinine and quinidine in healthy Thai males.
1. Eight healthy Thai males, aged 19-27 years, received quinine or quinidine dihydrochloride 10 mg kg-1 body weight by intravenous infusion over 1 h. At least 1 week later, the alternative alkaloid was administered. 2. The terminal elimination half-time of quinidine was shorter than that of quinine (median [range]; 5.7 [5.0-10.0] vs 9.9 [8.8-15.1] h, P < 0.01), the volume of distribution at steady state (Vss) for quinidine was larger than that for quinine (3.5 [2.5-5.6] vs 3.1 [1.8-4.1] 1 kg-1; P = 0.02) and quinidine was less bound to plasma proteins (% free drug: 22.8 [15.4-47.2] vs 9.4 [7.3-15.0]%, P < 0.01). Total clearance was greater for quinidine (7.7 [3.9-11.4] vs 3.4 [1.8-4.6] ml min-1 kg-1, P < 0.01) but not for clearance of unbound drug (32.2 [14.6-50.4] vs 29.9 [20.2-50.9] ml min-1 kg-1 respectively, P > 0.2). 3. Side-effects, including transient hypotension after quinidine in two cases, were mild. 4. Both drugs produced prolongation of the rate-corrected QT interval (QTc), with similar rates of elimination from the cardiac conduction 'effect' compartment (keo; 4.14 [0.03-15.33] h-1 for quinine, 3.74 [1.63-13.14] h-1 for quinidine, P > 0.19). Using a linear concentration-response model, the intercept ('threshold') for quinidine effect was lower than that for quinine (P = 0.004) but the slopes (change in QTc for a given change in free drug concentration) were similar (P = 0.56).(ABSTRACT TRUNCATED AT 250 WORDS)


Bayesian priors are encoded independently from likelihoods in human multisensory perception.
It has been shown that human combination of crossmodal information is highly consistent with an optimal Bayesian model performing causal inference. These findings have shed light on the computational principles governing crossmodal integration/segregation. Intuitively, in a Bayesian framework priors represent a priori information about the environment, i.e., information available prior to encountering the given stimuli, and are thus not dependent on the current stimuli. While this interpretation is considered as a defining characteristic of Bayesian computation by many, the Bayes rule per se does not require that priors remain constant despite significant changes in the stimulus, and therefore, the demonstration of Bayes-optimality of a task does not imply the invariance of priors to varying likelihoods. This issue has not been addressed before, but here we empirically investigated the independence of the priors from the likelihoods by strongly manipulating the presumed likelihoods (by using two drastically different sets of stimuli) and examining whether the estimated priors change or remain the same. The results suggest that the estimated prior probabilities are indeed independent of the immediate input and hence, likelihood.


Dihydroorotate dehydrogenase Inhibitors Target c-Myc and Arrest Melanoma, Myeloma and Lymphoma cells at S-phase.
Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the de novo biosynthesis pathway of pyrimidines. Inhibition of this enzyme impedes cancer cell proliferation but the exact mechanisms of action of these inhibitors in cancer cells are poorly understood. In this study, we showed that cancer cells, namely melanoma, myeloma and lymphoma overexpressed DHODH protein and treatment with A771726 and Brequinar sodium resulted in cell cycle arrest at S-phase. Transfection with DHODH shRNA depleted DHODH protein expression and impeded the proliferation of melanoma cells. shRNA knockdown of DHODH in combination with DHODH inhibitors further reduced the cancer cell proliferation, suggesting that knockdown of DHODH had sensitized the cells to DHODH inhibitors. Cell cycle regulatory proteins, c-Myc and its transcriptional target, p21 were found down- and up-regulated, respectively, following treatment with DHODH inhibitors in melanoma, myeloma and lymphoma cells. Interestingly, knockdown of DHODH by shRNA had also similarly affected the expression of c-Myc and p21 proteins. Our findings suggest that DHODH inhibitors induce cell cycle arrest in cancer cells via additional DHODH-independent pathway that is associated with p21 up-regulation and c-Myc down-regulation. Hence, DHODH inhibitors can be explored as potential therapeutic agents in cancer therapy.


