Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy.
Ground glass hepatocytes (GGHs) harboring hepatitis B virus (HBV) pre-S mutants have been recognized as precursor lesions of hepatocellular carcinoma (HCC). Previously, we observed the activation of mammalian target of rapamycin (mTOR) in GGHs and HCCs, together with a decreased expression of HBV surface antigen (HBsAg) in HCC tissues. It is, therefore, hypothesized that the activation of mTOR during HBV tumorigenesis may potentially down-regulate HBsAg expression. In this study, we verified an inverse relationship between the expression of HBsAg and phosphorylated mTOR (p-mTOR) in 13 of 20 paired nontumorous liver and HCC tissues. In vitro, wild-type or mutant pre-S proteins could activate mTOR in the HuH-7 cell line. Interestingly, the up-regulated mTOR, in turn, suppressed HBsAg synthesis at the transcriptional level via the transcription factor, Yin Yang 1 (YY1), which bound to nucleotide 2812-2816 of the pre-S1 promoter. This inhibitory effect by the mTOR signal could be abolished by the knockdown of histone deacetylase 1 (HDAC1). Furthermore, YY1 was physically associated with HDAC1 in a manner dependent on mTOR activation. Collectively, pre-S protein-induced mTOR activation may recruit the YY1-HDAC1 complex to feedback suppress transcription from the pre-S1 promoter. The activation of mTOR signal in GGHs may feedback suppress HBsAg synthesis during HBV tumorigenesis and explain the observed decrease or absence of HBsAg in HCC tissues. Therapy using mTOR inhibitors for HCCs may potentially activate HBV replication in patients with chronic HBV infection.


Translating Behavior Change Principles Into a Blended Exercise Intervention for Older Adults: Design Study.
Physical activity can prevent or delay age-related impairments and prolong the ability of older adults to live independently. Community-based programs typically offer classes where older adults can exercise only once a week under the guidance of an instructor. The health benefits of such programs vary. Exercise frequency and the duration of the program play a key role in realizing effectiveness. An auxiliary home-based exercise program can provide older adults the opportunity to exercise more regularly over a prolonged period of time in the convenience of their own homes. Furthermore, mobile electronic devices can be used to motivate and remotely guide older adults to exercise in a safe manner. Such a blended intervention, where technology is combined with personal guidance, needs to incorporate behavior change principles to ensure effectiveness. The aim of this study was to identify theory-based components of a blended intervention that supports older adults to exercise at home. The Medical Research Council framework was used to develop the blended intervention. Insights from focus group, expert panels, and literature were combined into leading design considerations. A client-server system had been developed that combined a tablet app with a database in the cloud and a Web-based dashboard that can be used by a personal coach to remotely monitor and guide older adults. The app contains several components that facilitate behavior change-an interactive module for goal setting, the ability to draw up a personal training schedule from a library containing over 50 exercise videos, progress monitoring, and possibilities to receive remote feedback and guidance of a personal coach. An evidence-based blended intervention was designed to promote physical activity among older adults. The underlying design choices were underpinned by behavior change techniques that are rooted in self-regulation. Key components of the tablet-supported intervention were a tailored program that accommodates individual needs, demonstrations of functional exercises, monitoring, and remote feedback. The blended approach combines the convenience of a home-based exercise program for older adults with the strengths of mobile health and personal guidance.


Engagement with eHealth Self-Monitoring in a Primary Care-Based Weight Management Intervention.
While eHealth approaches hold promise for improving the reach and cost-effectiveness of behavior change interventions, they have been challenged by declining participant engagement over time, particularly for self-monitoring behaviors. These are significant concerns in the context of chronic disease prevention and management where durable effects are important for driving meaningful changes. "Be Fit, Be Well" was an eHealth weight loss intervention that allowed participants to self-select a self-monitoring modality (web or interactive voice response (IVR)). Participants could change their modality. As such, this study provides a unique opportunity to examine the effects of intervention modality choice and changing modalities on intervention engagement and outcomes. Intervention participants, who were recruited from community health centers, (n = 180) were expected to self-monitor health behaviors weekly over the course of the 24-month intervention. We examined trends in intervention engagement by modality (web, IVR, or changed modality) among participants in the intervention arm. The majority (61%) of participants chose IVR self-monitoring, while 39% chose web. 56% of those who selected web monitoring changed to IVR during the study versus no change in those who initially selected IVR. Self-monitoring declined in both modalities, but completion rates were higher in those who selected IVR. There were no associations between self-monitoring modality and weight or blood pressure outcomes. This is the first study to compare web and IVR self-monitoring in an eHealth intervention where participants could select and change their self-monitoring modality. IVR shows promise for achieving consistent engagement.


The contribution of trees to ecosystem methane emissions in a temperate forested wetland.
Wetland-adapted trees are known to transport soil-produced methane (CH4 ), an important greenhouse gas to the atmosphere, yet seasonal variations and controls on the magnitude of tree-mediated CH4 emissions remain unknown for mature forests. We examined the spatial and temporal variability in stem CH4 emissions in situ and their controls in two wetland-adapted tree species (Alnus glutinosa and Betula pubescens) located in a temperate forested wetland. Soil and herbaceous plant-mediated CH4 emissions from hollows and hummocks also were measured, thus enabling an estimate of contributions from each pathway to total ecosystem flux. Stem CH4 emissions varied significantly between the two tree species, with Alnus glutinosa displaying minimal seasonal variations, while substantial seasonal variations were observed in Betula pubescens. Trees from each species emitted similar quantities of CH4 from their stems regardless of whether they were situated in hollows or hummocks. Soil temperature and pore-water CH4 concentrations best explained annual variability in stem emissions, while wood-specific density and pore-water CH4 concentrations best accounted for between-species variations in stem CH4 emission. Our study demonstrates that tree-mediated CH4 emissions contribute up to 27% of seasonal ecosystem CH4 flux in temperate forested wetland, with the largest relative contributions occurring in spring and winter. Tree-mediated CH4 emissions currently are not included in trace gas budgets of forested wetland. Further work is required to quantify and integrate this transport pathway into CH4 inventories and process-based models.


Land-use emissions play a critical role in land-based mitigation for Paris climate targets.
Scenarios that limit global warming to below 2 °C by 2100 assume significant land-use change to support large-scale carbon dioxide (CO2) removal from the atmosphere by afforestation/reforestation, avoided deforestation, and Biomass Energy with Carbon Capture and Storage (BECCS). The more ambitious mitigation scenarios require even greater land area for mitigation and/or earlier adoption of CO2 removal strategies. Here we show that additional land-use change to meet a 1.5 °C climate change target could result in net losses of carbon from the land. The effectiveness of BECCS strongly depends on several assumptions related to the choice of biomass, the fate of initial above ground biomass, and the fossil-fuel emissions offset in the energy system. Depending on these factors, carbon removed from the atmosphere through BECCS could easily be offset by losses due to land-use change. If BECCS involves replacing high-carbon content ecosystems with crops, then forest-based mitigation could be more efficient for atmospheric CO2 removal than BECCS.


Effects of Melatonin and Bright Light Treatment in Childhood Chronic Sleep Onset Insomnia With Late Melatonin Onset: A Randomized Controlled Study.
Chronic sleep onset insomnia with late melatonin onset is prevalent in childhood, and has negative daytime consequences. Melatonin treatment is known to be effective in treating these sleep problems. Bright light therapy might be an alternative treatment, with potential advantages over melatonin treatment. In this study, we compare the effects of melatonin and bright light treatment with a placebo condition in children with chronic sleep onset insomnia and late melatonin onset. Eighty-four children (mean age 10.0 years, 61% boys) first entered a baseline week, after which they received melatonin (N = 26), light (N = 30), or placebo pills (N = 28) for 3 to 4 weeks. Sleep was measured daily with sleep diaries and actigraphy. Before and after treatment children completed a questionnaire on chronic sleep reduction, and Dim Light Melatonin Onset (DLMO) was measured. Results were analyzed with linear mixed model analyses. Melatonin treatment and light therapy decreased sleep latency (sleep diary) and advanced sleep onset (sleep diary and actigraphy), although for sleep onset the effects of melatonin were stronger. In addition, melatonin treatment advanced DLMO and had positive effects on sleep latency and sleep efficiency (actigraphy data), and sleep time (sleep diary and actigraphy data). However, wake after sleep onset (actigraphy) increased with melatonin treatment. No effects on chronic sleep reduction were found. We found positive effects of both melatonin and light treatment on various sleep outcomes, but more and stronger effects were found for melatonin treatment.


Health-related quality of life in low-income older African Americans.
This study examined the relationships among comorbid conditions, symptom stress, depression, functional status and health-related quality of life (HRQOL) in low-income older African Americans with chronic diseases. A convenience sample of 83 older African American adults living in subsidized housing for elders participated in the study. Data were collected in face-to-face interviews. Participants reported lower scores on HRQOL than the SF-36 norms for age 60 or older in the general U.S. population. Comorbid conditions, symptom distress, depression, and functional status significantly predicted both the physical (F = 38.92, p < .001) and mental (F = 23.21, p < .001) health components of HRQOL, accounting for 63% of variance in the SF-36 physical health score and 55% of the variance in the SF-36 mental health score. The findings suggested that developing interventions to assist older African Americans to better manage their symptoms and depression are of prime importance for improving HRQOL.


Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variants.
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is the name given to a family of parasite proteins that are inserted into the infected erythrocyte surface. Studies using agglutination assays have shown previously that PfEMP1 epitopes are extremely diverse. In a study in Kenya, 21 parasite isolates, including nine from children with severe malaria, were tested for agglutination by 33 pairs of plasma, 21 of which were from the corresponding children. Each plasma pair consisted of a sample taken at the time of disease (acute) and one taken 3 weeks later (convalescent). In agreement with previous studies, infection was generally followed by the induction of antibodies specific to the homologous parasite isolate. In addition however, the results show that (i) some isolates were agglutinated very frequently by heterologous plasma; (ii) unexpectedly, these frequently agglutinated isolates tended to be from individuals with severe malaria; (iii) an inverse relationship existed between the agglutination frequency of each parasite isolate in heterologous plasma and the agglutinating antibody repertoire of the homologous child at the time of disease; and (iv) A 3-month-old child apparently still carrying maternal antibodies was infected by a rarely agglutinated isolate. This child's plasma agglutinated all isolates at the time of disease, apart from the homologous isolate. These results support the idea that preexisting anti-PfEMP1 antibodies can select the variants that are expressed during a new infection and may suggest the existence of a dominant subset of PfEMP1 variants.


The mixed effects of migration: community-level migration and birthweight in Mexico.
Research on the relationship between migration and infant health in Mexico finds that migration has mixed impacts on the risk of low birthweight (LBW). Whereas the departure and absence of household and community members are harmful, remittances are beneficial. We extend this work by considering a different measure of infant health in addition to LBW: macrosomia (i.e., heavy birthweight), which is associated with infant, child, and maternal morbidities but has a different social risk profile from LBW. We link the 2008 and 2009 Mexican birth certificates with community data from the 2000 Mexican census to analyze the association between various dimensions of community-level migration (i.e., rates of out-migration, receipt of remittances, and return migration) and the risk of LBW and macrosomia. We examine this association using two sets of models which differ in the extent to which they account for endogeneity. We find that the health impacts of migration differ depending not only on the dimension of migration, but also on the measure of health, and that they are robust to potential sources of endogeneity. Whereas community remittances and return migration are associated with lower risk of LBW, they are associated with increased risk of macrosomia. By contrast, out-migration is associated with increased risk of LBW and lower risk of macrosomia. Our analysis of endogeneity suggests that bias resulting from unmeasured differences between communities with different levels of migration may result in an underestimate of the impacts of community migration on birthweight.


High vulnerability of juvenile Nathusius' pipistrelle bats (Pipistrellus nathusii) at wind turbines.
Large numbers of bats are killed by wind turbines globally, yet the specific demographic consequences of wind turbine mortality are still unclear. In this study, we compared characteristics of Nathusius' pipistrelles (Pipistrellus nathusii) killed at wind turbines (N = 119) to those observed within the live population (N = 524) during the summer migration period in Germany. We used generalized linear mixed-effects modeling to identify demographic groups most vulnerable to wind turbine mortality, including sex (female or male), age (adult or juvenile), and geographic origin (regional or long-distance migrant; depicted by fur stable hydrogen isotope ratios). Juveniles contributed with a higher proportion of carcasses at wind turbines than expected given their frequency in the live population suggesting that juvenile bats may be particularly vulnerable to wind turbine mortality. This effect varied with wind turbine density. Specifically, at low wind turbine densities, representing mostly inland areas with water bodies and forests where Nathusius' pipistrelles breed, juveniles were found more often dead beneath turbines than expected based on their abundance in the live population. At high wind turbine densities, representing mostly coastal areas where Nathusius' pipistrelles migrate, adults and juveniles were equally vulnerable. We found no evidence of increased vulnerability to wind turbines in either sex, yet we observed a higher proportion of females than males among both carcasses and the live population, which may reflect a female bias in the live population most likely caused by females migrating from their northeastern breeding areas migrating into Germany. A high mortality of females is conservation concern for this migratory bat species because it affects the annual reproduction rate of populations. A distant origin did not influence the likelihood of getting killed at wind turbines. A disproportionately high vulnerability of juveniles to wind turbine mortality may reduce juvenile recruitment, which may limit the resilience of Nathusius' pipistrelles to environmental stressors such as climate change or habitat loss. Schemes to mitigate wind turbine mortality, such as elevated cut-in speeds, should be implemented throughout Europe to prevent population declines of Nathusius' pipistrelles and other migratory bats.


A Neural Chronometry of Memory Recall.
Episodic memory allows us to mentally travel through time. How does the brain convert a simple reminder cue into a full-blown memory of past events and experiences? In this review, we integrate recent developments in the cognitive neuroscience of human memory retrieval, pinpointing the neural chronometry underlying successful recall. Electrophysiological recordings suggest that sensory cues proceed into the medial temporal lobe within the first 500 ms. At this point, a hippocampal process sets in, geared toward internal pattern completion and coordination of cortical memory reinstatement between 500 and 1500 ms. We further highlight the dynamic principles governing the recall process, which include a reversal of perceptual information flows, temporal compression, and theta clocking.


Haemoglobin (Hb) G-Philadelphia, Hb Stanleyville-II, Hb G-Norfolk, Hb Matsue-Oki and Hb Mizushi can form a panel of α-chain variants that overlap in their phenotype: the novel use of StyI to screen for Hb G-Philadelphia.
Haemoglobin (Hb) G-Philadelphia mutation is a common alpha-globin chain variant [α68(E17)Asn > Lys]. Combined high performance liquid chromatography (HPLC) and isoelectric focusing (IEF) can be used in a presumptive diagnosis of Hb G-Philadelphia, but there are other α-chain variants with a similar phenotype that cannot be excluded. Our aim was to develop a novel StyI restriction enzyme assay to diagnose the common Hb G-Philadelphia mutation and to identify any other variants with a similar phenotype by DNA sequencing. Thirty-one cases given a presumptive diagnosis as Hb G-Philadelphia by HPLC and IEF were subjected to DNA analysis by restriction enzyme digestion using StyI. Negative cases were then subjected to DNA sequencing. Twenty-two cases (78.6%) of 28 cases amplified were tested positive for Hb G-Philadelphia by StyI restriction digestion. Sequencing of the six negative cases revealed two cases of Hb G-Philadelphia with C→A mutation in codon 68 in α2 globin gene, plus one case each of Hb G-Norfolk Hb Stanleyville-II, Hb Matsue-Oki and Hb Mizushi. A novel StyI restriction enzyme can be used to confirm the commonest type of Hb G-Philadelphia. DNA sequencing identified four other α-chain variants with a similar HPLC and IEF phenotype.


Neural organization and responses to complex stimuli in the dorsal cochlear nucleus.
The dorsal division of the cochlear nucleus (DCN) is the most complex of its subdivisions in terms of both anatomical organization and physiological response types. Hypotheses about the functional role of the DCN in hearing are as yet primitive, in part because the organizational complexity of the DCN has made development of a comprehensive and predictive model of its input-output processing difficult. The responses of DCN cells to complex stimuli, especially filtered noise, are interesting because they demonstrate properties that cannot be predicted, without further assumptions, from responses to narrow band stimuli, such as tones. In this paper, we discuss the functional organization of the DCN, i.e. the morphological organization of synaptic connections within the nucleus and the nature of synaptic interactions between its cells. We then discuss the responses of DCN principal cells to filtered noise stimuli that model the spectral sound localization cues produced by the pinna. These data imply that the DCN plays a role in interpreting sound localization cues; supporting evidence for such a role is discussed.


Aer and Tsr guide Escherichia coli in spatial gradients of oxidizable substrates.
The Aer and Tsr chemoreceptors in Escherichia coli govern tactic responses to oxygen and redox potential that are parts of an overall behaviour known as energy taxis. They are also proposed to mediate responses to rapidly utilized carbon sources, glycerol and succinate, via the energy taxis mechanism. In this study, the Aer and Tsr proteins were individually expressed in an 'all-transducer-knockout' strain of E. coli and taxis was analysed in gradients of various oxidizable carbon sources. In addition to the known response to glycerol and succinate, it was found that Aer directed taxis towards ribose, galactose, maltose, malate, proline and alanine as well as the phosphotransferase system (PTS) carbohydrates glucose, mannitol, mannose, sorbitol and fructose, but not to aspartate, glutamate, glycine and arabinose. Tsr directed taxis towards sugars (including those transported by the PTS), but not to organic acids or amino acids. When a mutated Aer protein unable to bind the FAD cofactor was expressed in the receptor-less strain, chemotaxis was not restored to any substrate. Aer appears to mediate responses to rapidly oxidizable substrates, whether or not they are effective growth substrates, whereas Tsr appears to mediate taxis to substrates that support maximal growth, whether or not they are rapidly oxidizable. This correlates with the hypothesis that Aer and Tsr sense redox and proton motive force, respectively. Taken together, the results demonstrate that Aer and Tsr mediate responses to a broad range of chemicals and their attractant repertoires overlap with those of specialized chemoreceptors, namely Trg (ribose, galactose) and Tar (maltose).


Effects of maternal care on the development of midbrain dopamine pathways and reward-directed behavior in female offspring.
Variation within mesolimbic dopamine (DA) pathways has significant implications for behavioral responses to rewards, and previous studies have indicated long-term programming effects of early life stress on these pathways. In the current study, we examined the impact of natural variations in maternal care in Long Evans rats on the development of DA pathways in female offspring and the consequences for reward-directed behaviors. We found that tyrosine hydroxylase (TH) immunoreactivity in the ventral tegmental area was elevated by postnatal day 6 in response to maternal licking/grooming (LG), and that these effects were sustained into adulthood. Increased TH immunoreactivity was not found to be associated with altered epigenetic regulation or transcriptional activation of Th, but probably involved LG-associated changes in the differentiation of postnatal DA neurons through increased expression of Cdkn1c, and enhanced survival of DA projections through LG-associated increases in Lmx1b and brain-derived neurotrophic factor. At weaning, high-LG offspring had elevated DA receptor mRNA levels within the nucleus accumbens and increased conditioned place preference for a high-fat diet. In contrast, high-LG, as compared with low-LG, juvenile offspring had a reduced preference for social interactions with siblings, and haloperidol administration abolished group differences in conditioned place preference through a shift towards increased social preferences in high-LG offspring. The effects of maternal care on developing DA pathways and reward-directed behavior of female offspring that we have observed may play a critical role in the behavioral transmission of maternal LG from mother to daughter, and account for individual differences in the mesolimbic DA system.


