Fatty acid oxidation and the regulation of malonyl-CoA in human muscle.
Questions concerning whether malonyl-CoA is regulated in human muscle and whether malonyl-CoA modulates fatty acid oxidation are still unanswered. To address these questions, whole-body fatty acid oxidation and the concentration of malonyl-CoA, citrate, and malate were determined in the vastus lateralis muscle of 16 healthy nonobese Swedish men during a sequential euglycemic-hyperinsulinemic clamp. Insulin was infused at rates of 0.25 and 1.0 mU x kg(-1) x min(-1), and glucose was infused at rates of 2.0 +/- 0.2 and 8.1 +/- 0.7 mg x kg(-1) x min(-1), respectively. During the low-dose insulin infusion, whole-body fatty acid oxidation, as determined by indirect calorimetry, decreased by 22% from a basal rate of 0.94 +/- 0.06 to 0.74 +/- 0.07 mg x kg(-1) x min(-1) (P = 0.005), but no increase in malonyl-CoA was observed. In contrast, during the high-dose insulin infusion, malonyl-CoA increased from 0.20 +/- 0.01 to 0.24 +/- 0.01 nmol/g (P < 0.001), and whole-body fatty acid oxidation decreased by an additional 41% to 0.44 +/- 0.06 mg x kg(-1) x min(-1) (P < 0.001). The increase in malonyl-CoA was associated with 30-50% increases in the concentrations of citrate (102 +/- 6 vs. 137 +/- 7 nmol/g, P < 0.001), an allosteric activator of the rate-limiting enzyme in the malonyl-CoA formation, acetyl-CoA carboxylase, and malate (80 +/- 6 vs. 126 +/- 9 nmol/g, P = 0.002), an antiporter for citrate efflux from the mitochondria. Significant correlations were observed between the concentration of malonyl-CoA and both glucose utilization (r = 0.53, P = 0.002) and the sum of the concentrations of citrate and malate (r = 0.52, P < 0.001), a proposed index of the cytosolic concentration of citrate. In addition, an inverse correlation between malonyl-CoA concentration and fatty acid oxidation was observed (r = -0.32, P = 0.03). The results indicate that an infusion of insulin and glucose at a high rate leads to increases in the concentration of malonyl-CoA in skeletal muscle and to decreases in whole-body and, presumably, muscle fatty acid oxidation. Furthermore, they suggest that the increase in malonyl-CoA in this situation is due, at least in part, to an increase in the cytosolic concentration of citrate. Because cytosolic citrate is also an inhibitor of phosphofructokinase, an attractive hypothesis is that changes in its concentration are part of an autoregulatory mechanism by which glucose modulates its own use and the use of fatty acids as fuels for skeletal muscle.


Mechanisms of spindle positioning: cortical force generators in the limelight.
Correct positioning of the spindle governs placement of the cytokinesis furrow and thus plays a crucial role in the partitioning of fate determinants and the disposition of daughter cells in a tissue. Converging evidence indicates that spindle positioning is often dictated by interactions between the plus-end of astral microtubules that emanate from the spindle poles and an evolutionary conserved cortical machinery that serves to pull on them. At the heart of this machinery lies a ternary complex (LIN-5/GPR-1/2/Gα in Caenorhabditis elegans and NuMA/LGN/Gαi in Homo sapiens) that promotes the presence of the motor protein dynein at the cell cortex. In this review, we discuss how the above components contribute to spindle positioning and how the underlying mechanisms are precisely regulated to ensure the proper execution of this crucial process in metazoan organisms.


Epidemiology, etiology, and natural treatment of seasonal affective disorder.
There is much more seasonal difference in higher latitudes than in lower latitudes. In a significant portion of the population of the northern United States, the shorter days of fall and winter precipitate a syndrome that can consist of depression, fatigue, hypersomnolence, hyperphagia, carbohydrate craving, weight gain, and loss of libido. If these symptoms persist in the winter, abate as the days grow longer, and disappear in the summer, the diagnosis of seasonal affective disorder (SAD) can be made. Many hypotheses exist regarding the biochemical mechanisms behind the predisposition toward this disease, including circadian phase shifting, abnormal pineal melatonin secretion, and abnormal serotonin synthesis. Although the mechanism(s) behind this disease is not fully known, one treatment appears to address each of the theories. Light therapy is a natural, non-invasive, effective, well-researched method of treatment for SAD. Various light temperatures and times of administration of light therapy have been studied, and a combination of morning and evening exposure appears to offer the best efficacy. Other natural methods of treatment have been studied, including L-tryptophan, Hypericum perforatum (St. John's wort), and melatonin.


HLA-B27.
Possession of the human leukocyte antigen (HLA) class I molecule B27 is strongly associated with ankylosing spondylitis (AS), but the pathogenic role of HLA-B27 is unknown. Two broad theories most likely explain the role of HLA-B27 in AS pathogenesis. The first is based on the natural immunological function of HLA-B27 of presenting antigenic peptides to cytotoxic T cells. Thus, HLA-B27-restricted immune responses to self-antigens, or arthritogenic peptides, might drive immunopathology. B27 can also "behave badly," misfolding during assembly and leading to endoplasmic reticulum stress and autophagy responses. β2m-free B27 heavy chain structures including homodimers (B272) can also be expressed at the cell surface following endosomal recycling of cell surface heterotrimers. Cell surface free heavy chains and B272 bind to innate immune receptors on T, NK, and myeloid cells with proinflammatory effects. This review describes the natural function of HLA-B27, its disease associations, and the current theories as to its pathogenic role.


Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity.
The true causes of the obesity epidemic are not well understood and there are few longitudinal population-based data published examining this issue. The objective of this analysis was to examine trends in occupational physical activity during the past 5 decades and explore how these trends relate to concurrent changes in body weight in the U.S. Analysis of energy expenditure for occupations in U.S. private industry since 1960 using data from the U.S. Bureau of Labor Statistics. Mean body weight was derived from the U.S. National Health and Nutrition Examination Surveys (NHANES). In the early 1960's almost half the jobs in private industry in the U.S. required at least moderate intensity physical activity whereas now less than 20% demand this level of energy expenditure. Since 1960 the estimated mean daily energy expenditure due to work related physical activity has dropped by more than 100 calories in both women and men. Energy balance model predicted weights based on change in occupation-related daily energy expenditure since 1960 for each NHANES examination period closely matched the actual change in weight for 40-50 year old men and women. For example from 1960-62 to 2003-06 we estimated that the occupation-related daily energy expenditure decreased by 142 calories in men. Given a baseline weight of 76.9 kg in 1960-02, we estimated that a 142 calories reduction would result in an increase in mean weight to 89.7 kg, which closely matched the mean NHANES weight of 91.8 kg in 2003-06. The results were similar for women. Over the last 50 years in the U.S. we estimate that daily occupation-related energy expenditure has decreased by more than 100 calories, and this reduction in energy expenditure accounts for a significant portion of the increase in mean U.S. body weights for women and men.


The effect of extending high-frequency bandwidth on the acceptable noise level (ANL) of hearing-impaired listeners.
This study examined the effects of extending high-frequency bandwidth, for both a speech signal and a background noise, on the acceptable signal-to-noise ratio (SNR) of listeners with mild sensorineural hearing loss through utilization of the Acceptable Noise Level (ANL) procedure. In addition to extending high-frequency bandwidth, the effects of reverberation time and background noise type and shape were also examined. The study results showed a significant increase in the mean ANL (i.e. participants requested a better SNR for an acceptable listening situation) when high-frequency bandwidth was extended from 3 to 9 kHz and from 6 to 9 kHz. No change in the ANL of study participants was observed as a result of isolated modification to reverberation time or background noise stimulus. An interaction effect, however, of reverberation time and background noise stimulus was demonstrated. These findings may have implications for future design of hearing aid memory programs for listening to speech in the presence of broadband background noise.


Use of 3D adaptive raw-data filter in CT of the lung: effect on radiation dose reduction.
The purpose of this study was to determine the effectiveness of a 3D adaptive raw-data filter in improving image quality and the role of the filter in radiation dose reduction in lung CT. Fifty-eight chest CT examinations were performed with a 16-MDCT scanner. Two acquisitions were performed with different tube current-exposure time settings (50 and 150 mAs, 120 kVp). Four series of lung images were prepared from two sets of raw data with and without application of a 3D adaptive filter (50 mAs, 50 mAs with filter, 150 mAs, 150 mAs with filter). Three blinded readers using a 5-point scale from 1 (nondiagnostic) to 5 (excellent) independently evaluated image quality in five lobes and the lingula. A set of images was considered acceptable when scores in all six regions were 3 (acceptable) or higher. The SD of attenuation was calculated in 24 regions of interest. The overall mean image quality scores were 3.09, 3.53, 4.02, and 4.38 for the 50 mAs, 50 mAs with filter, 150 mAs, and 150 mAs with filter sets, respectively. Scores were significantly better with filter application (p < 0.001). A significant decrease in SD of attenuation was observed with filter application (p < 0.001). Among the respective series of images, 18, 52, 50, and 58 sets were judged acceptable with no significant difference in acceptability between images obtained at 50 mAs with a filter and at 150 mAs (p = 0.72). With filter application, the acceptability of 50-mAs images became comparable with that of 150-mAs images, making dose reduction to 50 mAs practical. Use of a 3D adaptive raw-data filter improved the quality of lung images, making dose reduction to 50 mAs attainable with use of the filter.


Advancing Dialogue About Consent and Molecular HIV Surveillance in the United States: Four Proposals Following a Federal Advisory Panel's Call for Major Reforms.
Policy Points Molecular HIV surveillance and cluster detection and response (MHS/CDR) programs have been a core public health activity in the United States since 2018 and are the "fourth pillar" of the Ending the HIV Epidemic initiative launched in 2019. MHS/CDR has caused controversy, including calls for a moratorium from networks of people living with HIV. In October 2022, the Presidential Advisory Council on HIV/AIDS (PACHA) adopted a resolution calling for major reforms. We analyze the policy landscape and present four proposals to federal stakeholders pertaining to PACHA's recommendations about incorporating opt-outs and plain-language notifications into MHS/CDR programs.