Terahertz Beam Steering Concept Based on a MEMS-Reconfigurable Reflection Grating.
With an increasing number of applications of terahertz systems in industrial fields and communications, terahertz beamforming and beam steering techniques are required for high-speed, large-area scanning. As a promising means for beam steering, micro-electro-mechanical system (MEMS)-based reflection gratings have been successfully implemented for terahertz beam control. So far, the diffraction grating efficiency is relatively low due to the limited vertical displacement range of the reflectors. In this paper, we propose a design for a reconfigurable MEMS-based reflection grating consisting of multiple subwavelength reflectors which are driven by 5-bit, high-throw electrostatic actuators. We vary the number of the reflectors per grating period and configure the throw of individual reflectors so that the reflection grating is shaped as a blazed grating to steer the terahertz beam with maximum diffraction grating efficiency. Furthermore, we provide a mathematical model for calculating the radiation pattern of the terahertz wave reflected by general reflection gratings consisting of subwavelength reflectors. The calculated and simulated radiation patterns of the designed grating show that we can steer the angle of the terahertz waves in a range of up to ± 56.4 ∘ with a maximum sidelobe level of -10 dB at frequencies from 0.3 THz to 1 THz.


Genotyping of SNPs associated with meat tenderness: comparison of two PCR-based methods.
Single nucleotide polymorphisms (SNPs) carried in calpain (CAPN1), calpastatin (CAST), and leptin (LEP) genes are associated with meat tenderness. Due to the economic importance of this meat quality attribute, the development of fast, reliable, and affordable methods to identify bovine carriers of favorable alleles is of great importance for genetic improvement. Currently, PCR-RFLP is accepted as the standard gold method for genotyping SNPs associated with meat tenderness. But these SNPs can be detected by other techniques as high-resolution melting (HRM) analysis - a post-PCR method - that offers several advantages and has great application potential in the meat industry. In this study, we standardized, validated, and compared the performance of PCR-HRM to that of PCR-RFLP in genotyping bovine SNPs associated with meat tenderness: CAPN4751, CAPN316, CAST2959, CAST282, LEPE2FB, and LEPE2JW. We analyzed genotypes of a total of 380 bovines, 110 Bos taurus and 270 Bos indicus. Results obtained with PCR-HRM were consistent with those found by PCR-RLFP. Furthermore, HRM was found to be highly sensitive, and our results confirmed the repeatability (intra-assay precision) and reproducibility (inter-assay precision) of this assay. An internal control for endonuclease activity was created using site-directed mutagenesis to generate an additional enzymatic restriction point useful to discriminate SNP alleles. Our results show that PCR-HRM is an efficient method that produces reliable and rapid results. However, should be had in account that the method of DNA extraction, the quality and quantity of DNA, analyst-related variations, and primer design may generate challenges for allele discrimination.


Measurements of the atmospheric carbon monoxide column with a ground-based length-modulated radiometer.
A ground-based remote sounding instrument that uses a length-modulated radiometer to measure the total atmospheric carbon monoxide (CO) column has been built. Measurements made in Toronto during August and September of 1994 showed average CO concentrations of 125 to 150 parts per billion in volume (ppbv, parts in 10(9)). Similar measurements made in October at a rural site 80 km north of Toronto showed concentrations of approximately 100 ppbv. The latter measurements are shown to agree with other simultaneous ground- and satellite-based measurements. This instrument is an advanced prototype of the MOPITT (Measurements of Pollution in the Troposphere) satellite instrument.


Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy.
To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells. Expansion of CD8(+) tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding T-cell receptors (TCR) was used to define HLA-restriction elements and specific reactivity. TIL were expanded from metastases in all patients, and new tumor cell lines were generated in 5 patients. Autologous tumor recognition without cross-reactivity against allogeneic HLA-matched gastrointestinal tumors was found in CD8(+) TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8(+) TIL was dominated by cytolytic sister clones reactive to 2 out of 4 autologous cancer cell lines restricted by HLA-C*0701. From the same patient, a rare CD8(+) TIL clone with a distinct TCR recognized all four cancer cell lines restricted by HLA-B*4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8(+) TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8(+) TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype. This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD8(+) TIL at the molecular level.


Research Translation and Emerging Health Technologies: Synthetic Biology and Beyond.
New health technologies are rapidly emerging from various areas of bioscience research, such as gene editing, regenerative medicine and synthetic biology. These technologies raise promising medical possibilities but also a range of ethical considerations. Apart from the issues involved in considering whether novel health technologies can or should become part of mainstream medical treatment once established, the process of research translation to develop such therapies itself entails particular ethical concerns. In this paper I use synthetic biology as an example of a new and largely unexplored area of health technology to consider the ways in which novel health technologies are likely to emerge and the ethical challenges these will present. I argue that such developments require us to rethink conventional attitudes towards clinical research, the roles of doctors/researchers and patients/participants with respect to research, and the relationship between science and society; and that a broader framework is required to address the plurality of stakeholder roles and interests involved in the development of treatments based on novel technologies.