Polarity of bacterial magnetotaxis is controlled by aerotaxis through a common sensory pathway.
Most motile bacteria navigate within gradients of external chemical stimuli by regulating the length of randomly oriented swimming episodes. Magnetotactic bacteria are characterized by chains of intracellular ferromagnetic nanoparticles and their ability to sense the geomagnetic field, which is believed to facilitate directed motion, but is not well understood at the behavioural and molecular level. Here, we show that cells of Magnetospirillum gryphiswaldense unexpectedly display swimming polarity that depends on aerotactic signal transduction through one of its four chemotaxis operons (cheOp1). Growth of cells in magnetic fields superimposed on oxygen gradients results in a gradual inherited bias of swimming runs with one of the cell poles leading, such that the resulting overall swimming direction of entire populations can be reversed by changes in oxygen concentration. These findings clearly show that there is a direct molecular link between aerotactic sensing and the determination of magnetotactic polarity, through the sensory pathway, CheOp1.


Evaluating State Space Discovery by Persistent Cohomology in the Spatial Representation System.
Persistent cohomology is a powerful technique for discovering topological structure in data. Strategies for its use in neuroscience are still undergoing development. We comprehensively and rigorously assess its performance in simulated neural recordings of the brain's spatial representation system. Grid, head direction, and conjunctive cell populations each span low-dimensional topological structures embedded in high-dimensional neural activity space. We evaluate the ability for persistent cohomology to discover these structures for different dataset dimensions, variations in spatial tuning, and forms of noise. We quantify its ability to decode simulated animal trajectories contained within these topological structures. We also identify regimes under which mixtures of populations form product topologies that can be detected. Our results reveal how dataset parameters affect the success of topological discovery and suggest principles for applying persistent cohomology, as well as persistent homology, to experimental neural recordings.


Regional risk of exporting cattle seropositive for bluetongue virus from the United States.
To create a stochastic model to quantify the risk that shipments of cattle from regions within the United States would contain animals seropositive for bluetongue virus and to determine shipment-level accuracy of serologic testing by use of a competitive ELISA (c-ELISA). 19,216 shipments containing 528,918 cattle and calves. Data were obtained on number of animals and state of origin of cattle in export shipments originating within the United States between January 1994 and March 2002. Probability distributions for size of export shipments were determined for all states within the United States, and distributions for agar gel immunodiffusion and c-ELISA accuracy (sensitivity and specificity) were determined from expert opinion and review of the literature. The model simulated selection of a shipment and then determined the probability that a threshold number or percentage of cattle within that shipment would have a positive c-ELISA result. Shipment-level sensitivity, specificity, positive-predictive value, and negative-predictive value were calculated. Substantial differences were evident in the regional probability of a shipment being declared positive, with shipments from northeastern states having the lowest probability and shipments from southwestern states having the highest probability. The c-ELISA had variable predictive values at the shipment level, depending on the threshold used and the prevalence of antibody-positive cattle within the region. Results from this study will aid importers in making scientifically based decisions regarding risk of importing antibody-positive cattle.


Evaluation of generic medical information accessed via mobile phones at the point of care in resource-limited settings.
Many mobile phone resources have been developed to increase access to health education in the developing world, yet few studies have compared these resources or quantified their performance in a resource-limited setting. This study aims to compare the performance of resident physicians in answering clinical scenarios using PubMed abstracts accessed via the PubMed for Handhelds (PubMed4Hh) website versus medical/drug reference applications (Medical Apps) accessed via software on the mobile phone. A two-arm comparative study with crossover design was conducted. Subjects, who were resident physicians at the University of Botswana, completed eight scenarios, each with multi-part questions. The primary outcome was a grade for each question. The primary independent variable was the intervention arm and other independent variables included residency and question. Within each question type there were significant differences in 'percentage correct' between Medical Apps and PubMed4Hh for three of the six types of questions: drug-related, diagnosis/definitions, and treatment/management. Within each of these question types, Medical Apps had a higher percentage of fully correct responses than PubMed4Hh (63% vs 13%, 33% vs 12%, and 41% vs 13%, respectively). PubMed4Hh performed better for epidemiologic questions. While mobile access to primary literature remains important and serves an information niche, mobile applications with condensed content may be more appropriate for point-of-care information needs. Further research is required to examine the specific information needs of clinicians in resource-limited settings and to evaluate the appropriateness of current resources in bridging location- and context-specific information gaps.


Demographic models and IPCC climate projections predict the decline of an emperor penguin population.
Studies have reported important effects of recent climate change on Antarctic species, but there has been to our knowledge no attempt to explicitly link those results to forecasted population responses to climate change. Antarctic sea ice extent (SIE) is projected to shrink as concentrations of atmospheric greenhouse gases (GHGs) increase, and emperor penguins (Aptenodytes forsteri) are extremely sensitive to these changes because they use sea ice as a breeding, foraging and molting habitat. We project emperor penguin population responses to future sea ice changes, using a stochastic population model that combines a unique long-term demographic dataset (1962-2005) from a colony in Terre Adélie, Antarctica and projections of SIE from General Circulation Models (GCM) of Earth's climate included in the most recent Intergovernmental Panel on Climate Change (IPCC) assessment report. We show that the increased frequency of warm events associated with projected decreases in SIE will reduce the population viability. The probability of quasi-extinction (a decline of 95% or more) is at least 36% by 2100. The median population size is projected to decline from approximately 6,000 to approximately 400 breeding pairs over this period. To avoid extinction, emperor penguins will have to adapt, migrate or change the timing of their growth stages. However, given the future projected increases in GHGs and its effect on Antarctic climate, evolution or migration seem unlikely for such long lived species at the remote southern end of the Earth.


Object naming at multiple hierarchical levels: a comparison of preschoolers with and without word-finding deficits.
According to the storage hypothesis (Kail & Leonard, 1986), word-finding deficits in young children are not the direct results of deficient retrieval strategies; they are a manifestation of a general delay in language development that affects lexical storage. In the current study, we explored one aspect of lexical storage, the hierarchical organization of the semantic system, in 13 preschoolers with word-finding deficits (WF) and 13 preschoolers with normal language abilities (ND), ranging in age from 3;3 to 6;7. The children named a series of objects at multiple levels of the noun hierarchy in response to contrast questions (e.g. for rose they were asked, 'Is this an animal?' to elicit plant [superordinate]; 'Is this a tree?' to elicit flower [basic]; 'Is this a dandelion?' to elicit rose [subordinate]). Both groups readily named at multiple levels, providing evidence of hierarchical organization of the lexicon. However, there were several differences between WF and ND groups that suggested that WF children did not have enough stored information to discriminate between similar semantic neighbours. We conclude (1) that hierarchical organization of the semantic lexicon is a robust developmental phenomenon, apparent in both ND and WF preschoolers and (2) that the word-finding deficits of preschoolers appear to reflect insufficient depth and breadth of storage elaboration rather than deficits in hierarchical semantic organization.


Efficacy of treatment modalities in refractive amblyopia.
The pediatric clinic of the State College of Optometry/University Optometric Center develops a yearly quality management plan to monitor patient care. One of the areas retrospectively reviewed for all outcomes is refractive amblyopia. A retrospective review of records was performed on patients diagnosed with refractive amblyopia. With the use of a prescribed protocol, each patient's progress was tracked for a period of 6 months. Major emphasis was placed on outcome as related to treatment modality. Treatment alternatives were optical correction alone, optical correction in conjunction with patching, and optical correction and patching with vision therapy. Improvement criteria included a 2-line increase in visual acuity on the Snellen chart and an increase of 20 seconds of arc of stereopsis, as measured by the Wirt circles. The groups that patched with correction and those that received vision therapy had similar visual acuity improvement's; however, the latter group had a significantly greater improvement in stereopsis. Both groups performed significantly better in both categories when compared to the group receiving optical correction alone. Though patching alone may be sufficient for improvement of visual acuity, binocular performance is significantly better when vision therapy is included in the treatment regimen.


Cidofovir efficacy in recurrent respiratory papillomatosis: a randomized, double-blind, placebo-controlled study.
We performed a prospective, double-blind, placebo-controlled, longitudinal adjuvant therapy trial to determine the efficacy of cidofovir in the treatment of severe recurrent respiratory papillomatosis (RRP). Although results of case series suggest that cidofovir may decrease the frequency and rapidity of papilloma regrowth, no blinded placebo-controlled studies have demonstrated efficacy. Adults and children (n = 19) with aggressive RRP received either active drug (cidofovir) or placebo. When surgical intervention was needed, drug or placebo was injected into affected areas after surgical removal of disease. The following measures were made at baseline and at 2-month intervals for the course of 12 months: Derkay papilloma severity grading scale, Voice Handicap Index, Health-Related Quality of Life, and total number of procedures performed over 12 months. At 2- and 12-month follow-ups, there was a significant (p < .05) improvement in the Derkay Severity Score within the cidofovir and placebo groups, but no difference between groups, and no difference between groups in the number of procedures performed. Significant improvement was found in Voice Handicap Index scores in the cidofovir group at the 12-month follow-up. No differences were seen in Health-Related Quality of Life. A randomized, blinded, placebo-controlled trial is necessary in the study of RRP, because the natural history of the disease can include remissions and reactivations. We found a significant improvement in the Derkay Severity Score 12 months after the baseline assessment in patients treated with cidofovir. This effect, however, was also seen in the placebo group. Accordingly, we were unable to provide proof of efficacy of cidofovir in the treatment of RRP.


