A screen for transcription factor targets of glycogen synthase kinase-3 highlights an inverse correlation of NFκB and androgen receptor signaling in prostate cancer.
Expression of Glycogen Synthase Kinase-3 (GSK-3) is elevated in prostate cancer and its inhibition reduces prostate cancer cell proliferation, in part by reducing androgen receptor (AR) signaling. However, GSK-3 inhibition can also activate signals that promote cell proliferation and survival, which may preclude the use of GSK-3 inhibitors in the clinic. To identify such signals in prostate cancer, we screened for changes in transcription factor target DNA binding activity in GSK-3-silenced cells. Among the alterations was a reduction in AR DNA target binding, as predicted from previous studies, and an increase in NFκB DNA target binding. Consistent with the latter, gene silencing of GSK-3 or inhibition using the GSK-3 inhibitor CHIR99021 increased basal NFκB transcriptional activity. Activation of NFκB was accompanied by an increase in the level of the NFκB family member RelB. Conversely, silencing RelB reduced activation of NFκB by CHIR99021. Furthermore, the reduction of prostate cancer cell proliferation by CHIR99021 was potentiated by inhibition of NFκB signaling using the IKK inhibitor PS1145. Finally, stratification of human prostate tumor gene expression data for GSK3 revealed an inverse correlation between NFκB-dependent and androgen-dependent gene expression, consistent with the results from the transcription factor target DNA binding screen. In addition, there was a correlation between expression of androgen-repressed NFκB target genes and reduced survival of patients with metastatic prostate cancer. These findings highlight an association between GSK-3/AR and NFκB signaling and its potential clinical importance in metastatic prostate cancer.


Pre-impact fall detection: optimal sensor positioning based on a machine learning paradigm.
The aim of this study was to identify the best subset of body segments that provides for a rapid and reliable detection of the transition from steady walking to a slipping event. Fifteen healthy young subjects managed unexpected perturbations during walking. Whole-body 3D kinematics was recorded and a machine learning algorithm was developed to detect perturbation events. In particular, the linear acceleration of all the body segments was parsed by Independent Component Analysis and a Neural Network was used to classify walking from unexpected perturbations. The Mean Detection Time (MDT) was 351±123 ms with an Accuracy of 95.4%. The procedure was repeated with data related to different subsets of all body segments whose variability appeared strongly influenced by the perturbation-induced dynamic modifications. Accordingly, feet and hands accounted for most data information and the performance of the algorithm were slightly reduced using their combination. Results support the hypothesis that, in the framework of the proposed approach, the information conveyed by all the body segments is redundant to achieve effective fall detection, and suitable performance can be obtained by simply observing the kinematics of upper and lower distal extremities. Future studies are required to assess the extent to which such results can be reproduced in older adults and in different experimental conditions.


A clonotypic Vγ4Jγ1/Vδ5Dδ2Jδ1 innate γδ T-cell population restricted to the CCR6⁺CD27⁻ subset.
Here we investigate the TCR repertoire of mouse Vγ4(+) γδ T cells in correlation with their developmental origin and homeostasis. By deep sequencing we identify a high frequency of straight Vδ5Dδ2Jδ1 germline rearrangements without P- and N-nucleotides within the otherwise highly diverse Trd repertoire of Vγ4(+) cells. This sequence is infrequent in CCR6(-)CD27(+) cells, but abundant among CCR6(+)CD27(-) γδ T cells. Using an inducible Rag1 knock-in mouse model, we show that γδ T cells generated in the adult thymus rarely contain this germline-rearranged Vδ5Dδ2Jδ1 sequence, confirming its fetal origin. Single-cell analysis and deep sequencing of the Trg locus reveal a dominant CDR3 junctional motif that completes the TCR repertoire of invariant Vγ4(+)Vδ5(+) cells. In conclusion, this study identifies an innate subset of fetal thymus-derived γδ T cells with an invariant Vγ4(+)Vδ5(+) TCR that is restricted to the CCR6(+)CD27(-) subset of γδ T cells.


Assessing Specialized Metabolite Diversity in the Cosmopolitan Plant Genus Euphorbia L.
Coevolutionary theory suggests that an arms race between plants and herbivores yields increased plant specialized metabolite diversity and the geographic mosaic theory of coevolution predicts that coevolutionary interactions vary across geographic scales. Consequently, plant specialized metabolite diversity is expected to be highest in coevolutionary hotspots, geographic regions, which exhibit strong reciprocal selection on the interacting species. Despite being well-established theoretical frameworks, technical limitations have precluded rigorous hypothesis testing. Here we aim at understanding how geographic separation over evolutionary time may have impacted chemical differentiation in the cosmopolitan plant genus Euphorbia. We use a combination of state-of-the-art computational mass spectral metabolomics tools together with cell-based high-throughput immunomodulatory testing. Our results show significant differences in specialized metabolite diversity across geographically separated phylogenetic clades. Chemical structural diversity of the highly toxic Euphorbia diterpenoids is significantly reduced in species native to the Americas, compared to Afro-Eurasia. The localization of these compounds to young stems and roots suggest a possible ecological relevance in herbivory defense. This is further supported by reduced immunomodulatory activity in the American subclade as well as herbivore distribution patterns. We conclude that computational mass spectrometric metabolomics coupled with relevant ecological data provide a strong tool for exploring plant specialized metabolite diversity in a chemo-evolutionary framework.


CCN4 induces IL-6 production through αvβ5 receptor, PI3K, Akt, and NF-κB singling pathway in human synovial fibroblasts.
Osteoarthritis (OA) is the most common degenerative joint disease that is involved in the degradation of articular cartilage. The exact etiology of OA is not completely understood. CCN4 is related to up-regulation in the cartilage of patients with osteoarthritis. Previous studies have shown that CCN4 might be associated with the pathogenesis of OA, but the exact signaling pathways in CCN4-mediated IL-6 expression in synovial fibroblasts (SF) are largely unknown. Therefore, we explored the intracellular signaling pathway involved in CCN4-induced IL-6 production in human synovial fibroblast cells. CCN4-induced IL-6 production was assessed with quantitative real-time qPCR and ELISA. The mechanisms of action of CCN4 in different signaling pathways were studied by using Western blotting. Neutralizing antibodies of integrin were used to block the integrin signaling pathway. Luciferase assays were used to study IL-6 and NF-κB promoter activity. Immunocytochemistry was used to examine the translocation activity of p65. Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCN4 and the expression was higher than in normal SFs. OASF stimulation with CCN4 induced concentration- and time-dependent increases in IL-6 production. Pretreatment of OASFs with αvβ5 but not α5β1 and αvβ3 integrin antibodies reduced CCN4-induced IL-6 production. CCN4-mediated IL-6 production was attenuated by PI3K inhibitor (LY294002 and Wortmannin), Akt inhibitor (Akti), and NF-κB inhibitor (PDTC and TPCK). Stimulation of cells with CCN4 also increased PI3K, Akt, and NF-κB activation. Our results suggest that CCN4 activates αvβ5 integrin, PI3K, Akt, and NF-κB pathways, leading to up-regulation of IL-6 production. According to our results, CCN4 may be an appropriate target for drug intervention in OA in the future.


The Burden of Viruses in Pneumonia Associated With Acute Respiratory Failure: An Underappreciated Issue.
Pneumonia associated with mechanical ventilation (MV) results in substantial mortality and represents a leading reason for the use of antibiotics. The role of viruses in this setting is unclear. Identifying a viral cause in such instances could facilitate antibiotic stewardship. We performed a secondary analysis of a prospective cohort with pneumonia requiring MV. We included both cases occurring in the community and hospital-onset cases and classified patients according to the cause of the pneumonia. The prevalence of viral pathogens represented the primary end point. We identified variables independently associated with isolation of a viral organism as the sole pathogen. The cohort included 364 patients, and a virus was the sole pathogen in 79 cases (21.7%). The most common viruses included rhinovirus/enterovirus (n = 20), influenza A (n = 12), and respiratory syncytial virus (n = 11). The rate of in-hospital death was high (37.2%) and did not differ from that seen in other patients (36.5%). The duration of MV, hospital length of stay, and 30-day readmission rates also did not differ based on the cause of pneumonia. Two variables were independently associated with recovery of a virus: an Acute Physiology and Health Evaluation II score of < 26 (adjusted odds ratio [AOR], 0.51; 95% CI, 0.28-0.93; P = .027) and stem cell transplantation (SCT) (AOR, 4.39; 95% CI, 2.03-9.50; P = .001). A sensitivity analysis excluding patients who underwent SCT did not substantially alter our observations. Viruses represent a major cause of pneumonia in critically ill patients requiring MV. Identifying such subjects presents an opportunity for discontinuing antibiotics. Clinicians should consider systematically evaluating patients with pneumonia requiring MV for viral pathogens.


An integrated approach to evaluating alternative risk prediction strategies: a case study comparing alternative approaches for preventing invasive fungal disease.
This article proposes an integrated approach to the development, validation, and evaluation of new risk prediction models illustrated with the Fungal Infection Risk Evaluation study, which developed risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive fungal disease (IFD). Our decision-analytical model compared alternative strategies for preventing IFD at up to three clinical decision time points (critical care admission, after 24 hours, and end of day 3), followed with antifungal prophylaxis for those judged "high" risk versus "no formal risk assessment." We developed prognostic models to predict the risk of IFD before critical care unit discharge, with data from 35,455 admissions to 70 UK adult, critical care units, and validated the models externally. The decision model was populated with positive predictive values and negative predictive values from the best-fitting risk models. We projected lifetime cost-effectiveness and expected value of partial perfect information for groups of parameters. The risk prediction models performed well in internal and external validation. Risk assessment and prophylaxis at the end of day 3 was the most cost-effective strategy at the 2% and 1% risk threshold. Risk assessment at each time point was the most cost-effective strategy at a 0.5% risk threshold. Expected values of partial perfect information were high for positive predictive values or negative predictive values (£11 million-£13 million) and quality-adjusted life-years (£11 million). It is cost-effective to formally assess the risk of IFD for non-neutropenic, critically ill adult patients. This integrated approach to developing and evaluating risk models is useful for informing clinical practice and future research investment.