Effect of compressed TiO2 nanoparticle thin film thickness on the performance of dye-sensitized solar cells.
In this study, dye-sensitized solar cells (DSSCs) were fabricated using nanocrystalline titanium dioxide (TiO2) nanoparticles as photoanode. Photoanode thin films were prepared by doctor blading method with 420 kg/cm2 of mechanical compression process and heat treatment in the air at 500°C for 30 min. The optimal thickness of the TiO2 NP photoanode is 26.6 μm with an efficiency of 9.01% under AM 1.5G illumination at 100 mW/cm2. The efficiency is around two times higher than that of conventional DSSCs with an uncompressed photoanode. The open-circuit voltage of DSSCs decreases as the thickness increases. One DSSC (sample D) has the highest conversion efficiency while it has the maximum short-circuit current density. The results indicate that the short-circuit current density is a compromise between two conflict factors: enlargement of the surface area by increasing photoanode thickness and extension of the electron diffusion length to the electrode as the thickness increases.


Antimicrobial resistance in the nasopharyngeal flora of children with acute otitis media and otitis media recurring after amoxicillin therapy.
The objective of this study was to investigate the antimicrobial susceptibility of the organisms isolated from the nasopharynx of children who presented with acute otitis media (AOM) or otitis media that recurred after amoxicillin therapy. Nasopharyngeal cultures obtained from 72 patients, 40 with AOM and 32 with recurrent otitis media (ROM), were analysed. Thirty-six potentially pathogenic organisms were recovered in 34 (85 %) of the children from the AOM group, and 42 were isolated from 29 (91 %) of the children from the ROM group. The organisms isolated were Streptococcus pneumoniae (n = 26), Haemophilus influenzae non-type b (n = 22), Moraxella catarrhalis (n = 13), Streptococcus pyogenes (n = 8) and Staphylococcus aureus (n = 9). Resistance to the eight antimicrobial agents used was found in 37 instances in the AOM group as compared to 99 instances in the ROM group (P < 0.005). The difference between AOM and ROM was significant with Streptococcus pneumoniae resistance to amoxicillin (P < 0.005), to amoxicillin/clavulanate (P < 0.005), to trimethoprim/sulfamethoxazole (P < 0.01), to cefixime (P < 0.01) and to azithromycin (P < 0.01), and for H. influenzae resistance to amoxicillin (P < 0.025). These data illustrate the higher recovery rate of antimicrobial-resistant Streptococcus pneumoniae and H. influenzae from the nasopharynx of children who had otitis media that recurred after amoxicillin therapy than those with AOM.


Online monitoring of hiPSC expansion and hepatic differentiation in 3D culture by dielectric spectroscopy.
Hepatocyte-like cells derived from human-induced pluripotent stem cells (hiPSC-HLC) are expected to have important applications in drug screening and regenerative medicine. However, hiPSC-HLC are difficult to produce on a large-scale to obtain relevant numbers for such applications. The aim of this study was to implement a novel integrated strategy for scalable production of hiPSC-HLC and demonstrate the applicability of dielectric spectroscopy to monitor hiPSC expansion/differentiation processes. We cultured hiPSC as three-dimensional (3D) aggregates in stirred-tank bioreactors (STB) operated in perfusion with an in situ capacitance probe. Dissolved oxygen concentration and dilution rate were controlled along the process and after 5 days of cell expansion, the hepatic differentiation was integrated in sequential steps for 28 days. The hiPSC were able to grow as 3D aggregates and the expression of hepatic markers and albumin production after differentiation confirmed that hepatocyte differentiation improved when compared to 2D culture. These hiPSC-HLC exhibited functional characteristics of hepatocytes including glycogen storage and drug metabolization capacity. Our results also show a good correlation between the cell permittivity measured online and the aggregate biovolume measured by standard offline methods, demonstrating for the first time the potential of dielectric spectroscopy to monitor hiPSC expansion and differentiation in STB.


CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease.
The infusion of donor regulatory T cells (Tregs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early Treg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where Tregs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 Treg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor Treg function in the transplant setting. Donor Tregs lacking CCR8 (CCR8(-/-)), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue Tregs from apoptosis. Instead, CCR8 potentiated Treg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c(+) antigen-presenting cells (APCs) were important for promoting donor Treg maintenance after transplant. In contrast, host CD11c(+) APCs appeared to be dispensable for early activation and expansion of donor Tregs. Collectively, our data indicate that a sustained donor Treg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c(+) APCs.


Gadolinium as a new emerging contaminant of aquatic environments.
Since the 1980s, gadolinium (Gd)-based contrast agents (GBCAs) have been routinely used in magnetic resonance imaging as stable chelates of the Gd3+ ion, without toxic effects. Generally, GBCAs are considered some of the safest contrast agents. However, it has been observed that they can accumulate in patient tissue, bone, and probably brain (causing nephrogenic systemic fibrosis in patients with kidney failure or insufficiency and disturbance of calcium homeostasis in the organism). The GBCAs are predominantly removed renally without metabolization. Subsequently, they do not undergo degradation processes in wastewater-treatment plants and are emitted into the aquatic ecosystem. Their occurrence was confirmed in surface waters (up to 1100 ng/L), sediments (up to 90.5 μg/g), and living organisms. Based on a literature review, there is a need to investigate the contamination of different ecosystems and to ascertain the environmental fate of Gd. Long-term ecotoxicological data, degradation, metabolism, bioaccumulation processes, and biochemical effects of the Gd complexes should be explored. These data can be used to assess detailed environmental risks because currently only hotspots with high levels of Gd can be marked as dangerous for aquatic environments according to environmental risk assessments. Environ Toxicol Chem 2018;37:1523-1534. © 2018 SETAC.


Gravity-Based Precise Cell Manipulation System Enhanced by In-Phase Mechanism.
This paper proposes a gravity-based system capable of generating high-resolution pressure for precise cell manipulation or evaluation in a microfluidic channel. While the pressure resolution of conventional pumps for microfluidic applications is usually about hundreds of pascals as the resolution of their feedback sensors, precise cell manipulation at the pascal level cannot be done. The proposed system successfully achieves a resolution of 100 millipascals using water head pressure with an in-phase noise cancelation mechanism. The in-phase mechanism aims to suppress the noises from ambient vibrations to the system. The proposed pressure system is tested with a microfluidic platform for pressure validation. The experimental results show that the in-phase mechanism effectively reduces the pressure turbulence, and the pressure-driven cell movement matches the theoretical simulations. Preliminary experiments on deformability evaluation with red blood cells under incremental pressures of one pascal are successfully performed. Different deformation patterns are observed from cell to cell under precise pressure control.


Mitochondrial stress triggers a pro-survival response through epigenetic modifications of nuclear DNA.
Mitochondrial dysfunction represents an important cellular stressor and when intense and persistent cells must unleash an adaptive response to prevent their extinction. Furthermore, mitochondria can induce nuclear transcriptional changes and DNA methylation can modulate cellular responses to stress. We hypothesized that mitochondrial dysfunction could trigger an epigenetically mediated adaptive response through a distinct DNA methylation patterning. We studied cellular stress responses (i.e., apoptosis and autophagy) in mitochondrial dysfunction models. In addition, we explored nuclear DNA methylation in response to this stressor and its relevance in cell survival. Experiments in cultured human myoblasts revealed that intense mitochondrial dysfunction triggered a methylation-dependent pro-survival response. Assays done on mitochondrial disease patient tissues showed increased autophagy and enhanced DNA methylation of tumor suppressor genes and pathways involved in cell survival regulation. In conclusion, mitochondrial dysfunction leads to a "pro-survival" adaptive state that seems to be triggered by the differential methylation of nuclear genes.


Biotemplated synthesis of magnetic filaments.
With the aim of creating one-dimensional magnetic nanostructures, we genetically engineered flagellar filaments produced by Salmonella bacteria to display iron- or magnetite-binding sites, and used the mutant filaments as templates for both nucleation and attachment of the magnetic iron oxide magnetite. Although nucleation from solution and attachment of nanoparticles to a pre-existing surface are two different processes, non-classical crystal nucleation pathways have been increasingly recognized in biological systems, and in many cases nucleation and particle attachment cannot be clearly distinguished. In this study we tested the magnetite-nucleating ability of four types of mutant flagella previously shown to be efficient binders of magnetite nanoparticles, and we used two other mutant flagella that were engineered to periodically display known iron-binding oligopeptides on their surfaces. All mutant filaments were demonstrated to be efficient as templates for the synthesis of one-dimensional magnetic nanostructures under ambient conditions. Both approaches resulted in similar final products, with randomly oriented magnetite nanoparticles partially covering the filamentous biological templates. In an external magnetic field, the viscosity of a suspension of the produced magnetic filaments showed a twofold increase relative to the control sample. The results of magnetic susceptibility measurements were also consistent with the magnetic nanoparticles occurring in linear structures. Our study demonstrates that biological templating can be used to produce one-dimensional magnetic nanostructures under benign conditions, and that modified flagellar filaments can be used for creating model systems in which crystal nucleation from solution can be experimentally studied.


Nanostructure ITO and Get More of It. Better Performance at Lower Cost.
In this paper, we investigated how different growth conditions (i.e., temperature, growth time, and composition) allows for trading off cost (i.e., In content) and performance of nanostructured indium tin oxide (ITO) for biosensing applications. Next, we compared the behavior of these functionalized nanostructured surfaces obtained in different growth conditions between each other and with a standard thin film as a reference, observing improvements in effective detection area up to two orders of magnitude. This enhanced the biosensor's sensitivity, with higher detection level, better accuracy and higher reproducibility. Results show that below 150 °C, the growth of ITO over the substrate forms a homogenous layer without any kind of nanostructuration. In contrast, at temperatures higher than 150 °C, a two-phase temperature-dependent growth was observed. We concluded that (i) nanowire length grows exponentially with temperature (activation energy 356 meV) and leads to optimal conditions in terms of both electroactive surface area and sensitivity at around 300 °C, (ii) longer times of growth than 30 min lead to larger active areas and (iii) the In content in a nanostructured film can be reduced by 10%, obtaining performances equivalent to those found in commercial flat-film ITO electrodes. In summary, this work shows how to produce appropriate materials with optimized cost and performances for different applications in biosensing.