Treating depression in older adults: challenges to implementing the recommendations of an expert panel.
Depression is increasingly recognized as a significant public health problem among older adults. Because the condition is highly treatable and currently undertreated among community-based older adults, late-life depression is an appropriate focus for disease prevention programs. We report findings from a recent project to review the scientific literature for published reports about treatment for depression among community-dwelling older adults and to recommend the interventions with proven effectiveness. We also summarize the research findings related to each recommended intervention and describe the elements of each. To show the difficulties involved in translating research into practice, we describe real-world experiences in implementing these evidence-based interventions in various community settings. Because depression among older people is viewed more and more as a public health problem, we suggest that partnerships of providers, patients, and policy makers be forged to overcome challenges related to funding, training, and implementing treatments for this condition.


Exploring the temporal dynamics of social facilitation in the Stroop task.
The importance of social context in affecting attention has recently been highlighted by the finding that the presence of a passive, nonevaluative confederate can improve selective attention. The underlying mechanism, however, remains unclear. In this paper, we argue that social facilitation can be caused by distractor inhibition. Two distinct sources of evidence are provided from an experiment employing the Stroop task with and without social presence. First, analysis of the response time (RT) distribution indicates that interference is reduced at relatively long RTs. This is consistent with an inhibitory mechanism, whose effects build up slowly. Further support is provided by showing that social facilitation is prevented by using short response-to-stimulus intervals that are thought to reduce cognitive control processes.


A comparison of treatment-seeking pathological gamblers based on preferred gambling activity.
To compare and contrast gamblers with different forms of problematic gambling activities. DESIGN, SETTING AND MEASUREMENTS: Pathological gamblers completed the Addiction Severity Index (ASI) and gambling questionnaires when initiating out-patient treatment. Participants (n = 347) were categorized by their most problematic form of gambling activity: sports, horse/dog-races, cards, slots and scratch/lottery tickets. Differences in demographics, gambling variables, and ASI composite scores were compared across groups. After controlling for demographic variables, the types of gamblers differed in severity of gambling, alcohol and psychiatric problems. Horse/dog-race gamblers were generally older, male and less educated; they began gambling regularly at a young age and spent relatively high amounts of money gambling. Sports gamblers were young males and had intermediary gambling problems; they had relatively high rates of current substance use but few psychiatric problems. Card players spent low to moderate amounts of time and money gambling, and they generally reported few alcohol problems and little psychiatric distress. Slot machine players were older and more likely to be female. Slot gamblers began gambling later in life, had high rates of bankruptcy and reported psychiatric difficulties. Scratch/lottery gamblers spent the least amount of money gambling, but they gambled the most frequently and had relatively severe alcohol and psychiatric symptoms. Gambling patterns and severity of psychosocial problems vary by form of problematic gambling, and these differences may influence treatment recommendations and outcomes.


Improving reproductive function in women with polycystic ovary syndrome with high-intensity interval training (IMPROV-IT): study protocol for a two-centre, three-armed randomised controlled trial.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age and the leading cause of anovulatory infertility. Women with PCOS have a 15-fold higher prevalence of infertility, compared with women without PCOS, independent of body mass index (BMI). A healthy lifestyle is recommended to improve overall health and fertility in PCOS but there is limited evidence on the isolated effects of exercise, especially for reproductive outcomes. Previous findings indicate superior metabolic health benefits after vigorous compared with moderate-intensity exercise. Our primary aim is to determine the effect of high-intensity interval training (HIT) on menstrual frequency, as a proxy of reproductive function, in women with PCOS. The study is a two-centre, randomised, controlled trial with three parallel groups. Women (n=64) from Trondheim (Norway) and Melbourne (Australia) with PCOS according to the Rotterdam criteria will be randomly allocated (1:1:1) to high-volume HIT, low-volume HIT or a control group with no exercise after stratifying for BMI < or ≥ 27 kg/m2 and study centre. Measurements for study end points will be undertaken at baseline, after a 16 week exercise intervention and at 12 months following baseline assessments. The primary outcome measure is menstruation frequency, measured as the number of self-reported menstrual bleedings divided by the number of expected menstrual bleedings during a 12-month period. Secondary outcome measurements include markers of cardiovascular, metabolic and reproductive health, as well as quality of life and adherence to and enjoyment of exercise. The Regional Committee Medical Research Ethics, Norway, and The Australian Catholic University Human Research Ethics Committee, Australia, have approved the trial protocol. This trial will provide new insight regarding the impact of exercise on fertility in PCOS. We expect this trial to contribute to new therapeutic exercise strategies as part of clinical care for women with PCOS. Clinical trial gov NCT02419482.


Mutation@A Glance: an integrative web application for analysing mutations from human genetic diseases.
Although mutation analysis serves as a key part in making a definitive diagnosis about a genetic disease, it still remains a time-consuming step to interpret their biological implications through integration of various lines of archived information about genes in question. To expedite this evaluation step of disease-causing genetic variations, here we developed Mutation@A Glance (http://rapid.rcai.riken.jp/mutation/), a highly integrated web-based analysis tool for analysing human disease mutations; it implements a user-friendly graphical interface to visualize about 40,000 known disease-associated mutations and genetic polymorphisms from more than 2600 protein-coding human disease-causing genes. Mutation@A Glance locates already known genetic variation data individually on the nucleotide and the amino acid sequences and makes it possible to cross-reference them with tertiary and/or quaternary protein structures and various functional features associated with specific amino acid residues in the proteins. We showed that the disease-associated missense mutations had a stronger tendency to reside in positions relevant to the structure/function of proteins than neutral genetic variations. From a practical viewpoint, Mutation@A Glance could certainly function as a 'one-stop' analysis platform for newly determined DNA sequences, which enables us to readily identify and evaluate new genetic variations by integrating multiple lines of information about the disease-causing candidate genes.


Does a Species' Extinction-Proneness Predict Its Contribution to Nestedness? A Test Using a Sunbird-Tree Visitation Network.
Animal pollinators and the plants they pollinate depend on networks of mutualistic partnerships and more broadly on the stability of such networks. Based mainly on insect-plant visitation networks, theory predicts that species that are most prone to extinction contribute the most to nestedness, however empirical tests are rare. We used a sunbird-tree visitation network within which were both extinction prone vs non extinction prone sunbird species to test the idea. We predicted that the extinction prone species would contribute the most to nestedness. Using local abundance as a proxy for extinction risk we considered that locally rare sunbird species, by virtue of their small population size and associated demographic stochasticity to be more at risk of extinction than the common species. Our network was not strongly nested and all sunbird species made similar contributions to nestedness, so that in our empirical test, extinction proneness did not predict contribution to nestedness. The consequences of this finding remain unclear. It may be that network theory based on plant-insect mutualisms is not widely applicable and does not work for tree- sunbird mutualistic networks. Alternatively it may be that our network was too small to provide results with any statistical power. Without doubt our study highlights the problems faced when testing network theory in the field; a plethora of ecological considerations can variously impact on results.


A Senescence Bystander Effect in Human Lung Fibroblasts.
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well established and several studies now describe a higher abundance of senescent fibroblasts and epithelial cells in the lungs of IPF patients compared with age-matched controls. The cause of this abnormal accumulation of senescent cells is unknown but evidence suggests that, once established, senescence can be transferred from senescent to non-senescent cells. In this study, we investigated whether senescent human lung fibroblasts (LFs) and alveolar epithelial cells (AECs) could induce a senescent-like phenotype in "naïve" non-senescent LFs in vitro. Primary cultures of LFs from adult control donors (Ctrl-LFs) with a low baseline of senescence were exposed to conditioned medium (CM) from: (i) Ctrl-LFs induced to become senescent using H2O2 or etoposide; (ii) LFs derived from IPF patients (IPF-LFs) with a high baseline of senescence; or (iii) senescence-induced A549 cells, an AEC line. Additionally, ratios of non-senescent Ctrl-LFs and senescence-induced Ctrl-LFs (100:0, 0:100, 50:50, 90:10, 99:1) were co-cultured and their effect on induction of senescence measured. We demonstrated that exposure of naïve non-senescent Ctrl-LFs to CM from senescence-induced Ctrl-LFs and AECs and IPF-LFs increased the markers of senescence including nuclear localisation of phosphorylated-H2A histone family member X (H2AXγ) and expression of p21, IL-6 and IL-8 in Ctrl-LFs. Additionally, co-cultures of non-senescent and senescence-induced Ctrl-LFs induced a senescent-like phenotype in the non-senescent cells. These data suggest that the phenomenon of "senescence-induced senescence" can occur in vitro in primary cultures of human LFs, and provides a possible explanation for the abnormal abundance of senescent cells in the lungs of IPF patients.