Structure of a bacterial cell surface decaheme electron conduit.
Some bacterial species are able to utilize extracellular mineral forms of iron and manganese as respiratory electron acceptors. In Shewanella oneidensis this involves decaheme cytochromes that are located on the bacterial cell surface at the termini of trans-outer-membrane electron transfer conduits. The cell surface cytochromes can potentially play multiple roles in mediating electron transfer directly to insoluble electron sinks, catalyzing electron exchange with flavin electron shuttles or participating in extracellular intercytochrome electron exchange along "nanowire" appendages. We present a 3.2-Å crystal structure of one of these decaheme cytochromes, MtrF, that allows the spatial organization of the 10 hemes to be visualized for the first time. The hemes are organized across four domains in a unique crossed conformation, in which a staggered 65-Å octaheme chain transects the length of the protein and is bisected by a planar 45-Å tetraheme chain that connects two extended Greek key split β-barrel domains. The structure provides molecular insight into how reduction of insoluble substrate (e.g., minerals), soluble substrates (e.g., flavins), and cytochrome redox partners might be possible in tandem at different termini of a trifurcated electron transport chain on the cell surface.


Rac1 is essential for platelet lamellipodia formation and aggregate stability under flow.
The role of Rac family proteins in platelet spreading on matrix proteins under static and flow conditions has been investigated by using Rac-deficient platelets. Murine platelets form filopodia and undergo limited spreading on fibrinogen independent of Rac1 and Rac2. In the presence of thrombin, marked lamellipodia formation is observed on fibrinogen, which is abrogated in the absence of Rac1. However, Rac1 is not required for thrombin-induced aggregation or elevation of F-actin levels. Formation of lamellipodia on collagen and laminin is also Rac1-dependent. Analysis of platelet adhesion dynamics on collagen under flow conditions in vitro revealed that Rac1 is required for platelet aggregate stability at arterial rates of shear, as evidenced by a dramatic increase in platelet embolization. Furthermore, studies employing intravital microscopy demonstrated that Rac1 plays a critical role in the development of stable thrombi at sites of vascular injury in vivo. Thus, our data demonstrated that Rac1 is essential for lamellipodia formation in platelets and indicated that Rac1 is required for aggregate integrity leading to thrombus formation under physiologically relevant levels of shear both in vitro and in vivo.


Modulation of hepatic drug metabolizing enzymes and oxidative status by rooibos (Aspalathus linearis) and Honeybush (Cyclopia intermedia), green and black (Camellia sinensis) teas in rats.
Rooibos and honeybush teas significantly (P < 0.05) enhanced the activity of cytosolic glutathione S-transferase alpha. A significant (P < 0.05) to marginal (P < 0.1) increase in the activity of the microsomal UDP-glucuronosyl transferase was obtained with unprocessed rooibos and honeybush teas, respectively. Oxidized glutathione (GSSG) levels were significantly (P < 0.05) reduced in the liver of all tea treated rats while reduced glutathione (GSH) was markedly increased in the liver of the herbal tea treated rats. These changes resulted in a significant (P < 0.05) increase in the GSH/GSSG ratio by the unprocessed, processed rooibos and unprocessed honeybush teas. Green and black teas markedly to significantly decreased the oxygen radical absorbance capacity in liver homogenates, respectively. Modulation of phase II drug metabolizing enzymes and oxidative status in the liver may be important events in the protection against adverse effects related to mutagenesis and oxidative damage.


Green's tensor technique for scattering in two-dimensional stratified media.
We present an accurate and self-consistent technique for computing the electromagnetic field in scattering structures formed by bodies embedded in a stratified background and extending infinitely in one direction (two-dimensional geometry). With this fully vectorial approach based on the Green's tensor associated with the background, only the embedded scatterers must be discretized, the entire stratified background being accounted for by the Green's tensor. We first derive the formulas for the computation of this dyadic and discuss in detail its physical substance. The utilization of this technique for the solution of scattering problems in complex structures is then illustrated with examples from photonic integrated circuits (waveguide grating couplers with varying periodicity).


Recurring weather extremes alter the flowering phenology of two common temperate shrubs.
The aim of this study is to explore the effects of heavy rain and drought on the flowering phenology of two shrub species Genista tinctoria and Calluna vulgaris. We conducted a field experiment over five consecutive years in Central Europe, applying annually recurring extreme drought and heavy rain events on constructed shrubland communities and recorded the flowering status. Further, we correlated spring temperature and precipitation with the onset of flowering. Both species showed a response to extreme weather events: drought delayed the mid flowering date of Genista tinctoria in 3 of 5 years by about 1 month and in 1 year advanced the mid flowering date by 10 days, but did not affect the length of flowering. Mid flowering date of Calluna vulgaris was not affected by drought, but the length of flowering was extended in 2 years by 6 and 10 days. For C. vulgaris the closer the drought occurred to the time of flowering, the larger the impact on the flowering length. Heavy rainfall advanced mid flowering date and reduced the length of flowering of Genista tinctoria by about 2 months in 1 year. Mid flowering date of Calluna vulgaris was not affected by heavy rain, but the length of flowering was reduced in 1 year by 4 days. Our data suggest that extreme weather events, including alterations to the precipitation regime, induce phenological shifts of plant species of a substantial magnitude. Thus, the impacts of climate extremes on plant life cycles may be as influential as gradual warming. Particularly, the variability in the timing of precipitation events appears to have a greater influence on flowering dynamics than the magnitude of the precipitation.


Second malignant neoplasms and cardiovascular disease following radiotherapy.
Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (i.e., radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (i.e., dose-response relationships). Major conclusions of the NCRP include: (1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and (2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include (1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; (2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; (3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; (4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and (5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.


Actinomycetes for marine drug discovery isolated from mangrove soils and plants in China.
The mangrove ecosystem is a largely unexplored source for actinomycetes with the potential to produce biologically active secondary metabolites. Consequently, we set out to isolate, characterize and screen actinomycetes from soil and plant material collected from eight mangrove sites in China. Over 2,000 actinomycetes were isolated and of these approximately 20%, 5%, and 10% inhibited the growth of Human Colon Tumor 116 cells, Candida albicans and Staphylococcus aureus, respectively, while 3% inhibited protein tyrosine phosphatase 1B (PTP1B), a protein related to diabetes. In addition, nine isolates inhibited aurora kinase A, an anti-cancer related protein, and three inhibited caspase 3, a protein related to neurodegenerative diseases. Representative bioactive isolates were characterized using genotypic and phenotypic procedures and classified to thirteen genera, notably to the genera Micromonospora and Streptomyces. Actinomycetes showing cytotoxic activity were assigned to seven genera whereas only Micromonospora and Streptomyces strains showed anti-PTP1B activity. We conclude that actinomycetes isolated from mangrove habitats are a potentially rich source for the discovery of anti-infection and anti-tumor compounds, and of agents for treating neurodegenerative diseases and diabetes.


Academic and Research Programs in Exercise Science, South Korea.
We appreciate the opportunity to review academic curriculum and current research focus of Exercise Science programs in South Korea. The information of this paper was collected by several different methods, including e-mail and phone interviews, and a discussion with Korean professors who attended the 2009 ACSM annual conference. It was agreed that exercise science programming in South Korea has improved over the last 60 years since being implemented. One of distinguishable achievement is that exercise science programs after the 1980's has been expanded to several different directions. It does not only produce physical education teachers but also attributes more to research, sports medicine, sports, leisure and recreation. Therefore, it has produced various jobs in exercise-related fields. Some of exercise science departments do not require teacher preparation course work in their curriculum which allows students to focus more on their specialty. Secondly, we believe we South Korea has caught up with advanced countries in terms of research quality. Many Korean researchers have recently published and presented their investigations in international journals and conferences. The quality and quantity of these studies introduced to international societies indicate that Exercise Science programs in South Korea is continuing to develop and plays an important part in the world.


Mechanical ventilation of the healthy lungs: lessons learned from recent trials.
Although there is clear evidence for benefit of protective ventilation settings [including low tidal volume and higher positive end-expiratory pressure (PEEP)] in patients with acute respiratory distress syndrome (ARDS), it is less clear what the optimal mechanical ventilation settings are for patients with healthy lungs. Use of low tidal volume during operative ventilation decreases postoperative pulmonary complications (PPC). In the critically ill patients with healthy lungs, use of low tidal volume is as effective as intermediate tidal volume. Use of higher PEEP during operative ventilation does not decrease PPCs, whereas hypotension occurred more often compared with use of lower PEEP. In the critically ill patients with healthy lungs, there are conflicting data regarding the use of a higher PEEP, which may depend on recruitability of lung parts. There are limited data suggesting that higher driving pressures because of higher PEEP contribute to PPCs. Lastly, use of hyperoxia does not consistently decrease postoperative infections, whereas it seems to increase PPCs compared with conservative oxygen strategies. In patients with healthy lungs, data indicate that low tidal volume but not higher PEEP is beneficial. Thereby, ventilation strategies differ from those in ARDS patients.