Delivery of recombinant gene product to canines with nonautologous microencapsulated cells.
An alternative and potentially cost-effective approach to somatic gene therapy is to engineer a universal cell line secreting the desired product suitable for implantation into different patients without immune rejection. Encapsulating these cells in immunoprotective alginate microcapsules showed that this approach was effective in treating murine models of human diseases. We now report that this approach is also effective in delivering recombinant gene products to large animals. Canine MDCK cells encapsulated in alginate microcapsules were able to deliver recombinant human growth hormone to nonautologous dogs in vivo. However, the same microcapsules capable of prolonged delivery in mice soon disappeared after implantation in dogs. In contrast, when these microcapsules were modified by using a higher concentration of alginate cross-linked with barium instead of calcium, and by fabricating the alginate as a gelled bead without solubilizing the core, more prolonged and higher levels of recombinant product were obtained. Laminating the surface of the beads with poly-L-lysine and alginate provided an even more mechanically stable device that lasted for >2 months instead of <14 days in vivo and delivered >20 ng of human growth hormone/ml of plasma within the first week. The apparent disappearance of the growth hormone from the circulation after day 14 was due to rapid clearance by anti-human growth hormone antibodies and not due to loss of cell viability. However, all microcapsules provoked an inflammatory reaction, causing mild omentitis, and eventually disappeared from the intraperitoneal cavity. In conclusion, systemic delivery of recombinant gene products with nonautologous cells protected in alginate microcapsules has been shown to be feasible in canine recipients. While improved level and duration of delivery have been achieved by increasing the mechanical stability of the microcapsules, further improvements in biocompatibility and stability will be required for human application.


Assessment of sampling strategies for estimation of site mean concentrations of stormwater pollutants.
The estimation of stormwater pollutant concentrations is a primary requirement of integrated urban water management. In order to determine effective sampling strategies for estimating pollutant concentrations, data from extensive field measurements at seven different catchments was used. At all sites, 1-min resolution continuous flow measurements, as well as flow-weighted samples, were taken and analysed for total suspend solids (TSS), total nitrogen (TN) and Escherichia coli (E. coli). For each of these parameters, the data was used to calculate the Event Mean Concentrations (EMCs) for each event. The measured Site Mean Concentrations (SMCs) were taken as the volume-weighted average of these EMCs for each parameter, at each site. 17 different sampling strategies, including random and fixed strategies were tested to estimate SMCs, which were compared with the measured SMCs. The ratios of estimated/measured SMCs were further analysed to determine the most effective sampling strategies. Results indicate that the random sampling strategies were the most promising method in reproducing SMCs for TSS and TN, while some fixed sampling strategies were better for estimating the SMC of E. coli. The differences in taking one, two or three random samples were small (up to 20% for TSS, and 10% for TN and E. coli), indicating that there is little benefit in investing in collection of more than one sample per event if attempting to estimate the SMC through monitoring of multiple events. It was estimated that an average of 27 events across the studied catchments are needed for characterising SMCs of TSS with a 90% confidence interval (CI) width of 1.0, followed by E.coli (average 12 events) and TN (average 11 events). The coefficient of variation of pollutant concentrations was linearly and significantly correlated to the 90% confidence interval ratio of the estimated/measured SMCs (R2 = 0.49; P < 0.01) as well as the number of events required to achieve certain accuracy, and hence could be a promising surrogate for determining the sampling frequency needed to accurately estimate SMCs of pollutants.


Structure vs. excitonic transitions in self-assembled porphyrin nanotubes and their effect on light absorption and scattering.
The optical properties of diprotonated meso-tetrakis(4-sulphonatophenyl)porphyrin (TPPS(4)) J-aggregates of elongated thin particles (nanotubes in solution and ribbons when deposited on solid interfaces) are studied by different polarimetric techniques. The selective light extinction in these structures, which depends on the alignment of the nanoparticle with respect to the polarization of light, is contributed by excitonic absorption bands and by resonance light scattering. The optical response as a function of the polarization of light is complex because, although the quasi-one-dimensional structure confines the local fields along the nanotube axis, there are two orthogonal excitonic bands, of H- and J-character, that can work in favor of or against the field confinement. Results suggest that resonance light scattering is the dominant effect in solid state preparations, i.e. in collective groups (bundles) of ribbons but in diluted solutions, i.e. with isolated nanotubes, the absorption at the excitonic transitions remains dominant and linear dichroism spectra can be a direct probe of the exciton orientations. Therefore, by analyzing scattering and absorption data we can determine the alignment of the excitonic bands within the nanoparticle, i.e. of the orientation of the basic 2D porphyrin architecture in the nanoparticle. This is a necessary first step for understanding the directions of energy transport, charge polarization and non-linear optical properties in these materials.


Neighborhood, route, and school environments and children's active commuting.
Walking and cycling to school represent an opportunity for children to achieve regular physical activity. These behaviors may be influenced by characteristics of the environment around homes and schools, yet few studies have quantified the potential associations between these two sets of factors. This study aims to assess whether objectively measured characteristics of the neighborhood, route, and school environments are associated with active commuting to school among children, and it explores whether distance acts as a moderator in this association. A cross-sectional study was conducted of 2012 children (899 boys and 1113 girls) aged 9-10 years attending 92 schools in the county of Norfolk, United Kingdom. Questionnaires were completed by children and parents during Summer 2007. Attributes around the home and children's route to school were assessed using a GIS. School environments were assessed using a newly developed school audit and via questionnaires completed by head teachers. Data were analyzed in 2008. Almost half of the children usually walked or cycled to school. Children who lived in a more deprived area and whose route to school was direct were less likely to walk or cycle to school, whereas those who had a higher density of roads in their neighborhood were more likely to walk. Further, children whose routes had a high density of streetlights were less likely to cycle to school. Distance did not moderate the observed associations. Objectively measured neighborhood and route factors are associated with walking and cycling to school. However, distance did not moderate the associations found here. Creating safe environments by improving urban design may influence children's commuting behavior. Intervention studies are needed to confirm the findings from this observational cross-sectional study.


Educating the surgeon-scientist: A qualitative study evaluating challenges and barriers toward becoming an academically successful surgeon.
The advancement of surgical science relies on educating new generations of surgeon-scientists. Career development awards (K Awards) from the National Institutes of Health, often considered a marker of early academic success, are one way physician-scientists may foster skills through a mentored research experience. This study aimed to develop a conceptual framework to understand institutional support and other factors leading to a K Award. A national, qualitative study was conducted with academic surgeons. Participants included 15 K Awardees and 12 surgery department Chairs. Purposive sampling ensured a diverse range of experiences. Semistructured, in-depth telephone interviews were conducted. Interviews were audio recorded and transcribed verbatim, and 2 reviewers analyzed the transcripts using Grounded Theory methodology. Participants described individual and institutional factors contributing to success. K Awardees cited personal factors such as perseverance and team leadership skills. Chairs described the K Awardee as an institutional "investment" requiring protected time for research, financial support, and mentorship. Both K Awardees and Chairs identified a number of challenges unique to the surgeon-scientist, including financial strains and competing clinical demands. Institutional support for surgeons pursuing K Awards is a complex investment with significant initial costs to the department. Chairs act as stewards of institutional resources and support those surgeon-scientists most likely to be successful. Although the K Award pathway is one way to develop surgeon-scientists, financial burdens and challenges may limit its usefulness. These findings, however, may better prepare young surgeons to develop career plans and identify new mechanisms for academic productivity.


Do portable nursing stations within bays of hospital wards reduce the rate of inpatient falls? An interrupted time-series analysis.
falls can negatively affect patients, resulting in loss of independence and functional decline and have substantial healthcare costs. Hospitals are a high-risk falls environment and regularly introduce, but seldom evaluate, policies to reduce inpatient falls. This study evaluated whether introducing portable nursing stations in ward bays to maximise nurse-patient contact time reduced inpatient falls. inpatient falls data from local hospital incident reporting software (Datix) were collected monthly (April 2014-December 2017) from 17 wards in Stoke Mandeville and Wycombe General Hospitals, the UK. Portable nursing stations were introduced in bays on these wards from April 2016. We used a natural experimental study design and interrupted time series analysis to evaluate changes in fall rates, measured by the monthly rate of falls per 1000 occupied bed days (OBDs). the wards reported 2875 falls (April 2014-December 2017). The fallers' mean age was 78 (SD = 13) and 58% (1624/2817) were men. Most falls, 99.41% (2858/2875), resulted in none, low or moderate harm, 0.45% (13/2875) in severe harm and 0.14% (4/2875) in death. The monthly falls rate increased by 0.119 per 1000 OBDs (95% CI: 0.045, 0.194; P = 0.002) before April 2016, then decreased by 0.222 per 1000 OBDs (95% CI: -0.350, -0.093; P = 0.001) until December 2017. At 12 months post-intervention, the absolute difference between the estimated post-intervention trend and pre-intervention projected estimate was 2.84 falls per 1000 OBDs, a relative reduction of 26.71%. portable nursing stations were associated with lower monthly falls rates and could reduce inpatient falls across the NHS.