Global Imperative of Suicidal Ideation in 10 Countries Amid the COVID-19 Pandemic.
Background: The novel coronavirus (COVID-19) has had a detrimental impact on individuals' psychological well-being; however, a multi-country comparison on the prevalence of suicidal ideation due to the virus is still lacking. Objectives: To examine the prevalence and correlates of suicidal ideation among the general population across 10 countries during the COVID-19 pandemic. Materials and methods: This was a cross-sectional study which used convenience sampling and collected data by conducting an online survey. Participants were sourced from 10 Eastern and Western countries. The Patient Health Questionnaire (PHQ-9) was used to measure the outcome variable of suicidal ideation. Ordinal regression analysis was used to identify significant predictors associated with suicidal ideation. Results: A total of 25,053 participants (22.7% male) were recruited. Results from the analysis showed that the UK and Brazil had the lowest odds of suicidal ideation compared to Macau (p < 0.05). Furthermore, younger age, male, married, and differences in health beliefs were significantly associated with suicidal ideation (p < 0.05). Conclusions: The findings highlight the need for joint international collaboration to formulate effective suicide prevention strategies in a timely manner and the need to implement online mental health promotion platforms. In doing so, the potential global rising death rates by suicide during the pandemic can be reduced.


Proton-coupled electron transfer reactions: analytical rate constants and case study of kinetic isotope effects in lipoxygenase.
A general theory has been developed for proton-coupled electron transfer (PCET), which is vital to a wide range of chemical and biological processes. This theory describes PCET reactions in terms of nonadiabatic transitions between reactant and product electron-proton vibronic states and includes the effects of thermal fluctuations of the solvent or protein environment, as well as the proton donor-acceptor motion. Within the framework of this general PCET theory, a series of analytical rate constant expressions has been derived for PCET reactions in well-defined regimes. Herein, the application of this theory to PCET in the enzyme soybean lipoxygenase illustrates the regimes of validity for the various rate constant expressions and elucidates the fundamental physical principles dictating PCET reactions. Such theoretical studies provide significant physical insights that guide the interpretation of experimental data and lead to experimentally testable predictions. A combination of theoretical treatments with atomic-level simulations is essential to understanding PCET.


Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood.
Due to a dismal prognosis of advanced lung cancer, novel screening tools and more effective treatments are clearly needed. Lately, an increasing number of tumour-released angiogenic cytokines which affect vessel formation, tumour growth, invasion, and metastasis have been identified. Vascular endothelial growth factors (VEGFs) and basic fibroblast growth factor (bFGF) are among the most important angiogenic factors. Based on available literature, we have explored the mechanisms of angiogenesis and its prognostic significance in non-small cell lung cancer, estimated by microvessel density (MVD) and the presence of VEGF and bFGF in the tumour and blood from NSCLC patients. Several comprehensive Pubmed searches for the period January 1993 to May 2005 were performed using strategic combinations of the terms non-small cell lung cancer, angiogenesis, vascular endothelial growth factor, basic fibroblast growth factor, tumour expression, microvessel density, circulating, and serum. NSCLC neoangiogenesis, as measured by MVD, and tumour expression of VEGF are poor prognostic factors for survival (MVD, HR 1.8-2.0; VEGF, HR 1.5). bFGF tumour expression is also associated with poor survival and more aggressive disease. When evaluating the prognostic impact of elevated VEGF levels in blood, 10 of 16 studies (63%) indicated a negative prognostic impact. Of five studies on the prognostic value of circulating bFGF, three studies reported a negative prognostic impact, while one indicated bFGF as a good prognostic factor and one was inconclusive. Angiogenic factors are poor prognostic indicators for tumour aggressiveness and survival in NSCLC. Assessments of circulating levels of VEGF and possibly bFGF may be valuable future tools for treatment planning and monitoring of treatment effect and relapse. First, however, these blood tests need to be standardised and validated in large-scale prospective clinical trials.


To evaluate the effect of combining photo-activation therapy with platelet-rich plasma injections for the novel treatment of osteoarthritis.
To evaluate the effect of combining photo-activation therapy with platelet-rich plasma injections for the novel treatment of osteoarthritis. We present a case report of osteoarthritis of the knee treated with photo-activated platelet-rich plasma injections (PAPRP). After utilising conventional osteoarthritis treatment methods a patient underwent a course of PAPRP injections. The patient outcome was measured using the numerical pain rating scale (NPRS) and the Western Ontario and McMaster Universities Arthritis (WOMAC) Index. Following treatment the patient reported improvements in both pain and function as measured by the NPRS and WOMAC Index, respectively. The patient was followed up for 18 weeks, at which time no significant complications were noted. In this case report of osteoarthritis, with strict control of conventional therapy variables, PAPRP injections demonstrated improvement in all recorded outcome measures. The results of this case report highlight the need to further investigate the use of PAPRP in the treatment of symptomatic knee osteoarthritis.


A preliminary study on methylphenidate-regulated gene expression in lymphoblastoid cells of ADHD patients.
Methylphenidate (MPH) is a commonly used stimulant medication for treating attention-deficit/hyperactivity disorder (ADHD). Besides inhibiting monoamine reuptake there is evidence that MPH also influences gene expression directly. We investigated the impact of MPH treatment on gene expression levels of lymphoblastoid cells derived from adult ADHD patients and healthy controls by hypothesis-free, genome-wide microarray analysis. Significant findings were subsequently confirmed by quantitative Real-Time PCR (qRT PCR) analysis. The microarray analysis from pooled samples after correction for multiple testing revealed 138 genes to be marginally significantly regulated due to MPH treatment, and one gene due to diagnosis. By qRT PCR we could confirm that GUCY1B3 expression was differential due to diagnosis. We verified chronic MPH treatment effects on the expression of ATXN1, HEY1, MAP3K8 and GLUT3 in controls as well as acute treatment effects on the expression of NAV2 and ATXN1 specifically in ADHD patients. Our preliminary results demonstrate MPH treatment differences in ADHD patients and healthy controls in a peripheral primary cell model. Our results need to be replicated in larger samples and also using patient-derived neuronal cell models to validate the contribution of those genes to the pathophysiology of ADHD and mode of action of MPH.


Identification of herpes simplex virus type 1 latency-associated transcript sequences that both inhibit apoptosis and enhance the spontaneous reactivation phenotype.
The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) gene is essential for the high spontaneous and induced reactivation phenotype of HSV-1 in the rabbit ocular model and for the high induced reactivation phenotype in the mouse ocular model. Recently we showed that LAT has an antiapoptosis function, and we hypothesized that LAT's ability to inhibit apoptosis played an important role in LAT's ability to enhance the reactivation phenotype. Expression of just the first 1.5 kb of the 8.3-kb LAT gene is sufficient for both inhibition of apoptosis in an in vitro transient-transfection assay and the high spontaneous reactivation phenotype in vivo. Here we show the results of more complex mapping studies in which inhibition of apoptosis and the enhanced spontaneous reactivation phenotype also appear to be linked. The HSV-1 mutant virus dLAT371 has a high spontaneous reactivation phenotype in rabbits, suggesting that the LAT region deleted in this mutant (LAT nucleotides 76 to 447) is not required for this phenotype. The LAT3.3A viral mutant (which expresses LAT nucleotides 1 to 1499) also has a high spontaneous reactivation phenotype, suggesting that the region of LAT not expressed by this mutant (LAT nucleotide 1500 to the end of LAT) is also not required for this phenotype. Surprisingly, LAT2.9A, which is a combination of dLAT371 and LAT3.3A (i.e., it expresses LAT nucleotides 1 to 76 and 447 to 1499), has a low spontaneous reactivation phenotype indistinguishable from that of LAT null mutants. We report here that consistent with the low spontaneous reactivation phenotype of LAT2.9A, a plasmid expressing the identical LAT RNA did not inhibit caspase 9-induced apoptosis. In contrast, plasmids containing the same deletion but able to transcribe up to or past LAT nucleotide 2850 (rather than just up to LAT nucleotide 1499) inhibited caspase 9-induced apoptosis, consistent with the high spontaneous reactivation phenotype of dLAT371. Thus, LAT2.9A may have a low spontaneous reactivation phenotype because the LAT RNA that is made cannot block apoptosis, and dLAT371 apparently has a high spontaneous reactivation phenotype because the LAT RNA made has significant antiapoptosis activity. Furthermore, LAT appeared to have at least two regions capable of interfering with caspase 9-induced apoptosis. One region partially overlaps LAT nucleotides 76 to 447. The second region is partially (or completely) downstream of LAT nucleotide 1499.


MicroRNA-9 coordinates proliferation and migration of human embryonic stem cell-derived neural progenitors.
Human pluripotent stem cells offer promise for use in cell-based therapies for brain injury and diseases. However, their cellular behavior is poorly understood. Here we show that the expression of the brain-specific microRNA-9 (miR-9) is turned on in human neural progenitor cells (hNPCs) derived from human embryonic stem cells. Loss of miR-9 suppressed proliferation but promoted migration of hNPCs cultured in vitro. hNPCs without miR-9 activity also showed enhanced migration when transplanted into mouse embryonic brains or adult brains of a mouse model of stroke. These effects were not due to precocious differentiation of hNPCs. One of the key targets directly regulated by miR-9 encodes stathmin, which increases microtubule instability and whose expression in hNPCs correlates inversely with that of miR-9. Partial inhibition of stathmin activity suppressed the effects of miR-9 loss on proliferation and migration of human or embryonic rat neural progenitors. These results identify miR-9 as a novel regulator that coordinates the proliferation and migration of hNPCs.


Quantitative gene profiling of long noncoding RNAs with targeted RNA sequencing.
We compared quantitative RT-PCR (qRT-PCR), RNA-seq and capture sequencing (CaptureSeq) in terms of their ability to assemble and quantify long noncoding RNAs and novel coding exons across 20 human tissues. CaptureSeq was superior for the detection and quantification of genes with low expression, showed little technical variation and accurately measured differential expression. This approach expands and refines previous annotations and simultaneously generates an expression atlas.