Emotion modulates early auditory response to speech.
In order to understand how emotional state influences the listener's physiological response to speech, subjects looked at emotion-evoking pictures while 32-channel EEG evoked responses (ERPs) to an unchanging auditory stimulus ("danny") were collected. The pictures were selected from the International Affective Picture System database. They were rated by participants and differed in valence (positive, negative, neutral), but not in dominance and arousal. Effects of viewing negative emotion pictures were seen as early as 20 msec (p = .006). An analysis of the global field power highlighted a time period of interest (30.4-129.0 msec) where the effects of emotion are likely to be the most robust. At the cortical level, the responses differed significantly depending on the valence ratings the subjects provided for the visual stimuli, which divided them into the high valence intensity group and the low valence intensity group. The high valence intensity group exhibited a clear divergent bivalent effect of emotion (ERPs at Cz during viewing neutral pictures subtracted from ERPs during viewing positive or negative pictures) in the time period of interest (r(Phi) = .534, p < .01). Moreover, group differences emerged in the pattern of global activation during this time period. Although both groups demonstrated a significant effect of emotion (ANOVA, p = .004 and .006, low valence intensity and high valence intensity, respectively), the high valence intensity group exhibited a much larger effect. Whereas the low valence intensity group exhibited its smaller effect predominantly in frontal areas, the larger effect in the high valence intensity group was found globally, especially in the left temporal areas, with the largest divergent bivalent effects (ANOVA, p < .00001) in high valence intensity subjects around the midline. Thus, divergent bivalent effects were observed between 30 and 130 msec, and were dependent on the subject's subjective state, whereas the effects at 20 msec were evident only for negative emotion, independent of the subject's behavioral responses. Taken together, it appears that emotion can affect auditory function early in the sensory processing stream.


Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase.
Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ≥2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9-71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa phase 3 clinical trial program.


Bullying and mental health and suicidal behaviour among 14- to 15-year-olds in a representative sample of Australian children.
To provide the first Australian population-based estimates of the association between bullying and adverse mental health outcomes and suicidality among Australian adolescents. Analysis of data from 3537 adolescents, aged 14-15 years from Wave 6 of the K-cohort of Longitudinal Study of Australian Children was conducted. We used Poisson and linear regression to estimate associations between bullying type (none, relational-verbal, physical, both types) and role (no role, victim, bully, victim and bully), and mental health (measured by the Strengths and Difficulties Questionnaire, symptoms of anxiety and depression) and suicidality. Adolescents involved in bullying had significantly increased Strengths and Difficulties Questionnaire, depression and anxiety scores in all bullying roles and types. In terms of self-harm and suicidality, bully-victims had the highest risk of self-harm (prevalence rate ratio 4.7, 95% confidence interval [3.26, 6.83]), suicidal ideation (prevalence rate ratio 4.3, 95% confidence interval [2.83, 6.49]), suicidal plan (prevalence rate ratio 4.1, 95% confidence interval [2.54, 6.58]) and attempts (prevalence rate ratio 2.7, 95% confidence interval [1.39, 5.13]), followed by victims then bullies. The experience of both relational-verbal and physical bullying was associated with the highest risk of self-harm (prevalence rate ratio 4.6, 95% confidence interval [3.15, 6.60]), suicidal ideation or plans (prevalence rate ratio 4.6, 95% confidence interval [3.05, 6.95]; and 4.8, 95% confidence interval [3.01, 7.64], respectively) or suicide attempts (prevalence rate ratio 3.5, 95% confidence interval [1.90, 6.30]). This study presents the first national, population-based estimates of the associations between bullying by peers and mental health outcomes in Australian adolescents. The markedly increased risk of poor mental health outcomes, self-harm and suicidal ideation and behaviours among adolescents who experienced bullying highlights the importance of addressing bullying in school settings.


Temporal regularity increases with repertoire complexity in the Australian pied butcherbird's song.
Music maintains a characteristic balance between repetition and novelty. Here, we report a similar balance in singing performances of free-living Australian pied butcherbirds. Their songs include many phrase types. The more phrase types in a bird's repertoire, the more diverse the singing performance can be. However, without sufficient temporal organization, avian listeners may find diverse singing performances difficult to perceive and memorize. We tested for a correlation between the complexity of song repertoire and the temporal regularity of singing performance. We found that different phrase types often share motifs (notes or stereotyped groups of notes). These shared motifs reappeared in strikingly regular temporal intervals across different phrase types, over hundreds of phrases produced without interruption by each bird. We developed a statistical estimate to quantify the degree to which phrase transition structure is optimized for maximizing the regularity of shared motifs. We found that transition probabilities between phrase types tend to maximize regularity in the repetition of shared motifs, but only in birds of high repertoire complexity. Conversely, in birds of low repertoire complexity, shared motifs were produced with less regularity. The strong correlation between repertoire complexity and motif regularity suggests that birds possess a mechanism that regulates the temporal placement of shared motifs in a manner that takes repertoire complexity into account. We discuss alternative musical, mechanistic and ecological explanations to this effect.


Targets for resuscitation from shock.
Resuscitation from circulatory and respiratory failure represent mainstays of emergency and critical care management. Importantly, no amount of resuscitative effort will be successful in promoting patient survival if the primary reason for the shock state is not identified and treated, independent of resuscitation. Having said that, aggressive resuscitation to normal functional levels of blood flow and organ perfusion pressure during the first 6 hours following the development of shock improves outcome both in patients with trauma or sepsis. However, clinical studies have demonstrated that restoration of total blood flow to supranormal levels in subjects with established shock that has been present for over 6 hours does not improve survival. Still, some defined clinical targets are essential in these patients as well to prevent further organ injury due to ischemia and its associated inflammatory response. Thus, the rapid restoration of normal hemodynamics by conventional means, including fluid resuscitation and surgical repair, results in a better log term outcome than inadequate or delayed resuscitative efforts. Clear initial targets for resuscitation are a mean arterial pressure > 60 mm Hg, and a cardiac output and O(2) transport to the body adequate enough to prevent tissue hypoperfusion. The level of cardiac output needed to achieve this goal is probably different among subjects and within subjects over time. Indirect signposts of adequate perfusion, such as venous O2 saturation, mentation, urine output and local measures of tissue blood flow are useful in monitoring this response.


Cooling athletes with a spinal cord injury.
Cooling strategies that help prevent a reduction in exercise capacity whilst exercising in the heat have received considerable research interest over the past 3 decades, especially in the lead up to a relatively hot Olympic and Paralympic Games. Progressing into the next Olympic/Paralympic cycle, the host, Rio de Janeiro, could again present an environmental challenge for competing athletes. Despite the interest and vast array of research into cooling strategies for the able-bodied athlete, less is known regarding the application of these cooling strategies in the thermoregulatory impaired spinal cord injured (SCI) athletic population. Individuals with a spinal cord injury (SCI) have a reduced afferent input to the thermoregulatory centre and a loss of both sweating capacity and vasomotor control below the level of the spinal cord lesion. The magnitude of this thermoregulatory impairment is proportional to the level of the lesion. For instance, individuals with high-level lesions (tetraplegia) are at a greater risk of heat illness than individuals with lower-level lesions (paraplegia) at a given exercise intensity. Therefore, cooling strategies may be highly beneficial in this population group, even in moderate ambient conditions (~21 °C). This review was undertaken to examine the scientific literature that addresses the application of cooling strategies in individuals with an SCI. Each method is discussed in regards to the practical issues associated with the method and the potential underlying mechanism. For instance, site-specific cooling would be more suitable for an athlete with an SCI than whole body water immersion, due to the practical difficulties of administering this method in this population group. From the studies reviewed, wearing an ice vest during intermittent sprint exercise has been shown to decrease thermal strain and improve performance. These garments have also been shown to be effective during exercise in the able-bodied. Drawing on additional findings from the able-bodied literature, the combination of methods used prior to and during exercise and/or during rest periods/half-time may increase the effectiveness of a strategy. However, due to the paucity of research involving athletes with an SCI, it is difficult to establish an optimal cooling strategy. Future studies are needed to ensure that research outcomes can be translated into meaningful performance enhancements by investigating cooling strategies under the constraints of actual competition. Cooling strategies that meet the demands of intermittent wheelchair sports need to be identified, with particular attention to the logistics of the sport.


A Mechanistic Link between Olfaction and Autism Spectrum Disorder.
Internal action models (IAMs) are brain templates for sensory-motor coordination underlying diverse behaviors. An emerging theory suggests that impaired IAMs are a common theme in autism spectrum disorder (ASD). However, whether impaired IAMs occur across sensory systems and how they relate to the major phenotype of ASD, namely impaired social communication, remains unclear. Olfaction relies on an IAM known as the sniff response, where sniff magnitude is automatically modulated to account for odor valence. To test the failed IAM theory in olfaction, we precisely measured the non-verbal non-task-dependent sniff response concurrent with pleasant and unpleasant odors in 36 children--18 with ASD and 18 matched typically developing (TD) controls. We found that whereas TD children generated a typical adult-like sniff response within 305 ms of odor onset, ASD children had a profoundly altered sniff response, sniffing equally regardless of odor valance. This difference persisted despite equal reported odor perception and allowed for 81% correct ASD classification based on the sniff response alone (binomial, p < 0.001). Moreover, increasingly aberrant sniffing was associated with increasingly severe ASD (r = -0.75, p < 0.001), specifically with social (r = -0.72, p < 0.001), but not motor (r < -0.38, p > 0.18), impairment. These results uncover a novel ASD marker implying a mechanistic link between the underpinnings of olfaction and ASD and directly linking an impaired IAM with impaired social abilities.