Heteronemin Induces Anti-Proliferation in Cholangiocarcinoma Cells via Inhibiting TGF-β Pathway.
A marine sesterterpenoid-type natural product, heteronemin, retains anticancer effects. In the current study, we investigate the antitumor mechanism of heteronemin in cholangiocarcinoma cells and further explore its molecular targets. Initially, heteronemin exhibited potent cytotoxic effects against cholangiocarcinoma HuccT1 and SSP-25 cells. In vitro, heteronemin altered the abilities of cell adhesion and cell migration in HuccT1 and SSP-25 cell lines. It repressed messenger ribonucleic acid (mRNA) expression levels of transforming growth factor (TGF)-β, mothers against decapentaplegic homolog (SMAD) and Myc, whose protein products play important roles in regulating cell growth, angiogenesis, and metastasis. In addition, heteronemin altered several signaling pathways. The results indicate that heteronemin was able to modulate cell adhesion, the expression of extracellular matrix (ECM) receptors, the TGF-β pathway, cell motility, the membrane integration, metastasis response, matrix metalloproteinase (MMP) remodeling, the regulation of metabolism, sprouting angiogenesis, transcription factors, and vasculogenesis in cholangiocarcinoma cell lines. The results also suggest that it activated multiple signal transduction pathways to induce an anti-proliferation effect and anti-metastasis in cholangiocarcinoma. In conclusion, heteronemin may be used as a potential medicine for anticancer therapy.


Environmental Impact of Food Packaging Materials: A Review of Contemporary Development from Conventional Plastics to Polylactic Acid Based Materials.
Plastics have remained the material of choice, and after serving their intended purpose, a large proportion ends up in the environment where they persist for centuries. The packaging industry is the largest and growing consumer of synthetic plastics derived from fossil fuels. Food packaging plastics account for the bulk of plastic waste that are polluting the environment. Additionally, given the fact that petroleum reserves are finite and facing depletion, there is a need for the development of alternative materials that can serve the same purpose as conventional plastics. This paper reviews the function of packaging materials and highlights the future potential of the adoption of green materials. Biopolymers have emerged as promising green materials although they still have very low market uptake. Polylactic acid (PLA) has emerged as the most favoured bioplastic. However, it is limited by its high cost and some performance drawbacks. Blending with agricultural waste and natural fillers can result in green composites at low cost, low greenhouse gas emissions, and with improved performance for food packaging applications. The continent of Africa is proposed as a rich source of fibres and fillers that can be sustainably exploited to fabricate green composites in a bid to achieve a circular economy.


AART-BC: a sensor system for monitoring Assistive Technology use beyond the clinic.
A wide range of assistive and rehabilitative technologies (ART) are available to assist with mobility and upper limb function. However, anecdotal evidence suggests many of the devices prescribed, or purchased, are either poorly used, or rejected entirely. This situation is costly, both for the healthcare provider and the user, and may be leading to secondary consequences, such as falls and/or social isolation. This paper reports on the development and initial feasibility testing of a system for monitoring when and how assistive devices are used outside of the clinic setting, and feeding this information to the device user themselves and/or prescribing clinician (where appropriate). Illustrative data from multiple time-synchronized device and body worn sensors are presented on a wheelchair user and a user of a "rollator" walking frame, moving along a walkway. Observation of the sensor data in both cases showed characteristic signatures corresponding to individual "pushes". In parallel with this work, other project partners are exploring clinician and patient data requirements, as well we sensor set acceptability The initial results highlight the potential for the approach and demonstrate the need for further work to reduce and optimize the sensor set.


Differential stability of therapeutic peptides with different proteolytic cleavage sites in blood, plasma and serum.
Proteolytic degradation of peptide-based drugs is often considered as major weakness limiting systemic therapeutic applications. Therefore, huge efforts are typically devoted to stabilize sequences against proteases present in serum or plasma, obtained as supernatants after complete blood coagulation or centrifugation of blood supplemented with anticoagulants, respectively. Plasma and serum are reproducibly obtained from animals and humans allowing consistent for clinical analyses and research applications. However, the spectrum of active or activated proteases appears to vary depending on the activation of proteases and cofactors during coagulation (serum) or inhibition of such enzymes by anticoagulants (plasma), such as EDTA (metallo- and Ca2+-dependent proteases) and heparin (e.g. thrombin, factor Xa). Here, we studied the presumed effects on peptide degradation by taking blood via cardiac puncture of CD-1 mice using a syringe containing a peptide solution. Due to absence of coagulation activators (e.g. glass surfaces and damaged cells), visible blood clotting was prevented allowing to study peptide degradation for one hour. The remaining peptide was quantified and the degradation products were identified using mass spectrometry. When the degradation rates (half-life times) were compared to serum derived freshly from the same animal and commercial serum and plasma samples, peptides of three different families showed indeed considerably different stabilities. Generally, peptides were faster degraded in serum than in plasma, but surprisingly all peptides were more stable in fresh blood and the order of degradation rates among the peptides varied among the six different incubation experiments. This indicates, that proteolytic degradation of peptide-based therapeutics may often be misleading stimulating efforts to stabilize peptides at degradation sites relevant only in vitro, i.e., for serum or plasma stability assays, but of lower importance in vivo.


Highly ordered n/p-co-assembled materials with remarkable charge mobilities.
Controlling self-organization and morphology of chemical architectures is an essential challenge in the search for higher energy-conversion efficiencies in a variety of optoelectronic devices. Here, we report a highly ordered donor/acceptor functional material, which has been obtained using the principle of ionic self-assembly. Initially, an electron donor π-extended tetrathiafulvalene and an electron-acceptor perylene-bisimide were self-organized separately obtaining n- and p-nanofibers at the same scale. These complementary n- and p-nanofibers are endowed with ionic groups with opposite charges on their surfaces. The synergic interactions establish periodic alignments between both nanofibers resulting in a material with alternately segregated donor/acceptor nanodomains. Photoconductivity measurements show values for these n/p-co-assembled materials up to 0.8 cm(2) V(-1) s(-1), confirming the effectiveness in the design of these heterojunction structures. This easy methodology offers great possibilities to achieve highly ordered n/p-materials for potential applications in different areas such as optoelectonics and photovoltaics.


Mixed emotions: Network analyses of intra-individual co-occurrences within and across situations.
This study revisits the structure of emotions by using a co-occurrence network analysis. While previous studies have examined the structure of emotions primarily through interindividual correlations, we investigated how often and which specific positive and negative emotions occur together within individuals. Two studies were conducted with high school students, one (N = 21,678) using retrospective emotion measures (open-ended questions and 28 rated items) and the other (N = 472) using in-the-moment emotion measures (experience sampling). As in previous studies, positive and negative emotion ratings were negatively correlated across individuals, and this negative correlation became stronger when measurement error was controlled. Nevertheless, network analyses of both the open-ended responses and of emotion rating scales found frequent co-occurrences between both positive and negative emotions within individuals and within situations. Across all networks, happy, tired, and stressed were among the most frequent emotions that occurred together with emotions of opposite valence. The network analyses presented in this article open new directions to the long-lasting debate about the structure of emotions by revealing co-occurrences that interindividual correlations would not show. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Regulation of innate and adaptive immunity by Notch.
Coordinated function of the innate and adaptive arms of the immune system in vertebrates is essential to promote protective immunity and to avoid immunopathology. The Notch signalling pathway, which was originally identified as a pleiotropic mediator of cell fate in invertebrates, has recently emerged as an important regulator of immune cell development and function. Notch was initially shown to be a key determinant of cell-lineage commitment in developing lymphocytes, but it is now known to control the homeostasis of several innate cell populations. Moreover, the roles of Notch in adaptive immunity have expanded to include the regulation of T cell differentiation and function. The aim of this Review is to summarize the current status of immune regulation by Notch. A better understanding of Notch function in both innate and adaptive immunity will hopefully provide multiple avenues for therapeutic intervention in disease.


Scalable Topological Data Analysis and Visualization for Evaluating Data-Driven Models in Scientific Applications.
With the rapid adoption of machine learning techniques for large-scale applications in science and engineering comes the convergence of two grand challenges in visualization. First, the utilization of black box models (e.g., deep neural networks) calls for advanced techniques in exploring and interpreting model behaviors. Second, the rapid growth in computing has produced enormous datasets that require techniques that can handle millions or more samples. Although some solutions to these interpretability challenges have been proposed, they typically do not scale beyond thousands of samples, nor do they provide the high-level intuition scientists are looking for. Here, we present the first scalable solution to explore and analyze high-dimensional functions often encountered in the scientific data analysis pipeline. By combining a new streaming neighborhood graph construction, the corresponding topology computation, and a novel data aggregation scheme, namely topology aware datacubes, we enable interactive exploration of both the topological and the geometric aspect of high-dimensional data. Following two use cases from high-energy-density (HED) physics and computational biology, we demonstrate how these capabilities have led to crucial new insights in both applications.


Analysis with missing data in drug prevention research.
Missing data problems have been a thorn in the side of prevention researchers for years. Although some solutions for these problems have been available in the statistical literature, these solutions have not found their way into mainstream prevention research. This chapter is meant to serve as an introduction to the systematic application of the missing data analysis solutions presented recently by Little and Rubin (1987) and others. The chapter does not describe a complete strategy, but it is relevant for (1) missing data analysis with continuous (but not categorical) data, (2) data that are reasonably normally distributed, and (3) solutions for missing data problems for analyses related to the general linear model in particular, analyses that use (or can use) a covariance matrix as input. The examples in the chapter come from drug prevention research. The chapter discusses (1) the problem of wanting to ask respondents more questions than most individuals can answer; (2) the problem of attrition and some solutions; and (3) the problem of special measurement procedures that are too expensive or time consuming to obtain for all subjects. The authors end with several conclusions: Whenever possible, researchers should use the Expectation-Maximization (EM) algorithm (or other maximum likelihood procedure, including the multiple-group structural equation-modeling procedure or, where appropriate, multiple imputation, for analyses involving missing data [the chapter provides concrete examples]); If researchers must use other analyses, they should keep in mind that these others produce biased results and should not be relied upon for final analyses; When data are missing, the appropriate missing data analysis procedures do not generate something out of nothing but do make the most out of the data available; When data are missing, researchers should work hard (especially when planning a study) to find the cause of missingness and include the cause in the analysis models; and Researchers should sample the cases originally missing (whenever possible) and adjust EM algorithm parameter estimates accordingly.


Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency.
The functions of the iron regulatory proteins (IRP1 and IRP2), which control cellular iron homeostasis are similar but not identical. As an inappropriate up-regulation of total IRP activity has been found in the duodenum and monocytes of patients with hereditary hemochromatosis (HH), we investigated the respective roles of IRP1 and IRP2 in these settings. Specific antibodies were used in RNA-supershift, immunoblotting and immunohistochemistry assays to evaluate IRP1 and IRP2 separately in monocytes, macrophages and duodenum of control subjects, and patients with HH or iron-deficiency anemia. The activity of both IRP1 and IRP2 and the levels of IRP2 were: (i) higher in monocytes and macrophages of HH patients than in those of control subjects; (ii) increased in the duodenal samples of the patients with HH and iron-deficiency anemia. IRP2 levels increased when monocytes differentiated to macrophages. Under all of the examined conditions, IRP2 was induced to a greater extent. In the duodenum of HH and anemic patients, IRP1 was shifted from the aconitase form (present in controls) to the apoform, whereas the IRP1 in monocytes/macrophages was always in the apoform, in both the patients and controls. The RNA-bound fraction of IRP1 was small in all of the samples. Both IRP were expressed more in the villi than in the crypts of the duodenum, with no differences in localization or expression between the patients and controls. These findings of the first extensive investigation of the comparative expression of the two IRP in human tissues and blood cells indicate that IRP2 is the major regulator of intracellular iron homeostasis in humans.


The role of ocular muscle proprioception in visual localization of targets.
The role of ocular muscle proprioception in the localization of visual targets has been investigated in normal humans by deviating one eye to create an experimental strabismus. The passively deviated eye was covered and the other eye viewed the target. With a hand-pointing task, targets were systematically mislocalized in the direction of the deviated nonviewing eye. A 4- to 6-degree error resulted when the nonviewing eye was offset 30 degrees from straight ahead. When the eye was deviated, the perceived "straight-ahead" was also displaced, by a similar amount, in the same direction. Since the efferent motor commands to the displaced and to the nondisplaced eyes are presumably identical by the law of equal innervation, the mislocalization of visual objects must be attributed to the change in proprioceptive information issued from the nonviewing, deviated eye. Thus proprioception contributes to the localization of objects in space.


Collaborative research between clinicians and researchers: a multiple case study of implementation.
Bottom-up, clinician-conceived and directed clinical intervention research, coupled with collaboration from researcher experts, is conceptually endorsed by the participatory research movement. This report presents the findings of an evaluation of a program in the Veterans Health Administration meant to encourage clinician-driven research by providing resources believed to be critical. The evaluation focused on the extent to which funded projects: maintained integrity to their original proposals; were methodologically rigorous; were characterized by collaboration between partners; and resulted in sustained clinical impact. Researchers used quantitative (survey and archival) and qualitative (focus group) data to evaluate the implementation, evaluation, and sustainability of four clinical demonstration projects at four sites. Fourteen research center mentors and seventeen clinician researchers evaluated the level of collaboration using a six-dimensional model of participatory research. Results yielded mixed findings. Qualitative and quantitative data suggested that although the process was collaborative, clinicians' prior research experience was critical to the quality of the projects. Several challenges were common across sites, including subject recruitment, administrative support and logistics, and subsequent dissemination. Only one intervention achieved lasting clinical effect beyond the active project period. Qualitative analyses identified barriers and facilitators and suggested areas to improve sustainability. Evaluation results suggest that this participatory research venture was successful in achieving clinician-directed collaboration, but did not produce sustainable interventions due to such implementation problems as lack of resources and administrative support.


Activation and desensitization of AMPA/kainate receptors by novel derivatives of willardiine.
Willardiine [(S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione] is a naturally occurring heterocyclic excitatory amino acid present in the seeds of Acacia and Mimosa. A series of 5-substituted willardiines were synthesized in single enantiomeric forms and tested for activity at AMPA/kainate receptors, using whole-cell recording from mouse embryonic hippocampal neurons. The (S)- but not (R)-isomers of willardiine and 5-bromowillardiine were potent agonists, producing rapidly but incompletely desensitizing responses. At equilibrium, (S)-5-fluorowillardiine (EC50, 1.5 microM) was seven times more potent than (R,S)-AMPA (EC50, 11 microM) and 30 times more potent than willardiine (EC50, 45 microM); the potency sequence was fluoro greater than nitro greater than chloro approximately bromo greater than iodo greater than willardiine. Willardiines produce strikingly different degrees of desensitization: at saturating doses the equilibrium response to the weakly desensitizing agonist (S)-5-iodowillardiine was similar in amplitude to the response to kainate and 10 times larger than the response to the strongly desensitizing agonist (S)-willardiine. The desensitization sequence was fluoro greater than willardiine greater than nitro approximately chloro greater than bromo greater than iodo greater than kainate. Cross-desensitization experiments confirm that willardiines bind to the same receptors activated by kainate and AMPA, and show that both the rapidly desensitizing and equilibrium responses to willardiines are mediated by the same receptor: (S)-5-iodowillardiine blocked activation of the rapidly desensitizing response evoked by (S)-willardiine and (S)-5-fluorowillardiine, while the latter agonists blocked the equilibrium response to (S)-5-iodowillardiine. A slowly decaying inward tail current was recorded after a brief application of (S)-5-fluorowillardiine but not (S)-willardiine, consistent with a model in which willardiines bind with different affinity to desensitized receptors, such that following removal of agonist, receptors trapped in the desensitized state can return to the open state before dissociation of agonist terminates receptor activation. Willardiines are the first compounds characterized in which simple changes in molecular structure are associated with marked differences in the ability of agonists to produce desensitization of AMPA/kainate receptors.


GENE-counter: a computational pipeline for the analysis of RNA-Seq data for gene expression differences.
GENE-counter is a complete Perl-based computational pipeline for analyzing RNA-Sequencing (RNA-Seq) data for differential gene expression. In addition to its use in studying transcriptomes of eukaryotic model organisms, GENE-counter is applicable for prokaryotes and non-model organisms without an available genome reference sequence. For alignments, GENE-counter is configured for CASHX, Bowtie, and BWA, but an end user can use any Sequence Alignment/Map (SAM)-compliant program of preference. To analyze data for differential gene expression, GENE-counter can be run with any one of three statistics packages that are based on variations of the negative binomial distribution. The default method is a new and simple statistical test we developed based on an over-parameterized version of the negative binomial distribution. GENE-counter also includes three different methods for assessing differentially expressed features for enriched gene ontology (GO) terms. Results are transparent and data are systematically stored in a MySQL relational database to facilitate additional analyses as well as quality assessment. We used next generation sequencing to generate a small-scale RNA-Seq dataset derived from the heavily studied defense response of Arabidopsis thaliana and used GENE-counter to process the data. Collectively, the support from analysis of microarrays as well as the observed and substantial overlap in results from each of the three statistics packages demonstrates that GENE-counter is well suited for handling the unique characteristics of small sample sizes and high variability in gene counts.


Psychiatric presentation of Crohn's disease. Diagnostic delay and increased morbidity.
Four children presented to child psychiatric clinics with a variety of symptoms. They were all later recognised as having Crohn's disease. There was a significant delay between the onset of symptoms and diagnosis, compared with a control group of patients with Crohn's disease whose presentation was with predominantly gastrointestinal symptoms, which was associated with evidence of increased morbidity. Children with abdominal and psychiatric symptoms occurring in combination need serial assessments of physical status, including height and weight, and measurements of inflammatory and nutritional status.


Effects of physical stress in alpine skiing on psychological, physiological, and biomechanical parameters: An individual approach.
Alpine skiing is an attractive winter sport that often includes mental and physical demands. Since skiing is often done for several hours, fatigue processes occur that might lead to action errors associated with a higher risk of accidents and injuries. The aim of this study was to investigate the timing of changes in subjective, physiological, and biomechanical parameters during a physically demanding, standardized, non-competitive alpine skiing session. A group of 22 experienced male skiers carried out 10 runs, each lasting between 150 and 180 s, at a turn rate of 80 turns per minute with their best skiing technique. Immediately after the run, skiers reported ratings of fatigue, and other affective states. During skiing, breathing pattern and biomechanical data of the ski turns as radial force, turn duration, edge angle symmetry, and a composed motion quality score were recorded. Analyses of variances on skiers showing signs of fatigue (n =16) revealed that only the subjective data changed significantly over time: fatigue and worry increased, vitality and calm decreased. Subsequently, individual change points analyses were computed to localize abrupt distribution or statistical changes in time series data. For some skiers, abrupt changes at certain runs in physiological and/or biomechanical parameters were observed in addition to subjective data. The results show general effects in subjective data, and individual fatigue-related patterns concerning the onset of changes in subjective, physiological, and biomechanical parameters. Individuality of response to fatigue should be considered when studying indicators of fatigue data. Based on the general effects in subjective data, it is concluded that focusing on self-regulation and self-awareness may play a key role, as subjective variables have been shown generally sensitive to the physical stress in alpine skiing. In the future, customized algorithms that indicate the onset of fatigue could be developed to improve alpine skiers' self-awareness and self-regulation, potentially leading to fewer action errors.


Why Do Migratory Birds Sing on Their Tropical Wintering Grounds?
Many long-distance migratory birds sing extensively on their tropical African wintering grounds, but the function of this costly behavior remains unknown. In this study, we carry out a first empirical test of three competing hypotheses, combining a field study of great reed warblers (Acrocephalus arundinaceus) wintering in Africa with a comparative analysis across Palearctic-African migratory songbird species. We asked whether winter song (i) functions to defend nonbreeding territories, (ii) functions as practice to improve complex songs for subsequent breeding, or (iii) is a nonadaptive consequence of elevated testosterone carryover. We found support for neither the long-assumed territory-defense hypothesis (great reed warblers had widely overlapping home ranges and showed no conspecific aggression) nor the testosterone-carryover hypothesis (winter singing in great reed warblers was unrelated to plasma testosterone concentration). Instead, we found strongest support for the song-improvement hypothesis, since great reed warblers sang a mate attraction song type rather than a territorial song type in Africa, and species that sing most intensely in Africa were those in which sexual selection acts most strongly on song characteristics; they had more complex songs and were more likely to be sexually monochromatic. This study underlines how sexual selection can have far-reaching effects on animal ecology throughout the annual cycle.