Fish oil and cod liver as safe and healthy food supplements.
The aim of this study is to determine the content of mercury, methylmercury and persistent organic pollutants in the capsules filled with fish oil from marine fish and in the canned cod liver and find out, whether analyse products are safe and suitable for human consumption. Total mercury was determined by cold vapour atomic absorption spectroscopy on an AMA-254 (Altec Ltd., Czech Republic) single-purpose mercury analyzer. Methylmercury in the cod liver in the form of chlorid methylmercury was determined by gas chromatography. Seven indicator congeners of PCB (PCB 28, 52, 101, 118, 138, 153, 180), HCH, HCB, DDT and its degradation products DDE and DDD, were determined by gas chromatography-mass spectrometry. In capsules filled with fish oil (n=19) total Hg levels were in the range of 0.013 to 2.03 ng/g. All the capsule oil samples analyzed for MeHg were below the detection limit. The highest concentration of total Hg was found in cod liver - can A (0.223 ng/g). The maximum percentage of MeHg in total Hg concentration was found in a liver sample - can B. The values of alpha-, beta-, gamma-, delta- HCH and of HCB were found below the detection limits in all the capsule samples analyzed. In eight capsules, the presence of highly lipophilic PCB congeners was demonstrated. DDT and its important DDE metabolite were found in ten samples. In canned cod liver the highest concentration of all PCB congeners was demonstrated in can D. The lowest congener concentrations, however, were found in smoked cod liver - can C. DDT with its main metabolite DDE was detected in can C. No additional DDT and DDD persistent pollutants were detected. The consumption of fish oil in capsules, and canned cod liver is safe and healthy and should be encouraged.


Serum Proenkephalin A Levels and Mortality After Long-Term Follow-Up in Patients with Type 2 Diabetes Mellitus (ZODIAC-32).
Two previous studies concluded that proenkephalin A (PENK-A) had predictive capabilities for stroke severity, recurrent myocardial infarction, heart failure and mortality in patients with stroke and myocardial infarction. This study aimed to investigate the value of PENK-A as a biomarker for predicting mortality in patients with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus were included from the prospective observational ZODIAC (Zwolle Outpatient Diabetes project Integrating Available Care) study. The present analysis incorporated two ZODIAC cohorts (1998 and 2001). Since blood was drawn for 1204 out of 1688 patients (71%), and information on relevant confounders was missing in 47 patients, the final sample comprised 1157 patients. Cox proportional hazard models were used for evaluating the relationship between PENK-A and (cardiovascular) mortality. Risk prediction capabilities were assessed with Harrell's C statistics and the integrated discrimination improvement (IDI). After a follow-up period of 14 years, 525 (45%) out of 1157 patients had died, of which 224 (43%) were attributable to cardiovascular factors. Higher Log PENK-A levels were not independently associated with increased (cardiovascular) mortality. Patients with PENK-A values in the highest tertile had a 49% (95%CI 1%-121%) higher risk of cardiovascular mortality compared to patients in the reference category (lowest tertile). C-values were not different after removing PENK-A from the Cox models and there were no significant differences in IDI values. The associations between PENK-A and mortality were strongly attenuated after accounting for all traditional risk factors. Furthermore, PENK-A did not seem to have additional value beyond conventional risk factors when predicting all-cause and cardiovascular mortality.


Cavitation and contrast: the use of bubbles in ultrasound imaging and therapy.
Microbubbles and cavitation are playing an increasingly significant role in both diagnostic and therapeutic applications of ultrasound. Microbubble ultrasound contrast agents have been in clinical use now for more than two decades, stimulating the development of a range of new contrast-specific imaging techniques which offer substantial benefits in echocardiography, microcirculatory imaging, and more recently, quantitative and molecular imaging. In drug delivery and gene therapy, microbubbles are being investigated/developed as vehicles which can be loaded with the required therapeutic agent, traced to the target site using diagnostic ultrasound, and then destroyed with ultrasound of higher intensity energy burst to release the material locally, thus avoiding side effects associated with systemic administration, e.g. of toxic chemotherapy. It has moreover been shown that the motion of the microbubbles increases the permeability of both individual cell membranes and the endothelium, thus enhancing therapeutic uptake, and can locally increase the activity of drugs by enhancing their transport across biologically inaccessible interfaces such as blood clots or solid tumours. In high-intensity focused ultrasound (HIFU) surgery and lithotripsy, controlled cavitation is being investigated as a means of increasing the speed and efficacy of the treatment. The aim of this paper is both to describe the key features of the physical behaviour of acoustically driven bubbles which underlie their effectiveness in biomedical applications and to review the current state of the art.


Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling.
Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor-induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b(+) conventional DCs (cDCs), CD8(+) cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow-derived DCs (BMDCs) displayed enhanced production of TNF-α, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP-deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP(+/-) macrophages. Additionally, the increased activation in c-FLIP-deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity.


Factors associated with positive D-dimer results in patients evaluated for pulmonary embolism.
Available D-dimer assays have low specificity and may increase radiographic testing for pulmonary embolism (PE). To help clinicians better target testing, this study sought to quantify the effect of risk factors for a positive quantitative D-dimer in patients evaluated for PE. This was a prospective, multicenter, observational study. Emergency department (ED) patients evaluated for PE with a quantitative D-dimer were eligible for inclusion. The main outcome of interest was a positive D-dimer. Odds ratio (ORs) and 95% confidence intervals (CIs) were determined by multivariable logistic regression. Adjusted estimates of relative risk were also calculated. A total of 4,346 patients had D-dimer testing, of whom 2,930 (67%) were women. A total of 2,500 (57%) were white, 1,474 (34%) were black or African American, 238 (6%) were Hispanic, and 144 (3%) were of other race or ethnicity. The mean (+/-SD) age was 48 (+/-17) years. Overall, 1,903 (44%) D-dimers were positive. Model fit was adequate (c-statistic = 0.739, Hosmer and Lemeshow p-value = 0.13). Significant positive predictors of D-dimer positive included female sex; increasing age; black (vs. white) race; cocaine use; general, limb, or neurologic immobility; hemoptysis; hemodialysis; active malignancy; rheumatoid arthritis; lupus; sickle cell disease; prior venous thromboembolism (VTE; not under treatment); pregnancy and postpartum state; and abdominal, chest, orthopedic, or other surgery. Warfarin use was protective. In contrast, several variables known to be associated with PE were not associated with positive D-dimer results: body mass index (BMI), estrogen use, family history of PE, (inactive) malignancy, thrombophilia, trauma within 4 weeks, travel, and prior VTE (under treatment). Many factors are associated with a positive D-dimer test. The effect of these factors on the usefulness of the test should be considered prior to ordering a D-dimer.


Recognition-mediated particle detection under microfluidic flow with waveguide-coupled 2D photonic crystals: towards integrated photonic virus detectors.
Label-free biodetection schemes compatible with standard CMOS fabrication methods constitute an important goal, as these are enabling tools for the mass production of high-sensitivity biosensors. Two-dimensional slab photonic crystal (2D slab-PhC) sensors have been posited as ultrahigh-sensitivity detection components, but to date recognition-mediated detection of viruses or simulants under flow has not been demonstrated. We report the design and optimization of a new W1 waveguide-coupled 2D slab-PhC sensor, with a geometry well suited to virus detection. Proof of concept experiments with fluorescent latex particles verified that the sensor could respond to infiltration of a single particle, both in air and under an aqueous cover layer. Subsequent experiments with antibody-functionalized sensors and virus simulants confirmed the ability of the device to detect virus-sized particles under flow via a recognition-mediated process. This work sets the stage for incorporation of 2D slab-PhC sensors into fully integrated photonic sensor systems.


Cortisol-induced enhancement of emotional face processing in social phobia depends on symptom severity and motivational context.
We investigated the effects of cortisol administration on approach and avoidance tendencies in 20 patients with social anxiety disorder (SAD). Event-related brain potentials (ERPs) were measured during a reaction time task, in which patients evaluated the emotional expression of photographs of happy and angry faces by making an approaching (flexion) or avoiding (extension) arm movement. Patients showed significant avoidance tendencies for angry but not for happy faces, both in the placebo and cortisol condition. Moreover, ERP analyses showed a significant interaction of condition by severity of social anxiety on early positive (P150) amplitudes during avoidance compared to approach, indicating that cortisol increases early processing of social stimuli (in particular angry faces) during avoidance. This result replicates previous findings from a non-clinical sample of high anxious individuals and demonstrates their relevance for clinical SAD. Apparently the cortisol-induced increase in processing of angry faces in SAD depends on symptom severity and motivational context.


The AT(N) framework for Alzheimer's disease in adults with Down syndrome.
The National Institute on Aging in conjunction with the Alzheimer's Association (NIA-AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which to select and enrich samples for clinical trials. This new framework is highly flexible and allows the addition of newly confirmed AD biomarkers into the existing AT(N) groups. As biomarkers for other pathological processes are validated, they can also be added to the AT(N) classification scheme, which will allow for better characterization and staging of AD in DS. These biological classifications can then be merged with clinical staging for an examination of factors that impact the biological and clinical progression of the disease. Here, we leverage previously published guidelines for the AT(N) framework to generate such a plan for AD among adults with DS.