Designed protein mimics of the Ebola virus glycoprotein GP2 α-helical bundle: stability and pH effects.
Ebola virus (EboV) belongs to the Filoviridae family of viruses that causes severe and fatal hemhorragic fever. Infection by EboV involves fusion between the virus and host cell membranes mediated by the envelope glycoprotein GP2 of the virus. Similar to the envelope glycoproteins of other viruses, the central feature of the GP2 ectodomain postfusion structure is a six-helix bundle formed by the protein's N- and C-heptad repeat regions (NHR and CHR, respectively). Folding of this six-helix bundle provides the energetic driving force for membrane fusion; in other viruses, designed agents that disrupt formation of the six-helix bundle act as potent fusion inhibitors. To interrogate determinants of EboV GP2-mediated membrane fusion, we designed model proteins that consist of the NHR and CHR segments linked by short protein linkers. Circular dichroism and gel filtration studies indicate that these proteins adopt stable α-helical folds consistent with design. Thermal denaturation indicated that the GP2 six-helix bundle is highly stable at pH 5.3 (melting temperature, T(m) , of 86.8 ± 2.0°C and van't Hoff enthalpy, ΔH(vH) , of -28.2 ± 1.0 kcal/mol) and comparable in stability to other viral membrane fusion six-helix bundles. We found that the stability of our designed α-helical bundle proteins was dependent on buffering conditions with increasing stability at lower pH. Small pH differences (5.3-6.1) had dramatic effects (ΔT(m) = 37°C) suggesting a mechanism for conformational control that is dependent on environmental pH. These results suggest a role for low pH in stabilizing six-helix bundle formation during the process of GP2-mediated viral membrane fusion.


Associations Between Social Capital and Depressive Symptoms Among College Students in 12 Countries: Results of a Cross-National Study.
A mental health crisis has hit university campuses across the world. This study sought to determine the prevalence and social determinants of depressive symptoms among university students in twelve countries. Particular focus was placed on the association between social capital and depressive symptoms. A cross-sectional study was conducted among students at their first year at university in Europe, Asia, the Western Pacific, and Latin and North America. Data were obtained through a self-administered questionnaire, including questions on sociodemographic characteristics, depressive symptoms, and social capital. The simplified Beck's Depression Inventory was used to measure the severity of depressive symptoms. Social capital was assessed using items drawn from the World Bank Integrated Questionnaire to Measure Social Capital. Multilevel analyses were conducted to determine the relationship between social capital and depressive symptoms, adjusting for individual covariates (e.g., perceived stress) and country-level characteristics (e.g., economic development). Among 4228 students, 48% presented clinically relevant depressive symptoms. Lower levels of cognitive (OR: 1.82, 95% CI: 1.44-2.29) and behavioral social capital (OR: 1.51, 95% CI: 1.29-1.76) were significantly associated with depressive symptoms. The likelihood of having depressive symptoms was also significantly higher among those living in regions with lower levels of social capital. The study demonstrates that lower levels of individual and macro-level social capital contribute to clinically relevant depressive symptoms among university students. Increasing social capital may mitigate depressive symptoms in college students.


Initial outcomes in the Multicenter Study of Epilepsy Surgery.
To obtain prospective data regarding seizures, anxiety, depression, and quality of life (QOL) outcomes after resective epilepsy surgery. The authors characterized resective epilepsy surgery patients prospectively at yearly intervals for seizure outcome, QOL, anxiety, and depression, using standardized instruments and patient interviews. Of 396 patients who underwent resective surgical procedures, 355 were followed for at least 1 year. Of these, 75% achieved a 1-year remission at some time during follow-up; patients with medial temporal (77%) were more likely than neocortical resections (56%) to achieve remission (p = 0.01). Relapse occurred in 59 (22%) patients who remitted, more often in medial temporal (24%) than neocortical (4%) resected patients (p = 0.02). QOL, anxiety, and depression all improved dramatically within 3 months after surgery (p < 0.0001), with no significant difference based on seizure outcome. After 3 months, QOL in seizure-free patients further improved gradually, and patients with seizures showed gradual declines. By 12 and 24 months, overall QOL and its epilepsy-targeted and physical health domains were significantly different in the two outcome groups. (Anxiety and depression scores also gradually diverged, with improvements in seizure-free and declines in continued seizure groups, but differences were not significant.) Resective surgery for treatment of epilepsy significantly reduces seizures, most strikingly after medial temporal resection (77% 1 year remission) compared to neocortical resection (56% 1 year remission). Resective epilepsy surgery has a gradual but lasting effect on QOL, but minimal effects on anxiety and depression. Longer follow-up will be essential to determine ultimate seizure, QOL, and psychiatric outcomes of epilepsy surgery.


Anesthesia and airway management in two cases of apert syndrome: case reports.
Apert syndrome is a type of acrocephalosyndactilia that consists of craniofacial synostosis, midface hypoplasia and syndactyly, with an autosomal dominant inheritance pattern. During anesthesia, difficult intubation and ventilation may be observed because of abnormal airways. In one of our patients, visceral anomalies, such as esophageal stricture and post-strictural dilatation, may cause respiratory problems because of aspiration. The second case was a Mallampati grade 2 with craniofacial synostoses, midface hypoplasia and syndactyly. In the case of apert syndrome, anesthetists must be prepared for intubation difficulties, airway and ventilation problems and even visceral anomalies.


Photocatalytic Protein Damage by Silver Nanoparticles Circumvents Bacterial Stress Response and Multidrug Resistance.
Silver nanoparticles (AgNPs) are known for their broad-spectrum antibacterial properties, especially against antibiotic-resistant bacteria. However, the bactericidal mechanism of AgNPs remains unclear. In this study, we found that the bactericidal ability of AgNPs is induced by light. In contrast to previous postulates, visible light is unable to trigger silver ion release from AgNPs or to promote AgNPs to induce reactive oxygen species (ROS) in Escherichia coli In fact, we revealed that light excited AgNPs to induce protein aggregation in a concentration-dependent manner in E. coli, indicating that the bactericidal ability of AgNPs relies on the light-catalyzed oxidation of cellular proteins via direct binding to proteins, which was verified by fluorescence spectra. AgNPs likely absorb the light energy and transfer it to the proteins, leading to the oxidation of proteins and thus promoting the death of the bacteria. Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics revealed that the bacteria failed to develop effective resistance to the light-excited AgNPs. This direct physical mechanism is unlikely to be counteracted by any known drug resistance mechanisms of bacteria and therefore may serve as a last resort against drug resistance. This mechanism also provides a practical hint regarding the antimicrobial application of AgNPs-light exposure improves the efficacy of AgNPs.IMPORTANCE Although silver nanoparticles (AgNPs) are well known for their antibacterial properties, the mechanism by which they kill bacterial cells remains a topic of debate. In this study, we uncovered the bactericidal mechanism of AgNPs, which is induced by light. We tested the efficacy of AgNPs against a panel of antimicrobial-resistant pathogens as well as Escherichia coli under conditions of light and darkness and revealed that light excited the AgNPs to promote protein aggregation within the bacterial cells. Our report makes a significant contribution to the literature because this mechanism bypasses microbial drug resistance mechanisms, thus presenting a viable option for the treatment of multidrug-resistant bacteria.


Matching the heart donor and heart transplant recipient. Clues for successful expansion of the donor pool: a multivariable, multiinstitutional report. The Cardiac Transplant Research Database Group.
Little information is available regarding donor-specific parameters that predict success or failure after heart transplantation. Furthermore, with increasing numbers of patients awaiting heart transplantation, there is tremendous pressure to expand the donor pool by stretching the margins of donor acceptability. To gain insight into donor-related and donor-recipient interrelated predictors of death after transplantation, 1719 consecutive primary transplantations performed at 27 institutions between Jan. 1, 1990, and June 30, 1992, were analyzed. Mean follow-up of survivors was 13.9 months, and actuarial survival was 85% at 1 year. By multivariable analysis, risk factors for death included younger recipient age (p = 0.006), older recipient age (p = 0.0005), ventilator support at time of transplantation (p = 0.0006), higher pulmonary vascular resistance (p = 0.02), older donor age (p < 0.0001), smaller donor body surface area (female donor heart placed into larger male patient) (p = 0.003), greater donor inotropic support (p = 0.01), donor diabetes mellitus (p = 0.01), longer ischemic time (p = 0.0003), diffuse donor heart wall motion abnormalities by echocardiography (p = 0.06), and, for pediatric donors, death from causes other than closed head trauma (p = 0.02). The overall 30-day mortality rate was 7% but increased to 11% when donor age exceeded 50 years and was 12% when inotropic support exceeded 20 micrograms/kg/min dopamine plus dobutamine and 22% with diffuse echocardiographic wall motion abnormalities. The interaction of donor risk factors was such that the heart of a smaller female donor given high-dose inotropes placed into a larger male recipient produced a predicted 30-day mortality rate of 26% and the heart of a 25-year-old male donor given high-dose inotropes with diffuse echocardiographic wall motion abnormalities transplanted into a 50-year-old male recipient led to a predicted 30-day mortality rate of 17%. This analysis supports cautious extension of criteria for donor acceptance but with an anticipated greater risk in the presence of diffuse echocardiographic wall motion abnormalities and long anticipated ischemic time, particularly in older donors given inotropic support.