Why behavioural health promotion endures despite its failure to reduce health inequities.
Increasing rates of chronic conditions have resulted in governments targeting health behaviour such as smoking, eating high-fat diets, or physical inactivity known to increase risk for these conditions. In the process, many have become preoccupied with disease prevention policies focused excessively and narrowly on behavioural health-promotion strategies. These aim to improve health status by persuading individuals to change their health behaviour. At the same time, health promotion policy often fails to incorporate an understanding of the social determinants of health, which recognises that health behaviour itself is greatly influenced by peoples' environmental, socioeconomic and cultural settings, and that chronic diseases and health behaviour such as smoking are more prevalent among the socially or economically disadvantaged. We identify several reasons why behavioural forms of health promotion are inadequate for addressing social inequities in health and point to a dilemma that, despite these inadequacies and increasing evidence of the social determinants of health, behavioural approaches and policies have strong appeal to governments. In conclusion, the article promotes strategies addressing social determinants that are likely to reduce health inequities. The article also concludes that evidence alone will not result in health policies aimed at equity and that political values and will, and the pressure of civil society are also crucial.


Academic Research in the 21st Century: Maintaining Scientific Integrity in a Climate of Perverse Incentives and Hypercompetition.
Over the last 50 years, we argue that incentives for academic scientists have become increasingly perverse in terms of competition for research funding, development of quantitative metrics to measure performance, and a changing business model for higher education itself. Furthermore, decreased discretionary funding at the federal and state level is creating a hypercompetitive environment between government agencies (e.g., EPA, NIH, CDC), for scientists in these agencies, and for academics seeking funding from all sources-the combination of perverse incentives and decreased funding increases pressures that can lead to unethical behavior. If a critical mass of scientists become untrustworthy, a tipping point is possible in which the scientific enterprise itself becomes inherently corrupt and public trust is lost, risking a new dark age with devastating consequences to humanity. Academia and federal agencies should better support science as a public good, and incentivize altruistic and ethical outcomes, while de-emphasizing output.


The impact of confounding on the associations of different adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent.
The data regarding the associations of body mass index (BMI) with cardiovascular (CVD) risk, especially for those at the low categories of BMI, are conflicting. The aim of our study was to examine the associations of body composition (assessed by five different measures) with incident CVD outcomes in healthy individuals. A total of 296 535 participants (57.8% women) of white European descent without CVD at baseline from the UK biobank were included. Exposures were five different measures of adiposity. Fatal and non-fatal CVD events were the primary outcome. Low BMI (≤18.5 kg m-2) was associated with higher incidence of CVD and the lowest CVD risk was exhibited at BMI of 22-23 kg m-2 beyond, which the risk of CVD increased. This J-shaped association attenuated substantially in subgroup analyses, when we excluded participants with comorbidities. In contrast, the associations for the remaining adiposity measures were more linear; 1 SD increase in waist circumference was associated with a hazard ratio of 1.16 [95% confidence interval (CI) 1.13-1.19] for women and 1.10 (95% CI 1.08-1.13) for men with similar magnitude of associations for 1 SD increase in waist-to-hip ratio, waist-to-height ratio, and percentage body fat mass. Increasing adiposity has a detrimental association with CVD health in middle-aged men and women. The association of BMI with CVD appears more susceptible to confounding due to pre-existing comorbidities when compared with other adiposity measures. Any public misconception of a potential 'protective' effect of fat on CVD risk should be challenged. Take home figureThe obesity paradox is mainly due to the effect of confounding on BMI and disappears on other adiposity measures.