Is Coffee and Green Tea Consumption Related to Serum Levels of Adiponectin and Leptin?
Coffee and green tea are two of most usual consumed beverages in the world which have several benefit components. Coffee and green tea have significantly inverse correlation with obesity, diabetes, and cardiovascular diseases. Adiponectin and leptin are the adipokines mostly secreted from adipose tissue and play the important roles on the status of chronic diseases. In the present study, we aimed to review the evidence about relationship between these beverages and adiponectin and leptin levels. We searched in PubMed to January 2013 using several key words such as coffee, green tea, caffeine, leptin, adiponectin, and adipokines. Finally, most related articles were recruited in this regard. Several findings suggested the positive association between coffee and adiponectin level. Different studies showed contradictory results regarding green tea and adiponectin level. However, most of them reported the positive role of green tea in adiponectin concentration. Fewer studies are conducted about the association between these beverages and leptin, and their results are controversial. More longitudinal investigations should be conducted in this regard to declare these associations.


Intradermal bleomycin injections into normal human skin. A histopathologic and immunopathologic study.
Intralesionally injected bleomycin is a useful agent for the treatment of recalcitrant warts. The mechanism of action in wart therapy has been thought to be due to DNA and antiviral effects. To further characterize the inflammatory response to intralesional bleomycin injections, we examined the clinical, histologic, and immunopathologic response to intradermal bleomycin injections in normal human skin. Four volunteers were each given four intradermal bleomycin injections (0.01 to 0.5 U/mL) into normal human skin to establish a dose response. These injections induced a localized time and dose-dependent inflammatory reaction and persistent postinflammatory hyperpigmentation. Nine biopsy specimens from two volunteers were taken at different time points after intradermal bleomycin injections (0.1 to 1.0 U/mL) into normal human skin. Routine histologic study demonstrated dyskeratosis and necrosis of epidermal keratinocytes and eccrine epithelium associated with a prominent neutrophilic infiltrate, closely resembling histopathologic findings seen in neutrophilic eccrine hidradenitis. Expression of HLA-DR and intercellular adhesion molecule 1 was induced on keratinocytes; intercellular adhesion molecule 1 was upregulated, and endothelial leukocyte adhesion molecule 1 was induced on superficial dermal blood vessels. These findings suggest that intradermal bleomycin injection is either directly or indirectly cytotoxic to keratinocytes and eccrine epithelium. Expression and upregulation of activation antigens and cell adhesion molecules suggest that a cellular immune system response and proinflammatory cytokine secretion occur after intralesional bleomycin injection into normal human skin. Histopathologic findings at some injection sites resemble neutrophilic eccrine hidradenitis.


Unravelling the diversity in water usage among wild banana species in response to vapour pressure deficit.
The rise in global temperature is not only affecting plant functioning directly, but is also increasing air vapour pressure deficit (VPD). The yield of banana is heavily affected by water deficit but so far breeding programs have never addressed the issue of water deficit caused by high VPD. A reduction in transpiration at high VPD has been suggested as a key drought tolerance breeding trait to avoid excessive water loss, hydraulic failure and to increase water use efficiency. In this study, stomatal and transpiration responses under increasing VPD at the leaf and whole-plant level of 8 wild banana (sub)species were evaluated, displaying significant differences in stomatal reactivity. Three different phenotypic groups were identified under increasing VPD. While (sub)species of group III maintained high transpiration rates under increasing VPD, M. acuminata ssp. errans (group I), M. acuminata ssp. zebrina (group II) and M. balbisiana (group II) showed the highest transpiration rate limitations to increasing VPD. In contrast to group I, group II only showed strong reductions at high VPD levels, limiting the cost of reduced photosynthesis and strongly increasing their water use efficiency. M. acuminata ssp. zebrina and M. balbisiana thus show the most favourable responses. This study provides a basis for the identification of potential parent material in gene banks for breeding future-proof bananas that cope better with lack of water.


Emergent SU(4) Symmetry in α-ZrCl_{3} and Crystalline Spin-Orbital Liquids.
While the enhancement of spin-space symmetry from the usual SU(2) to SU(N) is promising for finding nontrivial quantum spin liquids, its realization in magnetic materials remains challenging. Here, we propose a new mechanism by which SU(4) symmetry emerges in the strong spin-orbit coupling limit. In d^{1} transition metal compounds with edge-sharing anion octahedra, the spin-orbit coupling gives rise to strongly bond-dependent and apparently SU(4)-breaking hopping between the J_{eff}=3/2 quartets. However, in the honeycomb structure, a gauge transformation maps the system to an SU(4)-symmetric Hubbard model. In the strong repulsion limit at quarter filling, as realized in α-ZrCl_{3}, the low-energy effective model is the SU(4) Heisenberg model on the honeycomb lattice, which cannot have a trivial gapped ground state and is expected to host a gapless spin-orbital liquid. By generalizing this model to other three-dimensional lattices, we also propose crystalline spin-orbital liquids protected by this emergent SU(4) symmetry and space group symmetries.


Bilateral Herpes Simplex Uveitis: Review of the Literature and Own Reports.
Herpes simplex-associated uveitis is usually considered a unilateral eye disease, and rarely included in the differential diagnosis whenever there is bilateral involvement. We report three cases of bilateral herpetic anterior uveitis. We evaluated three patients who presented with clinical manifestations of bilateral uveitis suggestive of viral origin. We found intraocular hypertension, cells in the anterior chamber, paralytic mydriasis, iris atrophy with transillumination defects, and variable anterior vitreous cellularity. According to the clinical findings, supported with herpes-specific antibody titers and aqueous humor PCR results in two of them, they were diagnosed with bilateral anterior herpetic uveitis. Our patients were initially misdiagnosed as having non-infectious uveitis and were treated with immunomodulatory medications, which could have favored the extension of infection bilaterally. Although uncommon, bilateral herpetic uveitis should always be considered in the differential diagnoses, when patients present with hypertensive uveitis in both eyes.


In situ identification of cation-exchange-induced reversible transformations of 3D and 2D perovskites.
The optical and structural properties of hybrid perovskites can be tuned by the post-synthetic introduction of new cations. To advance the development of this approach, knowledge of the reaction mechanism is essential, but has not yet been elucidated. Here, the effect of n-octylamine on three-dimensional (3D) methylammonium lead bromide (MAPbBr3) was investigated by in situ X-ray photoelectron spectroscopy. Spectroscopic analysis indicated equimolar substitutions between octylammonium (OcA+) and methylammonium (MA+) cations that cause the formation of two-dimensional (2D) octylammonium lead bromide ((OcA)2PbBr4). The introduction of methylamine reversed these changes, and the cation exchange between MA+ and OcA+ caused the reverse conversion to MAPbBr3.


Predictors of motor vehicle collision injuries among a nationally representative sample of Canadians.
The purpose of this study was to examine predictors of subsequent motor vehicle collision injuries, with a particular focus on health-related variables, using the longitudinal dataset from the Canadian National Population Health Survey (NPHS) for the years 1994-2002. Multiple logistic regression analysis was used to determine the relations between motor vehicle collision injury and four risk factors: binge drinking, health status, distress, and medication use. Age and sex were included as control variables. The total sample size was 14,529. A higher percentage of females and younger persons reported a motor vehicle collision injury. Binge drinkers, respondents with poor health, respondents with distress, and respondents reported using two or more medications reported a higher percentage of subsequent injuries. Logistic regression analysis found that persons with poorer health status and persons who used more medications had higher odds of motor vehicle injuries. Only one statistically significant interaction effect was found: alcohol bingeing and medication use. Among a nationally representative sample of Canadians, various demographic and risk factors predict subsequent injuries. Given that this number represents a considerable economic burden, this study underscores the need for continued research and countermeasures on alcohol, drugs, and driving.


Precise control over supramolecular nanostructures via manipulation of H-bonding in π-amphiphiles.
Self-assembled supramolecular architectures are ubiquitous in nature. A synchronized combination of dynamic noncovalent interactions is the major driving force in forming unique structures with high-precision control over the self-assembly of supramolecular materials. Herein, we have achieved programmable nanostructures by introducing single/multiple H-bonding units in a supramolecular building block. A diverse range of nanostructures can be generated in aqueous medium by subtly tuning the structure of π-amphiphiles. 1D-cylindrical micelles, 2D-nanoribbons and hollow nanotubes are produced by systematically varying the number of H-bonding units (0-2) in structurally near identical π-amphiphiles. Spectroscopic measurements revealed the decisive role of H-bonding units for different modes of molecular packing. We have demonstrated that a competitive self-assembled state (a kinetically controlled aggregation state and a thermodynamically controlled aggregation state) can be generated by fine tuning the number of noncovalent forces present in the supramolecular building blocks. The luminescence properties of conjugated dithiomaleimide (DTM) provided insight into the relative hydrophobicity of the core in these nanostructures. In addition, fluorescence turn-off in the presence of thiophenol enabled us to probe the accessibility of the hydrophobic core in these assembled systems toward guest molecules. Therefore the DTM group provides an efficient tool to determine the relative hydrophobicity and accessibility of the core of various nanostructures which is very rarely studied in supramolecular assemblies.