Gender differences in related influential factors of regular exercise behavior among people in Taiwan in 2007: A cross-sectional study.
The purpose was to explore the exercise behavior of the Taiwanese population during leisure time and to examine the gender differences in related influential factors. The Leisure Time and Sport Questionnaire (LTSQ) conducted by the Academia Sinica in 2007 was used for analysis. Participants were drawn from the Taiwanese population aged over 18 years old. Multinomial logistic regression models were used to test the association between the frequency of exercise and related factors in all the participants, male, and female participants, respectively. In the total 2,147 participants, 47.8% reported they regularly exercised, 34.1% irregularly exercised, and 18.1% never exercised. There were no significant gender differences in the frequency of exercise, but a significant gender difference was found in the types of exercise most often practiced. Participants in one of following conditions, over 65 and under 40 years old, living in the city, having higher education levels, having a spouse or partner, enjoying exercise, feeling worthwhile to spend money on exercise, and not having to take care of others, were more likely to be engaged in regular exercise in the total population. The "enjoyment" in exercise was a significant influential factor for both sexes. Women were more likely to exercise regularly if they were aged 40-64 years old compared with those over 65 years old, have lower self-rated health scores, felt it was more worthwhile to spend money on exercise and did not have to care for another, whereas men who have higher education level and did not feel a lack of time were more likely to exercise regularly. There are gender differences in regular exercise behavior during leisure time and related influential factors among Taiwanese adults. The findings of the present study can be used when designing gender-specific health promotion programs.


A reductionist approach to model photosynthetic self-regulation in eukaryotes in response to light.
Along with the development of several large-scale methods such as mass spectrometry or micro arrays, genome wide models became not only a possibility but an obvious tool for theoretical biologists to integrate and analyse complex biological data. Nevertheless, incorporating the dynamics of photosynthesis remains one of the major challenges while reconstructing metabolic networks of plants and other photosynthetic organisms. In this review, we aim to provide arguments that small-scale models are still a suitable choice when it comes to discovering organisational principles governing the design of biological systems. We give a brief overview of recent modelling efforts in understanding the interplay between rapid, photoprotective mechanisms and the redox balance within the thylakoid membrane, discussing the applicability of a reductionist approach in modelling self-regulation in plants and outline possible directions for further research.


Supercritical fluid chromatography as a tool for enantioselective separation; a review.
Supercritical fluid chromatography (SFC) has become popular in the field of enantioselective separations. Many works have been reported during the last years. This review covers the period from 2000 till August 2013. The article is divided into three main chapters. The first one comprises a basic introduction to SFC. The authors provide a brief explanation of general principles and possibilities of this method. The advantages and drawbacks are also listed. Next part deals with chiral separation systems available in SFC, namely with the commonly used chiral stationary phases. Properties and interaction possibilities of the chiral separation systems are described. Recent theoretical papers are emphasized in this chapter. The last part of the paper gives an overview of applications of enantioselective SFC in analytical chemistry, in both analytical and preparative scales. Separation systems and conditions are summed up in tables so that they provide a helpful tool for analysts who search for a particular method of analysis.


First Report of Rust Caused by Phakopsora pachyrhizi on Soybean in Democratic Republic of Congo.
Nigeria (1) and Uganda (3) are the closest countries to the Democratic Republic of Congo (DRC) where soybean rust caused by Phakopsora pachyrhizi has been reported. In February 2007, during a disease survey in DRC, soybean (Glycine max) leaves with rust symptoms (tan, angular lesions with erumpent sori exuding urediniospores) were observed in 10 fields in the following areas in Bas Congo Province: Bangu, Kimpese, Kolo-Fuma, Lukala, Mbanza-Ngungu, Mpalukide, Mvuazi, and Ntemo. Rust incidence in these fields ranged from 85 to 100%, while severity ranged between 3 and 35% of the leaf area on infected plants. Urediniospores were hyaline, minutely echinulate, and 23 to 31 × 16 to 20 μm. Within a week of collection, infected leaf samples were sent to the USDA-ARS Foreign Disease-Weed Science Research Unit (FDWSRU) for pathogen identification. DNA was extracted from sections of leaves containing sori with the Qiagen DNeasy Plant Mini kit (Valencia, CA), and all 10 field samples amplified in a real-time fluorescent PCR with the P. pachyrhizi-specific primers Ppm1 and Ppa2 (2). Infected leaves of cultivar Vuangi collected from one field each in the INERA Research Station, Kimpese-Crawford, and Kimpese-Ceco were separately washed in sterile water to collect urediniospores that were used to separately inoculate three detached leaves of susceptible cultivar TGx 1485-1D (4). Lesions on inoculated leaves developed 5 days after inoculation (DAI), and pustules (110 to 130 μm) formed 7 DAI and erupted 2 days later exuding columns of urediniospores similar in size to the initially collected isolates. Inoculation of another set of detached leaves with a spore suspension (1 × 106 spores per ml) from the first set of detached leaves resulted in typical rust symptoms. Seedlings of cultivar Williams also showed typical rust symptoms when inoculated separately with urediniospores collected from nine fields (i.e., all except Kimpese-Ceco, which was infective in the detached leaf assay). Inoculation and incubation were carried out at the FDWSRU Plant Pathogen Containment Facility at Fort Detrick as described earlier (2). The PCR assay, morphological characters of the isolates, and pathogenicity tests demonstrate that P. pachyrhizi occurs in DRC. To our knowledge, this is the first report of P. pachyrhizi infecting soybean in DRC. References: (1) O. A. Akinsanmi et al. Plant Dis. 85:97, 2001. (2) R. D. Frederick et al. Phytopathology 92:217, 2002. (3) E. Kawuki et al. J. Phytopathol. 151:7, 2003. (4) M. Twizeyimana et al. Online publication. http://www.plantmanagementnetwork.org/ infocenter/topic/soybeanrust/2006/posters/41.asp. Plant Management Network, 2006.


Impact of exogenous sequences on the characteristics of an epidemic type 2 recombinant vaccine-derived poliovirus.
Pathogenic circulating vaccine-derived polioviruses (cVDPVs) have become a major obstacle to the successful completion of the global polio eradication program. Most cVDPVs are recombinant between the oral poliovirus vaccine (OPV) and human enterovirus species C (HEV-C). To study the role of HEV-C sequences in the phenotype of cVDPVs, we generated a series of recombinants between a Madagascar cVDPV isolate and its parental OPV type 2 strain. Results indicated that the HEV-C sequences present in this cVDPV contribute to its characteristics, including pathogenicity, suggesting that interspecific recombination contributes to the phenotypic biodiversity of polioviruses and may favor the emergence of cVDPVs.


Temporal trends in incidence of time-loss injuries in four male professional North American sports over 13 seasons.
Sports-related injuries increase healthcare cost burden, and in some instances have harmful long term physical and psychological implications. There is currently a lack of comprehensive data on temporal injury trends across professional North American sports. The purpose of this study was to compare temporal trends, according to incidence and time-loss injuries, by body part in professional baseball, basketball, football, and ice hockey. Public injury data from Major League Baseball, National Basketball Association, National Football League, and National Hockey League from 2007 to December 2019 were extracted and used. A mean of 62.49 injuries per 100 players per season was recorded for all professional sports. The groin/hip/thigh reported the greatest season proportional injury incidence for baseball, football, and ice hockey, with the groin/hip/thigh as the third highest injury incidence in basketball. When stratifying by more specific body part groupings, the knee demonstrated the greatest injury proportional incidence for basketball, football, and ice hockey, with the knee as the third highest proportional injury incidence for baseball. There was an increased in basketball ankle injuries following 2011-2012 season. Football and ice hockey reported the greatest concussion proportion incidence, with football demonstrating an increase in concussions over time, and a substantial increase in concussions from the 2014 to 2015 season. These publicly extracted data and findings can be used as a shared resource for professional baseball, basketball, football, and ice hockey for future individual and across sport collaborations concerning resource allocation and decision making in order to improve player health.


Adiposity Alters Genes Important in Inflammation and Cell Cycle Division in Human Cumulus Granulosa Cell.
To determine whether obesity alters genes important in cellular growth and inflammation in human cumulus granulosa cells (GCs). Eight reproductive-aged women who underwent controlled ovarian hyperstimulation followed by oocyte retrieval for in vitro fertilization were enrolled. Cumulus GC RNA was extracted and processed for microarray analysis on Affymetrix Human Genome U133 Plus 2.0 chips. Gene expression data were validated on GCs from additional biologically similar samples using quantitative real-time polymerase chain reaction (RT-PCR). Comparison in gene expression was made between women with body mass index (BMI) <25 kg/m(2) (group 1; n = 4) and those with BMI ≥25 kg/m(2) (group 2; n = 4). Groups 1 and 2 had significantly different BMI (21.4 ± 1.4 vs 30.4 ± 2.7 kg/m(2), respectively; P = .02) but did not differ in age (30.5 ± 1.7 vs 32.7 ± 0.3 years, respectively; P = .3). Comparative analysis of gene expression profiles by supervised clustering between group 1 versus group 2 resulted in the selection of 7 differentially expressed genes: fibroblast growth factor 12 (FGF-12), protein phosphatase 1-like (PPM1L), zinc finger protein multitype 2 (ZFPM2), forkhead box M1 (FOXM1), cell division cycle 20 (CDC20), interleukin 1 receptor-like 1 (IL1RL1), and growth arrest-specific protein 7 (GAS7). FOXM1, CDC20, and GAS7 were downregulated while FGF-12 and PPM1L were upregulated in group 2 when compared to group 1. Validation with RT-PCR confirmed the microarray data except for ZFPM2 and IL1RL. As BMI increased, expression of FOXM1 significantly decreased (r = -.60, P = .048). Adiposity is associated with changes in the expression of genes important in cellular growth, cell cycle progression, and inflammation. The upregulation of the metabolic regulator gene PPM1L suggests that adiposity induces an abnormal metabolic follicular environment, potentially altering folliculogenesis and oocyte quality.