Alterations in spatial memory and anxiety in the MAM E17 rat model of hippocampal pathology in schizophrenia.
Adult rats exposed to methylazoxymethanol acetate (MAM) at embryonic day 17 (E17) display robust pathological alterations in the hippocampus. However, discrepancies exist in the literature regarding the behavioural effects of this pre-natal manipulation. Therefore, a systematic assessment of MAM E17-induced behavioural alterations was conducted using a battery of dorsal and ventral hippocampus-dependent tests. Compared to saline controls, MAM E17-treated rats displayed deficits in spatial reference memory in both the aversive hidden platform watermaze task and an appetitive Y-maze task. Deficits in the spatial reference memory watermaze task were replicated across three different cohorts and two laboratories. In contrast, there was little, or no, effect on the non-spatial, visible platform watermaze task or an appetitive, non-spatial, visual discrimination task, respectively. MAM rats were also impaired in the spatial novelty preference task which assesses short-term memory, and displayed reduced anxiety levels in the elevated plus maze task. Thus, MAM E17 administration resulted in abnormal spatial information processing and reduced anxiety in a number of hippocampus-dependent behavioural tests, paralleling the effects of dorsal and ventral hippocampal lesions, respectively. These findings corroborate recent pathological and physiological studies, further highlighting the usefulness of MAM E17 as a model of hippocampal dysfunction in at least some aspects of schizophrenia.


Multicenter Study Demonstrates Standardization Requirements for Mold Identification by MALDI-TOF MS.
Rapid and accurate mold identification is critical for guiding therapy for mold infections. MALDI-TOF MS has been widely adopted for bacterial and yeast identification; however, few clinical laboratories have applied this technology for routine mold identification due to limited database availability and lack of standardized processes. Here, we evaluated the versatility of the NIH Mold Database in a multicenter evaluation. The NIH Mold Database was evaluated by eight US academic centers using a solid media extraction method and a challenge set of 80 clinical mold isolates. Multiple instrument parameters important for spectra optimization were evaluated, leading to the development of two specialized acquisition programs (NIH method and the Alternate-B method). A wide range in performance (33-77%) was initially observed across the eight centers when routine spectral acquisition parameters were applied. Use of the NIH or the Alternate-B specialized acquisition programs, which are different than those used routinely for bacterial and yeast spectral acquisition (MBT_AutoX), in combination with optimized instrument maintenance, improved performance, illustrating that acquisition parameters may be one of the key limiting variable in achieving successful performance. Successful mold identification using the NIH Database for MALDI-TOF MS on Biotyper systems was demonstrated across multiple institutions for the first time following identification of critical program parameters combined with instrument optimization. This significantly advances our potential to implement MALDI-TOF MS for mold identification across many institutions. Because instrument variability is inevitable, development of an instrument performance standard specific for mold spectral acquisition is suggested to improve reproducibility across instruments.


Luminosity determination in pp collisions at [Formula: see text] = 8 TeV using the ATLAS detector at the LHC.
The luminosity determination for the ATLAS detector at the LHC during pp collisions at [Formula: see text] 8 TeV in 2012 is presented. The evaluation of the luminosity scale is performed using several luminometers, and comparisons between these luminosity detectors are made to assess the accuracy, consistency and long-term stability of the results. A luminosity uncertainty of [Formula: see text] is obtained for the [Formula: see text] of pp collision data delivered to ATLAS at [Formula: see text] 8 TeV in 2012.


Evaluation of a nonradiometric system (BACTEC 9000 MB) for detection of mycobacteria in human clinical samples.
This study was carried out to evaluate the rate of recovery and time required for detection of mycobacteria from pulmonary and extrapulmonary human clinical samples, by using a fluorescence-quenching-based oxygen sensor (BACTEC 9000 MB; Becton Dickinson Microbiology Systems, Sparks, Md.). The results were compared with those obtained by microscopy, conventional culture in Lowenstein-Jensen (LJ) medium, and a BACTEC radiometric system (BACTEC 460 TB; Becton Dickinson). Of the 779 clinical samples processed, 364 from pulmonary sites and 415 from extrapulmonary sites, 62 (7.9%) were positive for mycobacterial isolates; of the positive samples, 59 (95.1%) were detected with the fluorescent BACTEC 9000 MB system, 57 (91.9%) were detected with the radiometric system (BACTEC 460 TB), and 43 (69.3%) were detected with LJ conventional culture. The mean times to detection of all mycobacteria with BACTEC 9000 MB and BACTEC 460 TB were similar (10.3 and 10.0 days, respectively). The results obtained indicate that the nonradiometric BACTEC (BACTEC 9000 MB) system is as efficient as Bactec 460 TB and significantly more efficient than LJ for the rapid recovery of mycobacteria from both pulmonary and extrapulmonary clinical specimens. Though the BACTEC 9000 MB system is recommended for respiratory specimens, we demonstrated that it can be successfully used also for recovery of mycobacteria from clinical specimens from various extrapulmonary sites.