Examination of passive ROM and capsular patterns in the hip.
The present study was conducted to examine passive hip range of motion (PROM) for patients with hip dysfunction, including pain, with or without hip osteoarthritis, to arrange and describe PROM patterns and to count the number of hips presenting Cyriax's and Kaltenborn's capsular patterns. The study is theory-testing, observational, cross-sectional and descriptive. One hundred and sixty-eight patients (mean age 61.7 years, range 36-90 years), 50 with no hip osteoarthritis, 77 with unilateral hip osteoarthritis and 41 with bilateral osteoarthritis, based on radiological reports, were consecutively recruited by physicians in primary health care and orthopaedic settings. One examiner tested PROM bilaterally, by use of a goniometer and a standardized protocol. PROM limitations were calculated by comparing norms from the symptom-free hips (n = 100) in the study, from Kaltenborn and, in patients with unilateral hip osteoarthritis (n = 77), from the non-osteoarthritis hip. The limitations were arranged by size in PROM patterns. The patterns and the numbers of hips with patterns corresponding to Cyriax's and Kaltenborn's capsular patterns were counted. Between 68 and 138 PROM patterns were identified by use of different PROM norms for defining limitations. Few osteoarthritis hips showed Cyriax's capsular pattern and none Kaltenborn's capsular pattern. The concept of capsular pattern for the hip should be re-examined. No support was found in the present study for its existence. It is impossible to anticipate radiological evidence of hip osteoarthritis from the multitude of PROM patterns. Every patient should be regarded as unique.


Development and evaluation of a toolkit to assess partnership readiness for community-based participatory research.
An earlier investigation by academic and community co-investigators led to the development of the Partnership Readiness for Community-Based Participatory Research (CBPR) Model, which defined major dimensions and key indicators of partnership readiness. As a next step in this process, we used qualitative methods, cognitive pretesting, and expert reviews to develop a working guide, or toolkit, based on the model for academic and community partners to assess and leverage their readiness for CBPR. The 75-page toolkit is designed as a qualitative assessment promoting equal voice and transparent, bi-directional discussions among all the partners. The toolkit is formatted to direct individual partner assessments, followed by team assessments, discussions, and action plans to optimize their goodness of fit, capacity, and operations to conduct CBPR. The toolkit has been piloted with two cohorts in the Medical University of South Carolina's (MUSC) Community Engaged Scholars (CES) Program with promising results from process and outcome evaluation data.


Extensive gene-specific translational reprogramming in a model of B cell differentiation and Abl-dependent transformation.
To what extent might the regulation of translation contribute to differentiation programs, or to the molecular pathogenesis of cancer? Pre-B cells transformed with the viral oncogene v-Abl are suspended in an immortalized, cycling state that mimics leukemias with a BCR-ABL1 translocation, such as Chronic Myelogenous Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL). Inhibition of the oncogenic Abl kinase with imatinib reverses transformation, allowing progression to the next stage of B cell development. We employed a genome-wide polysome profiling assay called Gradient Encoding to investigate the extent and potential contribution of translational regulation to transformation and differentiation in v-Abl-transformed pre-B cells. Over half of the significantly translationally regulated genes did not change significantly at the level of mRNA abundance, revealing biology that might have been missed by measuring changes in transcript abundance alone. We found extensive, gene-specific changes in translation affecting genes with known roles in B cell signaling and differentiation, cancerous transformation, and cytoskeletal reorganization potentially affecting adhesion. These results highlight a major role for gene-specific translational regulation in remodeling the gene expression program in differentiation and malignant transformation.


Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.
Recent evidence strongly implicates the inflammatory response to intrauterine infection in the pathogenesis of neonatal brain and lung injury. We hypothesized that lung and brain injury in preterm infants occurs during a common developmental window of vulnerability as the result of an inflammatory response in different compartments. To determine whether inflammatory markers in these compartments are associated with bronchopulmonary dysplasia (BPD) or cranial ultrasound (CUS) abnormalities in infants <33 wk gestation age (GA) and <1501 g birth weight, we analyzed placental pathology and serum and cerebrospinal fluid (CSF) IL-6, IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) concentrations in 276 infants. Logistic regressions were performed stratified by GA. Histologic chorioamnionitis was significantly associated with BPD in infants </=28 wk GA (OR 3.6, p = 0.027). Maternal stage of chorioamnionitis significantly correlated with severity of BPD. Presence of a fetal inflammatory response indicated by fetal vasculitis or elevated cytokines was not associated with the development of BPD. Serum IL-6 >/=17 pg/mL was associated with an abnormal CUS in infants >28 wk GA (OR 3.36, p = 0.023) but not </=28 wk GA. CSF concentrations of IL-6 >/=6.5 pg/mL and TNF-alpha >/=3 pg/mL were associated with abnormal CUS in infants </=28 wk GA (IL-6 OR 3.0; TNF-alpha OR 3.5; p < 0.05 each case) but not >/=28 wk GA. These data suggest that in infants </=28 wks GA, BPD may be initiated by inflammatory mediators in amniotic fluid, but brain injury may involve variations in the systemic inflammatory response.


Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones.
Nalidixic acid, enoxacin, and other antibacterial 4-quinolones inhibit DNA gyrase activity by interrupting DNA breakage and reunion by A subunits of the A2B2 gyrase complex. Despite their clinical importance, the mode of quinolone action and mechanisms of resistance are poorly understood at the molecular level. Using a DNA fragment enrichment procedure, we isolated the gyrA gene from a uropathogenic Escherichia coli strain that encodes a gyrase A protein cross-resistant to a variety of quinolones. When complemented with gyrase B subunit, the purified A protein reconstituted DNA supercoiling activity approximately 100-fold more resistant to inhibition by enoxacin than the susceptible enzyme and failed to mediate quinolone-dependent DNA cleavage. Nucleotide sequence analysis revealed that the gene differed at 58 nucleotide positions compared with the K-12 gyrA sequence. The 875-amino-acid residue-resistant gyrase A protein differed at three positions from its wild-type E. coli K-12 counterpart: tryptophan, glutamate, and serine replaced serine, aspartate, and alanine residues at positions 83, 678, and 828, respectively. By genetic analysis of chimeric gyrA genes in a gyrA(Ts) background, we showed that the Ser-83----Trp mutation in the gyrase A protein was solely responsible for high-level bacterial resistance to nalidixic acid and fluoroquinolones.


Effects of solute-coupled transport on lymph flow and oncotic pressures in cat ileum.
The effects of net volume absorption rate on steady-state lymphatic and capillary volume flows, lymphatic protein flux, and lymph oncotic pressure were analyzed in an isolated vascularly perfused cat ileum preparation. Solute-coupled fluid transport was stimulated by instilling either Tyrode solution, Tyrode + glucose, Tyrode + taurocholic acid (TC), Tyrode + TC + oleic acid, or Tyrode + aspartic acid, into the ileal lumen. Lymph flow increased in a sigmoidal fashion as net volume absorption rate increased. A linear relationship was observed between lymphatic protein flux and net volume absorption rate. The relative contributions of the intestinal capillary and lymphatic systems in removing absorbed volume from the mucosal interstitium was highly dependent on the rate of net volume absorption. Lymph oncotic pressure decreased progressively as net volume absorption rate increased with a maximal reduction in lymph oncotic pressure of 6.0-7.0 mmHg at the higher volume absorption rates. The results of this study indicate that 1) the rate of solute-coupled fluid transport greatly influences the rate of intestinal lympathic and capillary volume flows, lymphatic protein flux, and lymph oncotic pressure, 2) a reduction in tissue oncotic pressure may serve as the major driving force for vascular removal of absorved volume, and 3) the increase in capillary permeability to plasma proteins during fluid transport is related to the rate of volume absorption.


Noninvasive diagnosis of liver fibrosis by ultrasonic transient elastography (Fibroscan).
Methods for diagnosing hepatic fibrosis have progressed significantly over the last few years--notably with the appearance of minimally invasive biological tests (which avoid the need for liver needle biopsy but nevertheless require a blood sample). Hepatic ultrasonic transient elastography (Fibroscan) is a new diagnostic method for hepatic fibrosis: it is totally noninvasive and gives an immediate result. Here, we review the currently available data on the use of the Fibroscan. Today's main field of application is chronic, viral hepatitis C, with areas under the receiver operation characteristic curve of 0.79-0.83, 0.90-0.91 and 0.91-0.97 for the diagnosis of F2, F3 and F4 fibrosis (defined according to the Metavir classification system), respectively. Furthermore, the Fibroscan enables the noninvasive diagnosis of cirrhosis (regardless of the latter's aetiology), with positive and negative predictive values of 70-95% and 77-95%, respectively. Chronic viral hepatitis B, HIV-hepatitis C virus and HIV-hepatitis B virus coinfections, alcohol-related liver diseases and intrahepatic cholestatic diseases are the device's other main fields of application in hepatology. Today, the Fibroscan is a reliable alternative for the noninvasive diagnosis of hepatic fibrosis. Various diagnostic strategies and performing cost/benefit analyses are now necessary, to assess fully the value of hepatic elastography relative to biological tests for hepatic fibrosis.


Bipolaron recombination in conjugated polymers.
By using the Su-Schrieffer-Heeger model modified to include electron-electron interactions, the Brazovskii-Kirova symmetry breaking term and an external electric field, we investigate the scattering process between a negative and a positive bipolaron in a system composed of two coupled polymer chains. Our results show that the Coulomb interactions do not favor the bipolaron recombination. In the region of weak Coulomb interactions, the two bipolarons recombine into a localized excited state, while in the region of strong Coulomb interactions they can not recombine. Our calculations show that there are mainly four channels for the bipolaron recombination reaction: (1) forming a biexciton, (2) forming an excited negative polaron and a free hole, (3) forming an excited positive polaron and a free electron, (4) forming an exciton, a free electron, and a free hole. The yields for the four channels are also calculated.