Asynchrony of mother-infant hypothalamic-pituitary-adrenal axis activity following extinction of infant crying responses induced during the transition to sleep.
This study examines change in the synchrony between mothers' and infants' physiology as 25 infants (11 males; 4 to 10 months of age) participate in a 5-day inpatient sleep training program in which they learn to self-settle through extinction of crying responses during the transition to sleep. The mothers' and infants' experience during the extinction protocol was "yoked" by the infants' behavioral signaling during the sleep transition period. Saliva was sampled for mothers and infants at initiation of infants' nighttime sleep and following infants' falling to sleep on two program days and later assayed for cortisol. As expected on the first day of the program, mothers' and infants' cortisol levels were positively associated at initiation of nighttime sleep following a day of shared activities. Also, when infants expressed distress in response to the sleep transition, mother and infant cortisol responses were again positively associated. On the third day of the program, however, results showed that infants' physiological and behavioral responses were dissociated. They no longer expressed behavioral distress during the sleep transition but their cortisol levels were elevated. Without the infants' distress cue, mothers' cortisol levels decreased. The dissociation between infants' behavioral and physiological responses resulted in asynchrony in mothers' and infants' cortisol levels. The findings are discussed in relation to understanding the determinants and implications of maternal-infant physiological synchrony in early childhood.


[Total energy value and percentage contribution of calories from macronutrients in the diet of elderly individuals from Fortaleza, state of Ceará, Brazil].
Describe the total energy value and percentage contribution of calories from macronutrients in the diet of elderly individuals living in Fortaleza/CE. This is a population-based, cross-sectional domiciliary study, which included 458 elderly individuals (66.6% women). The variables evaluated were total energy value (TEV) and the percentage contribution of calories from proteins, carbohydrates, and lipids. The results are shown as mean, standard deviation, and percentile distribution (P5, P10, P25, P50, P75, P90, P95). The Student's t-test and analysis of variance (one-way ANOVA) with LSD post-hoc tests were used to determine the statistical significance of means between two groups and among three or more groups, respectively. When comparing the mean values of TEV among categories of socioeconomic and demographic variables, statistically significant differences were found between women for ethnicity, years of schooling and socioeconomic level. Among men, differences were found for years of schooling and socioeconomic level. The mean energy value of men's diet was significantly higher than that of women (1475.8 kcal and 1236.4 kcal, respectively). The mean values of calorie percentage contribution from proteins, carbohydrates, and lipids were similar between men and women. The elderly of this study showed significant differences in mean values of TEV between sexes and between the categories years of schooling and socioeconomic level. Women also showed significant differences between the ethnic categories. The mean relative contribution of macronutrients in TEV was similar between genders and age groups.


Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry.
Recently, we identified proteins that co-purify with the human spliceosome using mass spectrometry. One of the identified proteins, CDC5L, corresponds to the human homologue of the Schizosaccharomyces pombe CDC5(+) gene product. Here we show that CDC5L is part of a larger multiprotein complex in HeLa nuclear extract that incorporates into the spliceosome in an ATP-dependent step. We also show that this complex is required for the second catalytic step of pre-mRNA splicing. Immunodepletion of the CDC5L complex from HeLa nuclear extract inhibits the formation of pre-mRNA splicing products in vitro but does not prevent spliceosome assembly. The first catalytic step of pre-mRNA splicing is less affected by immunodepleting the complex. The purified CDC5L complex in HeLa nuclear extract restores pre-mRNA splicing activity when added to extracts that have been immunodepleted using anti-CDC5L antibodies. Using mass spectrometry and database searches, the major protein components of the CDC5L complex have been identified. This work reports a first purification and characterization of a functional, human non-snRNA spliceosome subunit containing CDC5L and at least five additional protein factors.


Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) study.
Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing ≈990 mg (high flavanols), ≈520 mg (intermediate flavanols), or ≈45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P=0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P<0.05) lower in subjects assigned to high flavanols (38.10±10.94 and 104.10±28.73 seconds, respectively) and intermediate flavanols (40.20±11.35 and 115.97±28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60±17.97 and 139.23±43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P<0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50±6.75 versus 22.30±8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained ≈40% of composite z score variability through the study period (partial r(2)=0.4013; P<0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.


Synthesis and biological activity evaluation of novel peroxo-bridged derivatives as potential anti-hepatitis B virus agents.
Previous studies have demonstrated that natural steroid compounds containing a peroxide bridge exhibited potential anti-hepatitis B virus activity. To continue our research, a simple and regioselective methodology, using Eosin Y as a clean photosensitized oxidation catalyst, was developed for the synthesis of a peroxide bridge in steroids. The method that using Eosin Y as the catalyst was exposed to visible light and furbished in high yields, did not involve tedious work-up or purification, and avoided using environmentally hazardous solvents. It can be regarded as a green protocol. Moreover, a series of cholesterol and β-sitosterol derivatives containing a peroxide bridge were synthesized using this method and screened for their anti-HBV activity. Among the compounds synthesized in this research, 5α,8α-cyclicobioxygen-6-vinyl-3-oxo-cholesterone (1f, 3.13 μg ml-1) had the most potent activity with inhibition rates of 77.45% ± 6.01% and 58.73% ± 8.64% on the secretion of HBsAg and HBeAg antigens, respectively, after 8 days. Further acute toxicity test showed that the LD50 value of compound 1f was 362.46 mg kg-1 after an intraperitoneal injection in mice. Moreover, structure-activity relationships of cholesterol and β-sitosterol derivatives were briefly discussed.


Ground emergency medical services requests for helicopter transfer of ST-segment elevation myocardial infarction patients decrease medical contact to balloon times in rural and suburban settings.
ST-segment elevation myocardial infarction (STEMI) care is time-dependent. Many STEMI patients require interhospital helicopter transfer for percutaneous coronary intervention (PCI) if ground emergency medical services (EMS) initially transport the patient to a non-PCI center. This investigation models potential time savings of ground EMS requests for helicopter EMS (HEMS) transport of a STEMI patient directly to a PCI center, rather than usual transport to a local hospital with subsequent transfer. Data from a multicenter retrospective chart review of STEMI patients transferred for primary PCI by a single HEMS agency over 12 months were used to model medical contact to balloon times (MCTB) for two scenarios: a direct-to-scene HEMS response and hospital rendezvous after ground EMS initiation of transfer. Actual MCTB median time for 36 hospital-initiated transfers was 160 minutes (range = 116 to 321 minutes). Scene response MCTB median time was estimated as 112 minutes (range = 69 to 187 minutes). The difference in medians was 48 minutes (95% confidence interval [CI] = 33 to 62 minutes). Hospital rendezvous MCTB median time was estimated as 113 minutes (range = 74 to 187 minutes). The difference in medians was 47 minutes (95% CI = 32 to 62 minutes). No patient had an actual MCTB time of less than 90 minutes; in the scene response and hospital rendezvous scenarios, 2 of 36 (6%) and 3 of 36 (8%), respectively, would have had MCTB times under 90 minutes. In this setting, ground EMS initiation of HEMS transfers for STEMI patients has the potential to reduce MCTB time, but most patients will still not achieve MCTB time of less than 90 minutes.


Variable patterns of distribution of PrP(CWD) in the obex and cranial lymphoid tissues of Rocky Mountain elk (Cervus elaphus nelsoni) with subclinical chronic wasting disease.
Sections of medulla oblongata, taken at the level of the obex, palatine tonsil and medial retropharyngeal lymph node from 10,269 captive Rocky Mountain elk (Cervus elaphus nelsoni), were examined by immunohistochemical staining with monoclonal antibody for the prion protein associated with the transmissible spongiform encephalopathy of cervids, chronic wasting disease (PrP(CWD)). The protein was detected in 226 of them. On the basis of the anatomical location of the deposits in the brainstem of 183 elk, four distinct patterns of distribution of PrP(CWD) within the parasympathetic region of the dorsal motor nucleus of the vagus nerve and the adjacent nuclei were observed. Mild gross lesions of chronic wasting disease (serous atrophy of fat) were observed in only three elk, all with spongiform degeneration; the other elk were considered to be in the preclinical stage of the disease. In contrast with the relatively predictable distribution of prion protein (PrP) in the brain and cranial nodes of sheep and mule deer, the distribution of PrP(CWD) in the brain and nodes of the elk was more variable and unrelated to their PrP genotype. One hundred and fifty-five of the 226 positive elk had deposits of PrP(CWD) in the brainstem and lymphoid tissues, 43 had deposits only in the lymphoid tissue and 28 had deposits only in the brainstem.


Urinary concentrations of AICAR and mannitol in athlete population.
Both AICAR and mannitol are prohibited for use in sports, but no decisive criteria that would guide anti-doping laboratories on data interpretation have been established so far. In an attempt to help harmonize reporting and management of analytical findings, reference population data collected for US athletes are presented. Upon analysis of 12 377 samples, mean urinary AICAR concentration was found to be 647 ± 365 ng/mL with median value of 574 ng/mL, 99th percentile at 1786 ng/mL and 99.7th percentile at 2151 ng/mL. Based on these results, we suggest that any sample with AICAR concentration greater than 2000 or 2500 ng/mL be analyzed by carbon isotope ratio mass spectrometry to establish the origin. Urinary mannitol concentrations demonstrate larger variation with the mean value of 72 ± 140 μg/mL and median at 41 μg/mL (n = 6407). While the 99.7th percentile for mannitol was measured to be 1094 μg/mL, the population data alone is not sufficient to suggest a threshold value. It is also shown that the use of mannitol as a sweetener in amounts of up to 20 g per day results in a urinary concentration of about 14 mg/mL. As only intravenous mannitol is prohibited in sports, controlled excretion studies are needed to see whether intravenous administration could in fact be discriminated from dietary intake. An important observation is that mannitol present in mg/mL quantities significantly increases urine specific gravity, which makes a widely accepted normalization approach not applicable.