The bacterial microbiome of Dermacentor andersoni ticks influences pathogen susceptibility.
Ticks are of medical importance owing to their ability to transmit pathogens to humans and animals. The Rocky Mountain wood tick, Dermacentor andersoni, is a vector of a number of pathogens, including Anaplasma marginale, which is the most widespread tick-borne pathogen of livestock. Although ticks host pathogenic bacteria, they also harbor bacterial endosymbionts that have a role in tick physiology, survival, as well as pathogen acquisition and transmission. The goal of this study was to characterize the bacterial microbiome and examine the impact of microbiome disruption on pathogen susceptibility. The bacterial microbiome of two populations of D. andersoni with historically different susceptibilities to A. marginale was characterized. In this study, the microbiome was disrupted and then ticks were exposed to A. marginale or Francisella novicida to determine whether the microbiome correlated with pathogen susceptibility. Our study showed that an increase in proportion and quantity of Rickettsia bellii in the microbiome was negatively correlated to A. marginale levels in ticks. Furthermore, a decrease in Francisella endosymbionts was associated with lower F. novicida infection levels, demonstrating a positive pathogen-endosymbiont relationship. We demonstrate that endosymbionts and pathogens have varying interactions, and suggest that microbiome manipulation may provide a possible method for biocontrol by decreasing pathogen susceptibility of ticks.


Regulation of α2B-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2.
The molecular mechanisms that control the targeting of newly synthesized G protein-coupled receptors (GPCRs) to the functional destinations remain poorly elucidated. Here, we have determined the role of Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins 1 and 2 (GGA1 and GGA2) in the cell surface transport of α2B-adrenergic receptor (α2B-AR), a prototypic GPCR, and studied the underlying mechanisms. We demonstrated that knockdown of GGA1 and GGA2 by shRNA and siRNA significantly reduced the cell surface expression of inducibly expressed α2B-AR and arrested the receptor in the perinuclear region. Knockdown of each GGA markedly inhibited the dendritic expression of α2B-AR in primary cortical neurons. Consistently, depleting GGA1 and GGA2 attenuated receptor-mediated signal transduction measured as ERK1/2 activation and cAMP inhibition. Although full length α2B-AR associated with GGA2 but not GGA1, its third intracellular loop was found to directly interact with both GGA1 and GGA2. More interestingly, further mapping of interaction domains showed that the GGA1 hinge region and the GGA2 GAE domain bound to multiple subdomains of the loop. These studies have identified an important function and revealed novel mechanisms of the GGA family proteins in the forward trafficking of a cell surface GPCR.


First Report of a Group 16SrVII-C Phytoplasma Associated with Shoot Proliferation of Sunn Hemp (Crotalaria juncea) in Brazil.
Sunn hemp (Crotalaria juncea) is widely grown in tropical and subtropical regions. In Brazil, this species is commonly used for green manure, since this legume is an efficient nitrogen fixer that produces organic residues for soil improvement. In July of 2012, C. juncea exhibiting intense shoot proliferation, leaf malformation, shortened internodes, and generalized yellowing were found in an experimental field located in Piracicaba, State of São Paulo, Brazil. The incidence was about 1 to 2% and the diseased plants were distributed at random. Since these symptoms are indicative of infection by phytoplasmas, the present study aimed to detect and identify the phytoplasma. Four symptomatic and two asymptomatic plants were sampled. Small segments of leaf veins were prepared for microscopy, as previously reported (1), and observations were made using a Jeol (Akishima/Japan) model Jem-1011 transmission electron microscope. Total DNA was extracted from leaves using a commercial kit (DNeasy Plant Mini, Qiagen Inc.), and nested PCR assays were performed with primers, P1/Tint followed by R16F2n/R16R2 (2). The initial assumption that disease symptoms were associated with phytoplasma was confirmed by PCR amplification of 1.2 kb DNA fragments from the 16S rDNA gene. In contrast, no amplicon was generated with PCR using template DNA from asymptomatic plants. The phytoplasma detected from each symptomatic sample was considered to be an isolate. PCR products were purified and cloned in Escherichia coli DH5α, using the pGEM-T Easy Vector System I (Promega). Three isolates were selected and the cloned 16S rDNA sequences from three colonies of each isolate were sequenced. Since no sequence polymorphisms were found, a majority consensus sequence was selected for each isolate. These sequences were identical and one of them, designated CrSP-Br01 (crotalaria shoot proliferation) with 1,249 bp (GenBank Accession KC756947), was used as representative of the sunn hemp phytoplasma. The 16S rDNA nucleotide sequence of this phytoplasma shared 100% sequence identity with the reference phytoplasma for subgroup VII-C (Argentinian Alfalfa witches'-broom phytoplasma, AY147038). According to the in silico RFLP analysis for delineation of subgroups (3), which is based on virtual RFLP patterns and similarity coefficient calculation, the C. juncea phytoplasma was classified as a member of group 16SrVII, subgroup C. Phylogenetic analysis supported that this phytoplasma is closely related to the representative of subgroup 16SrVII-C, since both phytoplasmas emerged from the same branch. Transmission electron microscopic examination revealed the presence of phytoplasmas by visualization of pleomorphic and round bodies 100 to 400 nm in diameter, in the phloem vessels of symptomatic plants. The present study reports the first occurrence of a 16SrVII-C phytoplasma in Brazil. In addition, C. juncea was identified as a new host for phytoplasmas belonging to this subgroup. References: (1) A. B. Maunsbach and B. A. Afzelius. Biomedical Electron Microscopy. Illustrated Methods and Interpretations. Page 381-426, San Diego, Academic Press, 1999. (2) M. C. C. Rappussi et al. Eur. J. Plant Pathol. 133:829, 2012. (3) W. Wei et al. Int. J. Syst. Evol. Microbiol. 57:1855, 2007.