Oligopeptide permease is required for expression of the Bacillus thuringiensis plcR regulon and for virulence.
PlcR is a pleiotropic regulator of virulence factors in the insect pathogen Bacillus thuringiensis and in the opportunistic human pathogen Bacillus cereus. It activates the transcription of at least 15 genes encoding extracellular proteins, including phospholipases C, proteases and enterotoxins. Expression of the plcR gene is autoregulated and activated at the onset of stationary phase. Here, we used mini-Tn10 transposition to generate a library of B. thuringiensis mutants, with the goal of characterizing genes involved in the expression of the plcR gene. Three mutant strains were identified carrying distinct mini-Tn10 insertions. The mutations impaired plcR expression and caused a deficient haemolytic phenotype, similar to the phenotype of a B. thuringiensis strain in which the plcR gene had been disrupted. The insertion sites of the three mini-Tn10 transposons mapped in a five-gene operon encoding polypeptides homologous to the components of the oligopeptide permease (Opp) system of Bacillus subtilis, and with a similar structural organization. By analogy, the five B. thuringiensis genes were designated oppA, B, C, D and F. In vitro disruption of the B. thuringiensis oppB gene reproduced the effect of the mini-Tn10 insertions (i.e. the loss of haemolytic activity) and reduced the virulence of the strain against insects. These phenotypes are similar to those of a DeltaplcR mutant. Opp is required for the import of small peptides into the cell. Therefore, plcR expression might be activated at the onset of stationary phase by the uptake of a signalling peptide acting as a quorum-sensing effector. The opp mutations impaired the sporulation efficiency of B. thuringiensis when the cells were cultured in LB medium. Thus, Opp is on the pathway that ultimately regulates Spo0A phosphorylation, as is the case in B. subtilis. However, analysis of plcR expression in DeltaoppB, Deltaspo0A and DeltaoppB Deltaspo0A mutants indicates that Opp is required for plcR expression via a Spo0A-independent mechanism.


Efficacy of antidepressants: bias in randomized clinical trials and related issues.
Countless antidepressant randomized trials were conducted and showed statistically significant benefits of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) over placebo. Meanwhile, critics are increasing regarding the efficacy of antidepressants in the treatment of MDD because at least a proportion of clinical trials could be hampered by various biases. In contrast, number of failed trials is increasing in the recent years which have made developing psychiatric medications progressively more time-consuming and expensive. Areas covered: Biases and related issues in clinical trials for antidepressants can be identified as an important common contributing factor to the two paradoxical phenomenon. This review identifies possible biases that can occur before, during, and after clinical trials of antidepressant. Expert commentary: Recent studies not only may over-estimate efficacy of antidepressants, but also may exaggerate placebo response because of various biases. Sponsorship and publication biases have been one of the targets of the criticism and ethical debate. Thus, initiating new trend of research by re-organizing academic-industry partnership will be the most important task in the next five years.


Wide-field depth-sectioning fluorescence microscopy using projector-generated patterned illumination.
We present a simple and cost-effective wide-field, depth-sectioning, fluorescence microscope utilizing a commercial multimedia projector to generate excitation patterns on the sample. Highly resolved optical sections of fluorescent pollen grains at 1.9 microm axial resolution are constructed using the structured illumination technique. This requires grid excitation patterns to be scanned across the sample, which is straightforwardly implemented by creating slideshows of gratings at different phases, projecting them onto the sample, and synchronizing camera acquisition with slide transition. In addition to rapid dynamic pattern generation, the projector provides high illumination power and spectral excitation selectivity. We exploit these properties by imaging mouse neural cells in cultures multistained with Alexa 488 and Cy3. The spectral and structural neural information is effectively resolved in three dimensions. The flexibility and commercial availability of this light source is envisioned to open multidimensional imaging to a broader user base.


Populous: a tool for building OWL ontologies from templates.
Ontologies are being developed for the life sciences to standardise the way we describe and interpret the wealth of data currently being generated. As more ontology based applications begin to emerge, tools are required that enable domain experts to contribute their knowledge to the growing pool of ontologies. There are many barriers that prevent domain experts engaging in the ontology development process and novel tools are needed to break down these barriers to engage a wider community of scientists. We present Populous, a tool for gathering content with which to construct an ontology. Domain experts need to add content, that is often repetitive in its form, but without having to tackle the underlying ontological representation. Populous presents users with a table based form in which columns are constrained to take values from particular ontologies. Populated tables are mapped to patterns that can then be used to automatically generate the ontology's content. These forms can be exported as spreadsheets, providing an interface that is much more familiar to many biologists. Populous's contribution is in the knowledge gathering stage of ontology development; it separates knowledge gathering from the conceptualisation and axiomatisation, as well as separating the user from the standard ontology authoring environments. Populous is by no means a replacement for standard ontology editing tools, but instead provides a useful platform for engaging a wider community of scientists in the mass production of ontology content.


Bilingualism: A Global Public Health Strategy for Healthy Cognitive Aging.
Dementia is a global public health priority which cost global societies $818 billion in 2015 and is disproportionately impacting low and middle-income countries (LMICs). With limited availability of disease modifying drugs to treat Alzheimer's disease (AD), researchers have increasingly focused on preventative strategies which may promote healthy cognitive aging and mitigate the risk of cognitive impairment in aging. Lifelong bilingualism has been presented as both a highly debated and promising cognitive reserve factor which has been associated with better cognitive outcomes in aging. A recent metanalysis has suggested that bilingual individuals present on average 4.05 years later with the clinical features of AD than monolinguals. Bilinguals are also diagnosed with AD ~2.0 years later than monolingual counterparts. In this perspective piece we critically evaluate the findings of this metanalysis and consider the specific implications of these findings to LMICs. Furthermore, we appraise the major epidemiological studies conducted globally on bilingualism and the onset of dementia. We consider how both impactful and robust studies of bilingualism and cognition in older age may be conducted in LMICs. Given the limited expenditure and resources available in LMICs and minimal successes of clinical trials of disease modifying drugs we propose that bilingualism should be positioned as an important and specific public health strategy for maintaining healthy cognitive aging in LMICs. Finally, we reflect upon the scope of implementing bilingualism within the education systems of LMICs and the promotion of bilingualism as a healthy cognitive aging initiative within government policy.


The role of leptin in human obesity and disease: a review of current evidence.
To review recent advances in the pathophysiology and potential clinical applications of leptin, an adipose tissue-derived hormone. A MEDLINE search of the literature on leptin and the bibliographies of relevant papers. All 1320 publications on leptin. All identified articles were reviewed. Cited publications were selected on the basis of study quality and relevance to human obesity and disease. Leptin is a 16-kilodalton adipocyte-derived hormone that circulates in the serum in the free and bound form. Serum levels of leptin reflect the amount of energy stored in adipose tissue. Short-term energy imbalance as well as serum levels of several cytokines and hormones influence circulating leptin levels. Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate neuroendocrine function and energy intake and expenditure. Thus, leptin plays an important role in the pathogenesis of obesity and eating disorders and is thought to mediate the neuroendocrine response to food deprivation. Phase I and II trials recently showed that leptin administration to humans is safe, and ongoing phase III trials are assessing the efficacy of leptin as a treatment for obesity and related disorders. Availability of leptin or smaller and more soluble leptin analogues for clinical studies in humans is expected to significantly advance understanding of the mechanisms underlying energy homeostasis in humans. Leptin is significantly broadening our understanding of the mechanisms underlying neuroendocrine function, body weight, and energy homeostasis. Elucidation of these mechanisms is expected to result in the development of novel therapeutic approaches for obesity and eating disorders.


Nanosized multifunctional polyplexes for receptor-mediated siRNA delivery.
Although our understanding of RNAi and our knowledge on designing and synthesizing active and safe siRNAs significantly increased during the past decade, targeted delivery remains the major limitation in the development of siRNA therapeutics. On one hand, practical considerations dictate robust chemistry reproducibly providing precise carrier molecules. On the other hand, the multistep delivery process requires dynamic multifunctional carriers of substantial complexity. We present a monodisperse and multifunctional carrier system, synthesized by solid phase supported chemistry, for siRNA delivery in vitro and in vivo. The sequence-defined assembly includes a precise cationic (oligoethanamino)amide core, terminated at the ends by two cysteines for bioreversible polyplex stabilization, at a defined central position attached to a monodisperse polyethylene glycol chain coupled to a terminal folic acid as cell targeting ligand. Complexation with an endosomolytic influenza peptide-siRNA conjugate results in nanosized functional polyplexes of 6 nm hydrodynamic diameter. The necessity of each functional substructure of the carrier system for a specific and efficient gene silencing was confirmed. The nanosized polyplexes showed stability in vivo, receptor-specific cell targeting, and silencing of the EG5 gene in receptor-positive tumors. The nanosized appearance of these particles can be precisely controlled by the oligomer design (from 5.8 to 8.8 nm diameter). A complete surface charge shielding together with the high stability result in good tolerability in vivo and the absence of accumulation in nontargeted tissues such as liver, lung, or spleen. Due to their small size, siRNA polyplexes are efficiently cleared by the kidney.


Safety and efficacy of dipeptidyl peptidase-4 inhibitors vs sulfonylurea in metformin-based combination therapy for type 2 diabetes mellitus: Systematic review and meta-analysis.
The purpose of this study was to compare the safety and efficacy of DPP-4 inhibitors versus sulfonylurea as adjunctive second-line therapy in patients with type 2 diabetes mellitus, inadequately controlled with metformin mono-therapy. A systematic review of published randomized controlled trials (RCTs) was performed in MEDLINE, EMBASE, PubMed and Cochrane library. Two reviewers independently selected the studies, extracted the data and assessed the risk of bias. Clinical outcomes were cardiovascular events, HbA1c % change from baseline, body weight and hypoglycemic event rate. A direct comparison meta-analysis using a random effect model was conducted to calculate mean differences in treatment effects and risk ratio between DPP-4 inhibitors and sulfonylurea. Ten RCTs on adult patients with type 2 diabetes and inadequate glycemic control were included in the final analysis. DPP-4 inhibitors compared to sulfonylureas produced a non-significant difference in HbA1c% change in 10,139 subjects, whereas a significant decrease in the rate of hypoglycemic events was observed in favor of DPP-4 inhibitors (RR= 0.12; P<0.00001) involving 10,616 patients, with at least one hypoglycemic event during the follow-up period (12-104 weeks). Body weight decreased by 2.2 kg (95% CI 1.7-2.7) with DPP-4 inhibitors, compared with sulfonylureas. There were insufficient data to assess a difference in the risk for cardiovascular events. The review shows that, in terms of clinical efficacy, there is no significant difference between DPP4-inhibitors and sulfonylurea when either is added to metformin mono-therapy. In contrast, the safety assessment analysis showed a significant decrease in the risk of hypoglycemic events in patients using DPP4-inhibitors.