Stereocontrolled organocatalytic strategy for the synthesis of optically active 2,3-disubstituted cis-2,3-dihydrobenzofurans.
An intramolecular, organocatalyzed Michael addition has been developed to obtain biologically important 2,3-disubstituted cis-2,3-dihydrobenzofurans. By using mandelic acid salts of primary aminocatalysts, derived from cinchona alkaloids, the intramolecular cyclization reaction has been developed to proceed in high yield, with moderate to good diastereoselectivity, and up to 99% ee. Based on the absolute configuration of the formed 2,3-disubstituted-cis-2,3-dihydrobenzofurans and by considering the observed substrate scope restrictions, a mechanistic rationalization has been presented.


A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.
Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone. We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n = 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n = 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals. Triglyceride levels were reduced by 51.9 +/- 7.8 mg/dl with pioglitazone, but were increased by 13.1 +/- 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 +/- 0.5 vs. 2.4 +/- 0.5 mg/dl; P < 0.001) and the increase in LDL cholesterol was less (12.3 +/- 1.6 vs. 21.3 +/- 1.6 mg/dl; P < 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P < 0.001). LDL particle size increased more with pioglitazone (P = 0.005). Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.


Circulating T follicular regulatory and helper cells have memory-like properties.
Follicular Tregs (Tfr cells) inhibit antibody production, whereas follicular Th cells (Tfh cells) stimulate it. Tfr cells are found in blood; however, relatively little is known about the developmental signals for these cells or their functions. Here we demonstrated that circulating Tfr and Tfh cells share properties of memory cells and are distinct from effector Tfr and Tfh cells found within lymph nodes (LNs). Circulating memory-like Tfh cells were potently reactivated by DCs, homed to germinal centers, and produced more cytokines than did effector LN Tfh cells. Circulating memory-like Tfr cells persisted for long periods of time in vivo and homed to germinal centers after reactivation. Effector LN Tfr cells suppressed Tfh cell activation and production of cytokines, including IL-21, and inhibited class switch recombination and B cell activation. The suppressive function of this population was not dependent on specific antigen. Similar to LN effector Tfr cells, circulating Tfr cells also suppressed B and Tfh cells, but with a much lower capacity. Our data indicate that circulating memory-like Tfr cells are less suppressive than LN Tfr cells and circulating memory-like Tfh cells are more potent than LN effector Tfh cells; therefore, these circulating populations can provide rapid and robust systemic B cell help during secondary antigen exposure.


[Mouthwash solutions with microencapsuled natural extracts: Efficiency for dental plaque and gingivitis].
Mouthwash solutions are mainly used for their antiseptic properties. They currently include synthetic agents (chlorhexidine, triclosan, etc.) or essential oils (especially Listerine). Many natural extracts may also be used. These associate both antiseptic effects and direct action on host response, due to their antioxidant, immunoregulatory, analgesic, buffering, or healing properties. The best known are avocado oil, manuka oil, propolis oil, grapefruit seed extract, pycnogenol, aloe vera, Q10 coenzyme, green tea, and megamin. The development of new technologies, such as microencapsulation (GingiNat concept), may allow an in situ slow release of active ingredients during several hours, and open new perspectives for mouthwash solutions.


The study of protein conformation in solution via direct sampling by desorption electrospray ionization mass spectrometry.
The direct sampling feature of liquid sample desorption electrospray ionization (DESI) allows the ionization of liquid samples without adding acids/organic solvents (i.e., without sample pretreatment). As a result, it provides a new approach for probing protein conformation in solution. In this study, it has been observed that native protein ions are generated from proteins in water by DESI. Interestingly, the intensities of the resulting protein ions appear to be higher than those generated by ESI of the proteins in water or in ammonium acetate. For protein solutions that already contain acids/organic solvents, DESI can be used to investigate the influences of these denaturants on protein conformations and the obtained results are in good agreement with spectroscopic data. In addition, online monitoring of protein conformational changes by DESI is feasible; for instance, heat-induced unfolding of ubiquitin can be traced with DESI in water without influences of organic solvents/acids. This DESI method provides a new alternative tool for the study of protein conformation in solution.


Nanoscale heat flux between nanoporous materials.
By combining stochastic electrodynamics and the Maxwell-Garnett description for effective media we study the radiative heat transfer between two nanoporous materials. We show that the heat flux can be significantly enhanced by air inclusions, which we explain by: (a) the presence of additional surface waves that give rise to supplementary channels for heat transfer throughout the gap, (b) an increase in the contribution given by the ordinary surface waves at resonance, (c) and the appearance of frustrated modes over a broad spectral range. We generalize the known expression for the nanoscale heat flux for anisotropic metamaterials.


1,8-Cineol inhibits nuclear translocation of NF-κB p65 and NF-κB-dependent transcriptional activity.
Natural plant-derived products are commonly applied to treat a broad range of human diseases, including cancer as well as chronic and acute airway inflammation. In this regard, the monoterpene oxide 1,8-cineol, the active ingredient of the clinically approved drug Soledum®, is well-established for the therapy of airway diseases, such as chronic sinusitis and bronchitis, chronic obstructive pulmonary disease and bronchial asthma. Although clinical trials underline the beneficial effects of 1,8-cineol in treating inflammatory diseases, the molecular mode of action still remains unclear. Here, we demonstrate for the first time a 1,8-cineol-depending reduction of NF-κB-activity in human cell lines U373 and HeLa upon stimulation using lipopolysaccharides (LPS). Immunocytochemistry further revealed a reduced nuclear translocation of NF-κB p65, while qPCR and western blot analyses showed strongly attenuated expression of NF-κB target genes. Treatment with 1,8-cineol further led to increased protein levels of IκBα in an IKK-independent matter, while FRET-analyses showed restoring of LPS-associated loss of interaction between NF-κB p65 and IκBα. We likewise observed reduced amounts of phosphorylated c-Jun N-terminal kinase 1/2 protein in U373 cells after exposure to 1,8-cineol. In addition, 1,8-cineol led to decreased amount of nuclear NF-κB p65 and reduction of its target gene IκBα at protein level in human peripheral blood mononuclear cells. Our findings suggest a novel mode of action of 1,8-cineol through inhibition of nuclear NF-κB p65 translocation via IκBα resulting in decreased levels of proinflammatory NF-κB target genes and may therefore broaden the field of clinical application of this natural drug for treating inflammatory diseases.


A western Eurasian male is found in 2000-year-old elite Xiongnu cemetery in Northeast Mongolia.
We analyzed mitochondrial DNA (mtDNA), Y-chromosome single nucleotide polymorphisms (Y-SNP), and autosomal short tandem repeats (STR) of three skeletons found in a 2,000-year-old Xiongnu elite cemetery in Duurlig Nars of Northeast Mongolia. This study is one of the first reports of the detailed genetic analysis of ancient human remains using the three types of genetic markers. The DNA analyses revealed that one subject was an ancient male skeleton with maternal U2e1 and paternal R1a1 haplogroups. This is the first genetic evidence that a male of distinctive Indo-European lineages (R1a1) was present in the Xiongnu of Mongolia. This might indicate an Indo-European migration into Northeast Asia 2,000 years ago. Other specimens are a female with mtDNA haplogroup D4 and a male with Y-SNP haplogroup C3 and mtDNA haplogroup D4. Those haplogroups are common in Northeast Asia. There was no close kinship among them. The genetic evidence of U2e1 and R1a1 may help to clarify the migration patterns of Indo-Europeans and ancient East-West contacts of the Xiongnu Empire. Artifacts in the tombs suggested that the Xiongnu had a system of the social stratification. The West Eurasian male might show the racial tolerance of the Xiongnu Empire and some insight into the Xiongnu society.


The effect of three alternative keyboard designs on forearm pronation, wrist extension, and ulnar deviation: a meta-analysis.
The growth of computer keyboard use in the workplace is believed to be one important determinant of the increased prevalence of work-related musculoskeletal disorders of the upper extremity (MSD-UE). One possible contributing factor to the development of MSD-UE is the flat standard keyboard, which places the forearm and wrist in biomechanically awkward postures. This meta-analysis examines the efficacy of three alternative keyboard designs, adjustable slope (AS), split fixed-angle (FA), and adjustable open-tented (AT), in reducing forearm pronation, wrist extension, and ulnar deviation. Analyses of pooled effect size from six studies indicated that the AT had a large effect on pronation (r= 0.85) and ulnar deviation whereas the FA had a large effect only on ulnar deviation (r= 0.79). The AS was found to have a large effect (r= 0.66) on wrist extension. The FA had a moderate effect on pronation (r= 0.33) and wrist extension (r= 0.30). None of these keyboards were found to have a significant effect on all three postures. This meta-analysis has implications for clinicians by providing objective information that may assist with the selection of an alternative keyboard that best reduces an identified problematic posture.


Inhibition of hepatic gluconeogenesis by the Rp-diastereomer of adenosine cyclic 3',5'-phosphorothioate.
The specific intracellular cyclic AMP-dependent protein kinase antagonist, the Rp-diastereomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS), inhibited both basal and cyclic AMP-agonist-induced rates of gluconeogenesis in hepatocytes isolated from fasted rats. Incubation of the cells in the presence of pyruvate and lactate and either the Sp-diastereomer of adenosine cyclic 3',5'-phosphorothioate (Sp-cAMPS) or glucagon produced a concentration-dependent increase in the rate of gluconeogenic glucose production which was shifted to higher concentrations of Sp-cAMPS or glucagon in the presence of Rp-cAMPS. Incubation of the cells with Rp-cAMPS in the absence of agonist produced no increase in the rate of glucose production and, in most cases, 100 microM-Rp-cAMPS resulted in 14-20% decrease in the substrate-stimulated rate of glucose production. Sp-cAMPS-induced gluconeogenesis was inhibited half-maximally at 1 microM-Rp-cAMPS and glucagon-induced gluconeogenesis was inhibited half-maximally at 12 microM-Rp-cAMPS. Approx. 10-15% of the inhibition of gluconeogenesis observed in the presence of Rp-cAMPS was due to conversion of glucose 6-phosphate to liver glycogen, consistent with Rp-cAMPS-induced reactivation of glycogen synthase. The remaining 85-90% inhibition of gluconeogenic glucose production resulted from the action of Rp-cAMPS on the cyclic AMP-sensitive enzymes controlling the rate of gluconeogenesis.