The Effect of 3-Dimensional Simulation on Neurosurgical Skill Acquisition and Surgical Performance: A Review of the Literature.
In recent years, 3-dimensional (3D) simulation of neurosurgical procedures has become increasingly popular as an addition to training programmes. However, there remains little objective evidence of its effectiveness in improving live surgical skill. This review analysed the current literature in 3D neurosurgical simulation, highlighting remaining gaps in the evidence base for improvement in surgical performance and suggests useful future research directions. An electronic search of the databases was conducted to identify studies investigating 3D virtual reality (VR) simulation for various types of neurosurgery. Eligible studies were those that used a combination of metrics to measure neurosurgical skill acquisition on a simulation trainer. Studies were excluded if they did not measure skill acquisition against a set of metrics or if they assessed skills that were not used in neurosurgical practice. This was not a systematic review however, the data extracted was tabulated to allow comparison between studies RESULTS: This study revealed that the average overall quality of the included studies was moderate. Only one study assessed outcomes in live surgery, while most other studies assessed outcomes on a simulator using a variety of metrics. It is concluded that in its current state, the evidence for 3D simulation suggests it as a useful supplement to training programmes but more evidence is needed of improvement in surgical performance to warrant large-scale investment in this technology.


Antibacterial and osteo-stimulatory effects of a borate-based glass series doped with strontium ions.
This work considered the effect of both increasing additions of Strontium (Sr2+) and incubation time on solubility and both antibacterial and osteo-stimulatory effects of a series of glasses based on the B2O3-P2O5-CaCO3-Na2CO3-TiO2-SrCO3 series. The amorphous nature of all the glasses was confirmed by X-ray diffraction. Discs of each glass were immersed in de-ionized water for 1, 7 and 30 days, and the water extracts were used for ion release profiles, pH measurements and cytotoxicity testing. Atomic absorption spectroscopy was employed to detect the release of Na+, Ca2+ and Sr2+ ions from the glasses with respect to maturation, which indicated that the addition of Sr2+ retarded solubility of the glass series. This effect was also confirmed by weight loss analysis through comparing the initial weight of glass discs before and after periods of incubation. The incorporation of Sr2+ in the glasses did not influence the pH of the water extracts when the glasses were stored for up to 30 days. Cytotoxicity testing with an osteoblastic cell line (MC3T3-E1) indicated that glasses with the higher (20 mol% and 25 mol%) Sr2+ incorporation promoted proliferation of osteoblast cells, while the glasses with lower Sr2+ contents inhibited cell growth. The glass series, except for Ly-B5 (which contained the highest Sr2+ incorporation; 25 mol%), were bacteriostatic against S. aureus in the short term (1-7 days) as a result of the dissolution products released.