Nitric Oxide and Mechano-Electrical Transduction in Cardiomyocytes.
The ability§ of the heart to adapt to changes in the mechanical environment is critical for normal cardiac physiology. The role of nitric oxide is increasingly recognized as a mediator of mechanical signaling. Produced in the heart by nitric oxide synthases, nitric oxide affects almost all mechano-transduction pathways within the cardiomyocyte, with roles mediating mechano-sensing, mechano-electric feedback (via modulation of ion channel activity), and calcium handling. As more precise experimental techniques for applying mechanical stresses to cells are developed, the role of these forces in cardiomyocyte function can be further understood. Furthermore, specific inhibitors of different nitric oxide synthase isoforms are now available to elucidate the role of these enzymes in mediating mechano-electrical signaling. Understanding of the links between nitric oxide production and mechano-electrical signaling is incomplete, particularly whether mechanically sensitive ion channels are regulated by nitric oxide, and how this affects the cardiac action potential. This is of particular relevance to conditions such as atrial fibrillation and heart failure, in which nitric oxide production is reduced. Dysfunction of the nitric oxide/mechano-electrical signaling pathways are likely to be a feature of cardiac pathology (e.g., atrial fibrillation, cardiomyopathy, and heart failure) and a better understanding of the importance of nitric oxide signaling and its links to mechanical regulation of heart function may advance our understanding of these conditions.


Financial barriers and pricing strategies related to participation in sports activities: the perceptions of people of low income.
Physical activity levels in most affluent countries are low and many people do not meet the current recommendations. Particularly for people with a low income, economic strategies seem promising to stimulate taking part in sports activities. This study investigated the importance of economic restraints for taking part in sports activities as well as perceptions of low-income people toward different pricing interventions. A qualitative study was conducted, using semistructured, individual interviews with 27 low-income men and women. The framework approach was used to analyze the transcripts of the interviews. The respondents considered finances to be an important barrier for participating in sports activities, together with some individual barriers. Promising pricing strategies are a discount on the subscription to the fitness or sports club, a 1 month free trial, and free entrance to the swimming pool once a week. Pricing strategies may be a promising intervention to increase physical activity levels of low-income people. However, this study indicates that this should be coupled with an intervention directed at individual barriers. Some pricing strategies will be used and appreciated more by low-income people than other pricing strategies. In addition, pricing strategies should be tailored to individual needs and preferences.


Local entrapment of interferon gamma in the recovery from Shigella dysenteriae type 1 infection.
In healthy controls (n = 8) living in shigella endemic areas, accumulation of interferon gamma (IFN gamma) in the epithelial lining was seen in the rectal tissues. At the single cell level, however, few or no IFN gamma protein producing cells or mRNA expressing cells were detected at that site indicating the involvement of the whole large intestine in the production of IFN gamma in controls. Persistent numbers of IFN gamma producing cells were detected in the rectum of patients with Shigella dysenteriae type 1 infection (n = 8) throughout the course of disease with a tendency to increase in the convalescent stage. A significantly increased extra cellular deposition of secreted IFN gamma in tissue was seen in convalescence when compared with the acute stage (p < 0.05). In addition, enzyme immunoassay showed increased stool concentration of IFN gamma in patients at the convalescent stage as well as in healthy controls. In situ hybridisation confirmed the results by showing increased frequency of IFN gamma mRNA containing cells at the late stage of the disease (p < 0.05). Extensive message for IFN gamma was evident in cells in the lamina propria with no detectable transcripts in the surface epithelium. A colocalisation of IFN gamma with the IFN gamma receptor expression, predominantly found in the epithelial lining was detected by immunohistochemistry. Semiquantitative evaluation by computerised image analysis showed a gradual increased expression of IFN gamma and its corresponding receptor in the convalescent stage of shigellosis. This suggested progressive entrapment and binding of IFN gamma to its specific receptor at the local site. The enhanced surface expression of IFN gamma receptor evident at the convalescent stage of shigellosis was comparable to the constitutive level of expression in the healthy subjects. Thus, immunity to shigellosis correlated to up-regulation of IFN gamma production and expression of IFN gamma receptor.


T2-weighted four dimensional magnetic resonance imaging with result-driven phase sorting.
T2-weighted MRI provides excellent tumor-to-tissue contrast for target volume delineation in radiation therapy treatment planning. This study aims at developing a novel T2-weighted retrospective four dimensional magnetic resonance imaging (4D-MRI) phase sorting technique for imaging organ/tumor respiratory motion. A 2D fast T2-weighted half-Fourier acquisition single-shot turbo spin-echo MR sequence was used for image acquisition of 4D-MRI, with a frame rate of 2-3 frames/s. Respiratory motion was measured using an external breathing monitoring device. A phase sorting method was developed to sort the images by their corresponding respiratory phases. Besides, a result-driven strategy was applied to effectively utilize redundant images in the case when multiple images were allocated to a bin. This strategy, selecting the image with minimal amplitude error, will generate the most representative 4D-MRI. Since we are using a different image acquisition mode for 4D imaging (the sequential image acquisition scheme) with the conventionally used cine or helical image acquisition scheme, the 4D dataset sufficient condition was not obviously and directly predictable. An important challenge of the proposed technique was to determine the number of repeated scans (NR) required to obtain sufficient phase information at each slice position. To tackle this challenge, the authors first conducted computer simulations using real-time position management respiratory signals of the 29 cancer patients under an IRB-approved retrospective study to derive the relationships between NR and the following factors: number of slices (NS), number of 4D-MRI respiratory bins (NB), and starting phase at image acquisition (P0). To validate the authors' technique, 4D-MRI acquisition and reconstruction were simulated on a 4D digital extended cardiac-torso (XCAT) human phantom using simulation derived parameters. Twelve healthy volunteers were involved in an IRB-approved study to investigate the feasibility of this technique. 4D data acquisition completeness (Cp) increases as NR increases in an inverse-exponential fashion (Cp = 100 - 99 × exp(-0.18 × NR), when NB = 6, fitted using 29 patients' data). The NR required for 4D-MRI reconstruction (defined as achieving 95% completeness, Cp = 95%, NR = NR,95) is proportional to NB (NR,95 ∼ 2.86 × NB, r = 1.0), but independent of NS and P0. Simulated XCAT 4D-MRI showed a clear pattern of respiratory motion. Tumor motion trajectories measured on 4D-MRI were comparable to the average input signal, with a mean relative amplitude error of 2.7% ± 2.9%. Reconstructed 4D-MRI for healthy volunteers illustrated clear respiratory motion on three orthogonal planes, with minimal image artifacts. The artifacts were presumably caused by breathing irregularity and incompleteness of data acquisition (95% acquired only). The mean relative amplitude error between critical structure trajectory and average breathing curve for 12 healthy volunteers is 2.5 ± 0.3 mm in superior-inferior direction. A novel T2-weighted retrospective phase sorting 4D-MRI technique has been developed and successfully applied on digital phantom and healthy volunteers.


The development of visuo-spatial working memory.
Children's performance on tests of visuo-spatial working memory improves with age, although relatively little is known about why this happens. One explanation concerns the development of the ability to recode visually presented information into phonological form. This process appears to be used from around 8 years of age and is a major contributor to tasks in which stimuli can be verbally labelled. However, evidence suggests that phonological recoding cannot account for all of the age-related change in performance on visuo-spatial working memory tasks. In this review, four other mechanisms (knowledge, processing strategies, processing speed, and attentional capacity) are considered in terms of their contribution to children's visuo-spatial working memory development.


Bipolar disorder and comorbid attention deficit hyperactivity disorder. A distinct clinical phenotype? Clinical characteristics and temperamental traits.
It has been suggested that bipolar disorder (BD) with comorbid ADHD represents a distinct clinical phenotype of BD. There are no data regarding potential heterogeneity between BD subjects with a diagnosis of ADHD in childhood whose ADHD remitted in adulthood (cADHD-BD) vs. BD patients with persistent ADHD diagnosis in adulthood (aADHD-BD). This heterogeneity may constitute a confounder in investigations of the nature of the co-occurrence between BD and ADHD. The aim of this paper is to compare BD patients without ADHD, to those with aADHD-BD, and those with cADHD-BD on clinical and temperamental characteristics, hypothesizing that maladaptive temperament will be increased in BD subjects with a stable diagnosis of ADHD in adulthood compared to those whose ADHD remitted. We further hypothesize that maladaptive temperament will be associated with the severity of both illnesses. A total of 100 outpatients (aged 18-30 years) with BD in remission were included. The assessment of ADHD was made according to a procedure aimed to reduce potential recall biases. Subjects had to have a parent available and had never been treated with stimulants. Temperamental traits were assessed with the California Child Q-sort (CCQ) and the Early Adolescent Temperament Questionnaire (EATQ). Rate of co-occurrence of ADHD-BD was 18% lifetime and 10% current diagnosis. Patients with ADHD-BD (aADHD-BD+cADHD-BD) reported a significantly earlier onset of mood disorder, higher number of previous mood episodes, and significantly higher impulsivity than BD patients without ADHD. aADHD-BD showed a significantly earlier BD onset, higher number of previous mood episodes, higher impulsivity, decreased Reactive Control and higher Negative Emotionality temperamental scores than cADHD patients. Findings suggest that patients with aADHD-BD present a clinical phenotype distinct from that of patients with BD without ADHD or with a childhood ADHD diagnosis that remitted with the age. This appealing hypothesis of a BD-distinct phenotype that can be detected early due to its associated maladaptive temperamental traits requires further investigation in larger samples, supported by neuropsychological, genetic and imaging data.


Identification of Amyloidogenic Regions in the Spine of Insulin Fibrils.
To reveal conformational changes resulting in the formation of insulin fibrils, it is necessary to identify amyloidogenic regions in the structure of protein monomers. Different models of insulin fibrillogenesis have been proposed previously. However, precise regions responsible for the formation of amyloid fibrils have not been identified. Using bioinformatics programs for predicting amyloidogenic regions, we have determined some common amyloidogenic sequences in the structure of insulin monomers. The use of limited proteolysis and mass spectrometry analysis of the obtained protein fragments resistant to the action of proteases allowed us to identify amino acid sequences in the insulin structure that can form the spine of the insulin fibrils. The obtained results are in agreement with the earlier proposed model of fibril formation from the ring-like oligomers and can be used for designing insulin analogs resistant to amyloidogenesis.