A novel RING finger protein, Znf179, modulates cell cycle exit and neuronal differentiation of P19 embryonal carcinoma cells.
Znf179 is a member of the RING finger protein family. During embryogenesis, Znf179 is expressed in a restricted manner in the brain, suggesting a potential role in nervous system development. In this report, we show that the expression of Znf179 is upregulated during P19 cell neuronal differentiation. Inhibition of Znf179 expression by RNA interference significantly attenuated neuronal differentiation of P19 cells and a primary culture of cerebellar granule cells. Using a microarray approach and subsequent functional annotation analysis, we identified differentially expressed genes in Znf179-knockdown cells and found that several genes are involved in development, cellular growth, and cell cycle control. Flow cytometric analyses revealed that the population of G0/G1 cells decreased in Znf179-knockdown cells. In agreement with the flow cytometric data, the number of BrdU-incorporated cells significantly increased in Znf179-knockdown cells. Moreover, in Znf179-knockdown cells, p35, a neuronal-specific Cdk5 activator that is known to activate Cdk5 and may affect the cell cycle, and p27, a cell cycle inhibitor, also decreased. Collectively, these results show that induction of the Znf179 gene may be associated with p35 expression and p27 protein accumulation, which lead to cell cycle arrest in the G0/G1 phase, and is critical for neuronal differentiation of P19 cells.


Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury.
Accidental radiation exposure is a threat to human health that necessitates effective clinical planning and diagnosis. Minimally invasive biomarkers that can predict long-term radiation injury are urgently needed for optimal management after a radiation accident. We have identified serum microRNA (miRNA) signatures that indicate long-term impact of total body irradiation (TBI) in mice when measured within 24 hours of exposure. Impact of TBI on the hematopoietic system was systematically assessed to determine a correlation of residual hematopoietic stem cells (HSCs) with increasing doses of radiation. Serum miRNA signatures distinguished untreated mice from animals exposed to radiation and correlated with the impact of radiation on HSCs. Mice exposed to sublethal (6.5 Gy) and lethal (8 Gy) doses of radiation were indistinguishable for 3 to 4 weeks after exposure. A serum miRNA signature detectable 24 hours after radiation exposure consistently segregated these two cohorts. Furthermore, using either a radioprotective agent before, or radiation mitigation after, lethal radiation, we determined that the serum miRNA signature correlated with the impact of radiation on animal health rather than the radiation dose. Last, using humanized mice that had been engrafted with human CD34(+) HSCs, we determined that the serum miRNA signature indicated radiation-induced injury to the human bone marrow cells. Our data suggest that serum miRNAs can serve as functional dosimeters of radiation, representing a potential breakthrough in early assessment of radiation-induced hematopoietic damage and timely use of medical countermeasures to mitigate the long-term impact of radiation.


Sub-1 dB/cm submicrometer-scale amorphous silicon waveguide for backend on-chip optical interconnect.
We demonstrate a submicrometer-scale hydrogenated amorphous silicon (a-Si:H) waveguide with a record low propagation loss of 0.60 ± 0.02 dB/cm because of the very low infrared optical absorption of our low defect a-Si:H film, the optimized waveguide structure and the fabrication process. The waveguide has a core with a thickness of 440 nm and a width of 780 nm that underlies a 100-nm-thick ridge structure, and is fabricated by low-cost i-line stepper photolithography and with low-temperature processing at less than 350°C, making it compatible with the backend process of complementary metal oxide semiconductor (CMOS) fabrication.


The effect of substrate topography on direct reprogramming of fibroblasts to induced neurons.
Cellular reprogramming holds tremendous potential for cell therapy and regenerative medicine. Recently, fibroblasts have been directly converted into induced neurons (iNs) by overexpression of the neuronal transcription factors Ascl1, Brn2 and Myt1L. Hypothesizing that cell-topography interactions could influence the fibroblast-to-neuron reprogramming process, we investigated the effects of various topographies on iNs produced by direct reprogramming. Final iN purity and conversion efficiency were increased on micrograting substrates. Neurite branching was increased on microposts and decreased on microgratings, with a simplified dendritic arbor characterized by the reduction of MAP2(+) neurites. Neurite outgrowth increased significantly on various topographies. DNA microarray analysis detected 20 differentially expressed genes in iNs reprogrammed on smooth versus microgratings, and quantitative PCR (qPCR) confirmed the upregulation of Vip and downregulation of Thy1 and Bmp5 on microgratings. Electrophysiology and calcium imaging verified the functionality of these iNs. This study demonstrates the potential of applying topographical cues to optimize cellular reprogramming.


GHSI EMERGENCY RADIONUCLIDE BIOASSAY LABORATORY NETWORK: SUMMARY OF A RECENT EXERCISE.
The Global Health Security Initiative (GHSI) established a laboratory network within the GHSI community to develop their collective surge capacity for radionuclide bioassay in response to a radiological or nuclear emergency. A recent exercise was conducted to test the participating laboratories for their capabilities in screening and in vitro assay of biological samples, performing internal dose assessment and providing advice on medical intervention, if necessary, using a urine sample spiked with a single radionuclide, 241Am. The laboratories were required to submit their reports according to the exercise schedule and using pre-formatted templates. Generally, the participating laboratories were found to be capable with respect to rapidly screening samples for radionuclide contamination, measuring the radionuclide in the samples, assessing the intake and radiation dose, and providing advice on medical intervention. However, gaps in bioassay measurement and dose assessment have been identified. The network may take steps to ensure that procedures and practices within this network be harmonised and a follow-up exercise be organised on a larger scale, with potential participation of laboratories from the networks coordinated by the International Atomic Energy Agency and the World Health Organization.


Relationship between metabolic status and behavior in dairy cows in week 4 of lactation.
Blood metabolite and hormone concentrations are indicative of metabolic status, but blood sampling and analysis is invasive and time-consuming. Monitoring behavior can be done automatically, and behaviors may also be used as indicators of metabolic status. The aim of this study was to analyze the relationships between metabolic status and feeding behavior, lying behavior, motion index and steps of dairy cows in week 4 postpartum. Behavioral data from 81 Holstein-Friesian cows were collected using computerized feeders and accelerometers, and blood samples were collected for analysis of free-fatty acid (FFA), β-hydroxybutyrate (BHB), glucose, insulin, IGF-1 and growth hormone (GH) concentrations. First, cluster analysis was performed to categorize cows as having poor, average, good or very good metabolic status based on their plasma FFA, BHB, glucose, insulin, IGF-1 and GH concentration. Subsequently, the performance and behavior of cows in clusters with poor, average and good metabolic status were compared using GLM. Cows with a poor or average metabolic status tended to have greater fat-and-protein-corrected milk yield than cows with good metabolic status. Furthermore, cows with a poor metabolic status had a lower energy balance and dry matter intake (DMI) than cows with an average or good metabolic status and had a lower number of meals than cows with good metabolic status. Daily number of visits to the feeder and lying time tended to be positively related with metabolic status. Feeding rate (kg/min), daily meal time (min/day), number of lying bouts per day, steps and motion index were not related with metabolic status. In conclusion, better metabolic status in dairy cows in early lactation was associated with a greater DMI, increased feeding activity and a tendency to more time spent lying, compared with poor metabolic status. These results suggest that compromised metabolic status is reflected in altered cow's behavior in week 4 of lactation.


Seasonal pasture myopathy in horses in the midwestern United States: 14 cases (1998-2005).
To determine clinical signs, diagnostic findings, tissue tremetone concentrations, and clinical outcome or postmortem findings in horses evaluated for acute severe nonexertional rhabdomyolysis initially attributed to white snakeroot toxicosis. Retrospective case series. 14 horses. Records of the University of Minnesota Veterinary Medical Center or Diagnostic Laboratory were searched from 1998 to 2005. Inclusion criteria included serum creatine kinase (CK) activity > 45,000 U/L, severe nonexertional myonecrosis of proximal postural muscles at necropsy, or signs of weakness without palpably firm muscles on physical examination. Vitamin E and selenium concentrations were measured in 6 horses; tremetone concentration was measured in 7. Clinical signs occurred during unfavorable weather conditions. Clinical signs of generalized weakness (n = 11 horses), muscle fasciculations (10), lethargy (6), and prolonged recumbency (4) were common. Serum CK activity ranged from 46,487 to 959,499 U/L (reference range, 82 to 449 U/L), and aspartate transaminase activity was > 1,500 U/L (reference range, 162 to 316 U/L). Two horses survived with aggressive antioxidant and fluid treatment. Postmortem examination revealed acute severe myonecrosis with lipid accumulation primarily in neck, proximal forelimb and hind limb, intercostal, and diaphragm muscles. Histopathologic signs of myocardial necrosis were detected in 7 horses. Vitamin E and selenium concentrations were within reference limits. Tremetone was not detected in liver or urine samples. Cases of rhabdomyolysis have been attributed to white snakeroot toxicosis; however, tremetone was not detected in any horses. Similarities exist between cases of seasonal pasture myopathy and cases of atypical myopathy in Europe.