Effects of Pyriproxifen on Aedes japonicus Development and Its Auto-Dissemination by Gravid Females in Laboratory Trials.
In a series of laboratory experiments, we investigated the effects of the juvenile-hormone analog pyriproxyfen on the inhibition of Aedes japonicus adult emergence after exposure of late-stage (3rd/4th) larvae (either field-collected or lab-reared from field-collected eggs) to pyriproxyfen. Emergence inhibition was 74%, 83%, 86%, and 92% at 0.01, 0.5, 2.5, and 5 μg/liter, respectively. Additionally, following a 1-day exposure of larvae to pyriproxyfen-containing water (5 μg/liter), and for a separate cohort exposed to that same water 10 days later, significantly more pupae died resulting in fewer adults emerged in the treatment versus control group. In 4 tent trials, gravid adult females were able to auto-disseminate a 5% pyriproxyfen powder to larval development habitats at high enough concentrations to cause a significant increase in inhibition of adult emergence. Therefore, we conclude that pyriproxyfen has a great potential for use in controlling this invasive cryptic breeder.


Growth-inhibiting effects of Coptis japonica root-derived isoquinoline alkaloids on human intestinal bacteria.
The growth-inhibiting activity of Coptis japonica (Makino) root-derived materials toward eight human intestinal bacteria was examined using an impregnated paper disk method and compared to that of four commercially available isoquinoline alkaloids [berberine sulfate (BS), berberine iodide (BI), palmatine chloride (PC), and palmatine sulfate(PS)], as well as that of Thea sinensis leaf-derived epigallocatechin gallate (EGCG). The biologically active constituents of the Coptis extract were characterized as the isoquinoline alkaloids berberine chloride (BC), palmatine iodide (PI), and coptisine chloride (CC) by spectral analysis. The growth responses varied with both chemical and bacterial strain used. In a test using 500 microg/disk, BC and PI produced a clear inhibitory effect against Bifidobacterium longum, Bifidobacterium bifidum, Clostridium perfringens, and Clostridium paraputrificum, whereas weak or no inhibition was observed in Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei, and Escherichia coli. At 1000 microg/ disk, CC revealed weak or no growth inhibition toward all test bacteria, whereas EGCG exhibited weak growth inhibition against only C. perfringens and C. paraputrificum. Among various isoquinoline alkaloids, BC exhibited more potent inhibitory activity toward C. perfringens than BI and BS, whereas the inhibitory effect was more pronounced in PI compared to PC and PS. The Coptis root-derived materials did not promote growth of B. longum and C. perfringens.


Psychiatric functioning and quality of life in young patients with cardiac rhythm devices.
Less is known about depression, anxiety and quality of life (QoL) in children and adolescents with pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs) than is known in adults with these devices. A standardized psychiatric interview diagnosed anxiety/depressive disorders in a cross-sectional study. Self-report measures of anxiety, depression and post-traumatic stress disorder were obtained. Medical disease severity, family functioning and QoL data were collected. A total of 166 patients were enrolled (52 ICD, 114 PM; median age 15 years). Prevalence of current and lifetime psychiatric disorders was higher in patients with ICDs than PMs (Current: 27% vs. 11%, P = .02; Lifetime: 52% ICD vs. 34% PM, P = .01). Patients with ICDs had more anxiety than a healthy population (25% vs. 7%, P < .01). Patients with ICDs and PMs had similar levels of depression as a healthy population (ICD 10%, PM 4%, reference 4%, P = .29). In multivariate analysis including a medical disease score, demographics, exposure to beta-blockers, activity limitations, hospitalizations, shocks and procedures, the type of device (PM versus ICD) did not predict psychiatric diagnoses when age at implantation and the severity of medical disease were controlled for. Patients with ICDs and PMs had lower physical QoL scores (ICD 45, PM 47.5, Norm 53, P ≤ .03), but similar psychosocial functioning scores (ICD 49, PM 51, Norm 51, P ≥ .16) versus a normal reference population. Anxiety is highly prevalent in young patients with ICDs, but the higher rates can be attributed to medical disease severity and age at implantation instead of type of device.


Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP.
Loss of plasticity-related gene 1 (PRG-1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg-1 (R345T/mutPRG-1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss-of-PRG-1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG-1(+/-) mice, which are animal correlates of human PRG-1(+/mut) carriers, showed an altered cortical network function and stress-related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA-synthesizing molecule autotaxin. In line, EEG recordings in a human population-based cohort revealed an E/I balance shift in monoallelic mutPRG-1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress-related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate-dependent symptoms in psychiatric diseases.