Consensus on interprofessional collaboration in hospitals: statistical agreement of ratings from ethnographic fieldwork and measurement scales.
Few methods are available for analysing psychometric properties of combined qualitative and quantitative data. While conventional reliability of measures - meaning reproducibility or consistency - may not be meaningful in small-N research, in some health services studies agreement on perceptions arising from data generated by fieldwork and quantitative measures can be examined to good effect. We studied interprofessional collaboration (IPC) in seven hospitals. An ethnographer shadowed and conducted interviews with regulated health professionals in medicine wards. Concurrently, nurses completed the nurse-doctor relations subscale of the Nursing Work Index (NWI-NDRS) and a new measurement scale for IPC with doctors in the domains of communication, accommodation, and isolation. After fieldwork, the ethnographer rank-ordered hospital sites on IPC from 1 to 7 based on interpretation of the qualitative data. Mean-scale scores were calculated for hospital sites and converted to ranks similarly. The Tinsley-Weiss T-index (Tinsley & Weiss, 1975) for agreement among rank orderings was calculated for dyadic combinations of fieldwork and measurement ranks. Perfect agreement was obtained for the most liberal agreement definitions considered - differences of two rank positions - involving qualitative data agreement with IPC subscales for accommodation and isolation. Defining agreement as a difference of 1 rank at most, the T-index was 0.77 for agreement between fieldworker and IPC accommodation and the same for NWI-NDRS and IPC isolation. Qualitative data from fieldwork rankings were substantially in accord with the contemporary IPC scales, less so with the NWI-NDRS. Qualitative data appear to be useful as an additional approach to confirming the validity of quantitative scale data in measuring a complex interpersonal relational construct.


Pharmacologic overview of Withania somnifera, the Indian Ginseng.
Withania somnifera, also called 'Indian ginseng', is an important medicinal plant of the Indian subcontinent. It is widely used, singly or in combination, with other herbs against many ailments in Indian Systems of Medicine since time immemorial. Withania somnifera contains a spectrum of diverse phytochemicals enabling it to have a broad range of biological implications. In preclinical studies, it has shown anti-microbial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective, and anti-diabetic properties. Additionally, it has demonstrated the ability to reduce reactive oxygen species, modulate mitochondrial function, regulate apoptosis, and reduce inflammation and enhance endothelial function. In view of these pharmacologic properties, W. somnifera is a potential drug candidate to treat various clinical conditions, particularly related to the nervous system. In this review, we summarize the pharmacologic characteristics and discuss the mechanisms of action and potential therapeutic applications of the plant and its active constituents.


Decline in titin content in rat skeletal muscle after denervation.
Titin, an elastic and giant myofibrillar protein, is responsible for generating passive tension and maintaining sarcomere structure in striated muscles. Several studies have reported attenuation of passive tension and disorganization of sarcomere in atrophic muscles, but the changes of titin have not been investigated after denervation. For this purpose, we used sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunofluorescent staining to examine titin in innervated and denervated tibialis anterior (TA) muscles of the rat. With increasing denervation time, we found a greater loss of titin than myosin heavy chain (MHC) and actin contents in atrophic TA muscle. The ratios of titin/MHC and titin/actin gradually decreased following denervation. In contrast, ratios of MHC/actin in the denervated groups showed no significant differences with the controls even at 56 days postdenervation. The ultrastructure of myofibrils also showed disturbed arrangements of myofilaments and a disorganized contractile apparatus in denervated muscle. Immunofluorescent staining displayed translocation of the titin epitope from the Z-line to the I-band, suggesting that the apparent cleavage of titin occurred near the Z-line region during the atrophying process. Our study provides evidence that titin is more sensitive to degradation than MHC and actin after denervation. Moreover, the titin decline results in the loss of titin-based sarcomeric integrity in atrophic muscle.


Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics.
The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety.


Pooled-sample testing as a herd-screening tool for detection of bovine viral diarrhea virus persistently infected cattle.
The study was conducted to develop methodology for least-cost strategies for using polymerase chain reaction (PCR)/probe testing of pooled blood samples to identify animals in a herd persistently infected with bovine viral diarrhea virus (BVDV). Cost was estimated for 5 protocols using Monte Carlo simulations for herd prevalences of BVDV persistent infection (BVDV-PI) ranging from 0.5% to 3%, assuming a cost for a PCR/probe test of $20. The protocol associated with the least cost per cow involved an initial testing of pools followed by repooling and testing of positive pools. For a herd prevalence of 1%, the least cost per cow was $2.64 (95% prediction interval = $1.72, $3.68), where pool sizes for the initial and repooled testing were 20 and 5 blood samples per pool, respectively. Optimization of the least cost for pooled-sample testing depended on how well a presumed prevalence of BVDV-PI approximated the true prevalence of BVDV infection in the herd. As prevalence increased beyond 3%, the least cost increased, thereby diminishing the competitive benefit of pooled testing. The protocols presented for sample pooling have general application to screening or surveillance using a sensitive diagnostic test to detect very low prevalence diseases or pathogens in flocks or herds.


Mitochondrial-nuclear epistasis contributes to phenotypic variation and coadaptation in natural isolates of Saccharomyces cerevisiae.
Mitochondria are essential multifunctional organelles whose metabolic functions, biogenesis, and maintenance are controlled through genetic interactions between mitochondrial and nuclear genomes. In natural populations, mitochondrial efficiencies may be impacted by epistatic interactions between naturally segregating genome variants. The extent that mitochondrial-nuclear epistasis contributes to the phenotypic variation present in nature is unknown. We have systematically replaced mitochondrial DNAs in a collection of divergent Saccharomyces cerevisiae yeast isolates and quantified the effects on growth rates in a variety of environments. We found that mitochondrial-nuclear interactions significantly affected growth rates and explained a substantial proportion of the phenotypic variances under some environmental conditions. Naturally occurring mitochondrial-nuclear genome combinations were more likely to provide growth advantages, but genetic distance could not predict the effects of epistasis. Interruption of naturally occurring mitochondrial-nuclear genome combinations increased endogenous reactive oxygen species in several strains to levels that were not always proportional to growth rate differences. Our results demonstrate that interactions between mitochondrial and nuclear genomes generate phenotypic diversity in natural populations of yeasts and that coadaptation of intergenomic interactions likely occurs quickly within the specific niches that yeast occupy. This study reveals the importance of considering allelic interactions between mitochondrial and nuclear genomes when investigating evolutionary relationships and mapping the genetic basis underlying complex traits.


Citizen surveillance for environmental monitoring: combining the efforts of citizen science and crowdsourcing in a quantitative data framework.
Citizen science and crowdsourcing have been emerging as methods to collect data for surveillance and/or monitoring activities. They could be gathered under the overarching term citizen surveillance. The discipline, however, still struggles to be widely accepted in the scientific community, mainly because these activities are not embedded in a quantitative framework. This results in an ongoing discussion on how to analyze and make useful inference from these data. When considering the data collection process, we illustrate how citizen surveillance can be classified according to the nature of the underlying observation process measured in two dimensions-the degree of observer reporting intention and the control in observer detection effort. By classifying the observation process in these dimensions we distinguish between crowdsourcing, unstructured citizen science and structured citizen science. This classification helps the determine data processing and statistical treatment of these data for making inference. Using our framework, it is apparent that published studies are overwhelmingly associated with structured citizen science, and there are well developed statistical methods for the resulting data. In contrast, methods for making useful inference from purely crowd-sourced data remain under development, with the challenges of accounting for the unknown observation process considerable. Our quantitative framework for citizen surveillance calls for an integration of citizen science and crowdsourcing and provides a way forward to solve the statistical challenges inherent to citizen-sourced data.


Coherence effects in scattering order expansion of light by atomic clouds.
We interpret cooperative scattering by a collection of cold atoms as a multiple-scattering process. Starting from microscopic equations describing the response of N atoms to a probe light beam, we represent the total scattered field as an infinite series of multiple-scattering events. As an application of the method, we obtain analytical expressions of the coherent intensity in the double-scattering approximation for Gaussian density profiles. In particular, we quantify the contributions of coherent backward and forward scattering.


Atherosclerosis in chronic kidney disease: the role of macrophages.
Patients with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease and loss of renal parenchyma accelerates atherosclerosis in animal models. Macrophages are central to atherogenesis because they regulate cholesterol traffic and inflammation in the arterial wall. CKD influences macrophage behavior at multiple levels, rendering them proatherogenic. Even at normal creatinine levels, macrophages from uninephrectomized Apoe(-/-) mice are enriched in cholesterol owing to downregulation of cholesterol transporter ATP-binding cassette subfamily A member 1 levels and activation of nuclear factor κB, which leads to impaired cholesterol efflux. Interestingly, treatment with an angiotensin-II-receptor blocker (ARB) improves these effects. Moreover, atherosclerotic aortas from Apoe(-/-) mice transplanted into renal-ablated normocholesterolemic recipients show plaque progression and increased macrophage content instead of the substantial regression seen in recipient mice with intact kidneys. ARBs reduce atherosclerosis development in mice with partial renal ablation. These results, combined with the clinical benefits of angiotensin-converting-enzyme (ACE) inhibitors and ARBs in patients with CKD, suggest an important role for the angiotensin system in the enhanced susceptibility to atherosclerosis seen across the spectrum of CKD. The role of macrophages could explain why these therapies may be effective in end-stage renal disease, one of the few conditions in which statins show no clinical benefit.