Serum NfL (Neurofilament Light Chain) Levels and Incident Stroke in Adults With Diabetes Mellitus.
Background and Purpose- Effective stroke prevention depends on accurate stroke risk prediction. We determined the discriminative ability of NfL (neurofilament light chain) levels for distinguishing between adults with diabetes mellitus who develop incident stroke and those who remain stroke free during a 7-year follow-up period. Methods- We performed a case-control study of participants selected from the previously completed ACCORD trial (Action to Control Cardiovascular Risk in Diabetes). Cases were all ACCORD subjects who were stroke free at enrollment and developed incident stroke during follow-up (n=113). Control subjects (n=250) were randomly selected ACCORD subjects who had no stroke events either before or after randomization. NfL was measured in baseline samples using Single Molecule Array technology (Quanterix). Results- Baseline NfL levels were higher in stroke subjects, compared to controls, after adjusting for age, race, blood pressure, weight, and the Framingham Stroke Risk Score. Relative to the subjects in the lowest quintile of NfL levels, the hazard ratios of incident stroke for subjects in the second to fifth quintiles were 3.91 (1.45-10.53), 4.05 (1.52-10.79), 5.63 (2.16-14.66), and 9.75 (3.84-27.71), respectively, after adjusting for race and Framingham Stroke Risk Score. Incorporating NfL levels into a predictive score that already included race and Framingham Stroke Risk Score increased the score's C statistic from 0.71 (95% CI, 0.66-0.77) to 0.78 (95% CI, 0.73-0.83), P<0.001. Older age, nonwhite race, higher systolic blood pressure, glomerular filtration rate <60, and higher hemoglobin A1C were independent predictors of serum NfL in this cohort but diastolic blood pressure, durations of hypertension or diabetes mellitus, and lipid levels were not. In total, cardiovascular disease risk factors explained 19.2% of the variability in baseline NfL levels. Conclusions- Serum NfL levels predict incident stroke and add considerably to the discriminatory power of the Framingham Stroke Risk Score in a cohort of middle-aged and older adults with diabetes mellitus.


Executive functioning and risk for Alzheimer's disease in the cognitively intact: Family history predicts Wisconsin Card Sorting Test performance.
Alzheimer's disease (AD) research typically focuses on memory. However, executive functioning (EF) deficits are also common among AD patients; these deficits are associated with decreased functioning in activities of daily living, an important criterion in diagnosing AD. A classic test of EF ability, the Wisconsin Card Sort Test (WCST), has demonstrated sensitivity to differentiating individuals with AD from healthy controls, discriminating AD groups based on disease severity, and distinguishing AD from other types of dementia. Such sensitivity to AD raises the possibility that the WCST is also sensitive to very early, preclinical differences between those who have heightened risk for AD and those with lower risks. The current study, therefore, examined WCST performance in healthy, cognitively intact older adults with a first-degree (i.e., sibling or parent) family history (FH) of AD (n = 18) and those with no such FH of AD (n = 24). Results revealed significant group differences for Categories Achieved, Percent Conceptual Level Responses, Total Errors, Perseverative Errors, and Non-Perseverative Errors, with the FH+ group consistently exhibiting poorer performance. Moreover, hierarchical regression analyses indicated that after accounting for age, sex, and education, FH significantly predicted all 5 of these variables. These results speak to the potential role of EF in bolstering the current understanding of early cognitive markers of future decline. Furthering what is known about the relationship between AD and nonmemory specific domains of cognition such as executive functioning may allow for better prediction of cognitive decline and potential progression to AD.


Update in hormone therapy use in menopause.
The original report from the Women's Health Initiative (WHI) changed our understanding of the benefits and risks of hormone therapy. Since that time, reanalysis of the WHI and additional data from other studies have further refined these concepts. Here we provide an update on recent advances in the field. Menopausal hormone therapy continues to have a clinical role in the management of vasomotor symptoms. However, our understanding of the role of hormones in cardiovascular disease and breast cancer continues to evolve. Further analyses of the effect of age and proximity to menopause at the time of initiation of therapy, duration of treatment, dose, route of administration, and the persistence of risks and benefits after stopping hormone therapy are described. In addition, recent data have emerged suggesting that there may be a link between hormone therapy and cancers of the lung and ovary. Finally, we discuss new advances in hormone therapy that will likely lead to a more favorable benefit-to-risk ratio, enabling safer effective menopausal symptom relief.