Dietary effects on life history traits in a terrestrial isopod: the importance of evaluating maternal effects and trade-offs.
Studies of life history aim to explain patterns in the evolution of reproductive investment, growth, and survival. Trade-offs between traits are a fundamental component of life history theory. In herbivorous arthropods life history traits are often responsive to variation in numerous environmental factors, especially diet quality. Using three artificial diets under controlled laboratory conditions, we examined changes in life history traits (i.e. growth rate, offspring number, offspring size, incubation period), trade-offs between traits, and maternal effect on the growth rate of offspring, in the common woodlouse (terrestrial isopod), Porcellio laevis. The high protein diet had significant impacts on offspring production, triggering a smaller-sized offspring, and demonstrating a trade-off between these last two traits. The high carbohydrate diet seldom exerted a significant effect on incubation period. The quality of dietary items evidently has important consequences on the life history of the mother and, thus, on offspring growth; the directions of these effects, however, were opposite. Mothers fed diets with high protein concentrations presented significant maternal effects, measured as offspring growth rate during later ontogeny. Our results support the notion that protein, rather than carbohydrate, concentrations in the diet limit herbivorous arthropods, and have significant consequences on life history traits, as was seen for P. laevis. Clearly, the change in phenotypic correlations between incubation period and offspring number from negative to positive is an empirical demonstration of the context dependence of life history trait trade-offs.


Genetic Diversity of Campylobacter jejuni and Campylobacter coli Isolates from Conventional Broiler Flocks and the Impacts of Sampling Strategy and Laboratory Method.
The genetic diversity of Campylobacter jejuni and Campylobacter coliisolates from commercial broiler farms was examined by multilocus sequence typing (MLST), with an assessment of the impact of the sample type and laboratory method on the genotypes of Campylobacter isolated. A total of 645C. jejuniand 106C. coli isolates were obtained from 32 flocks and 17 farms, with 47 sequence types (STs) identified. The Campylobacter jejuniisolates obtained by different sampling approaches and laboratory methods were very similar, with the same STs identified at similar frequencies, and had no major effect on the genetic profile of Campylobacter population in broiler flocks at the farm level. ForC. coli, the results were more equivocal. While some STs were widely distributed within and among farms and flocks, analysis of molecular variance (AMOVA) revealed a high degree of genetic diversity among farms forC. jejuni, where farm effects accounted for 70.5% of variance, and among flocks from the same farm (9.9% of variance for C. jejuni and 64.1% forC. coli). These results show the complexity of the population structure of Campylobacterin broiler production and that commercial broiler farms provide an ecological niche for a wide diversity of genotypes. The genetic diversity of C. jejuni isolates among broiler farms should be taken into account when designing studies to understand Campylobacter populations in broiler production and the impact of interventions. We provide evidence that supports synthesis of studies on C. jejuni populations even when laboratory and sampling methods are not identical.


Deterioration of metabolic coronary regulation in hemorrhagic shock. Role of hypoxia and the renin-angiotensin system.
The effect of hypoxia and the renin-angiotensin system on metabolic coronary regulation in hemorrhagic shock was studied in 22 anesthetized open-chest dogs. Left circumflex coronary blood flow was measured with an electromagnetic flowmeter. Dogs were ventilated with room air (n = 8) or 100% oxygen (n = 7). A third group of dogs was ventilated with room air and bilaterally nephrectomized 5 h prior to starting the experimental protocol (n = 7). After control data had been obtained, dogs were bled from the femoral arteries into a pressurized reservoir which maintained blood pressure at 45 +/- 1 mmHg. The angiotensin II receptor blocker, saralasin, was then infused i.v. (0.1, 1.0, 10.0 micrograms/kg per min). Coronary blood flow was reduced by hemorrhage, and no significant difference existed in coronary flow during hemorrhage among the three groups. Coronary sinus oxygen saturation was diminished in control animals during hemorrhage from 26% +/- 1% to 17% +/- 1% (P less than 0.05) but normal in 100% oxygen ventilated animals (30% +/- 3%) and in nephrectomized dogs (34% +/- 4%). Coronary oxygen extraction was reduced by saralasin in intact but not in nephrectomized dogs. In six additional experiments, in which blood pressure was not artificially held constant during saralasin infusion, saralasin still significantly improved coronary sinus oxygen saturation and thus reduced coronary oxygen extraction. The data suggest that both hypoxia and the renin-angiotensin system participate in the restriction of metabolic coronary regulation in hemorrhagic shock.


Immune tolerance attenuates gut dysbiosis, dysregulated uterine gene expression and high-fat diet potentiated preterm birth in mice.
Preterm delivery accounts for 85% of perinatal morbidity and mortality. Although the consumption of a high-fat diet leads to exaggerated proinflammatory responses and, in pregnant women, increased rates of spontaneous preterm birth, the underlying mechanisms remain unclear. We sought to elucidate the mechanisms by which maternal consumption of a high-fat diet leads to a dysregulated immune response and, subsequently, spontaneous preterm birth. We performed 16S ribosomal RNA sequencing of DNA extracted and amplified from stool samples and compared the gut microbiomes of lipopolysaccharide-induced pregnant mice that were maintained on a high-fat diet compared to a normal control diet. Next, we sequenced the uterine transcriptomes of the mice. To test the effect of dampening of the immune response on the microbiome, transcriptome, and risk of spontaneous preterm birth, we induced immune tolerance with repetitive subclinical doses (0.2 mg/kg/week for 8 weeks) of endotoxin and performed 16S ribosomal RNA and uterine transcriptome sequencing on these immunotolerized mice. High-fat diet potentiates lipopolysaccharide-induced preterm birth by affecting the maternal gut microbiome and uterine transcriptome and reduces antioxidant capacity in a murine model. High-fat diet consumption also increases the colonization of the gut by 5 immunogenic bacteria and decreases colonization by Lachnospiraceae_NK4A136_group. Uteri from high-fat diet mice had increased expression of genes that stimulate the inflammatory-oxidative stress axis, autophagy/apoptosis, and smooth muscle contraction. Repetitive endotoxin priming protects high-fat diet dams from spontaneous preterm birth, increases colonization of the gut by Lachnospiraceae_NK4A136_group, decreases levels of immunogenic bacteria in the gut microbiome, and reduces the number of dysregulated genes after high-fat diet consumption from 994 to 74. High-fat diet-potentiated spontaneous preterm birth is mediated by increased inflammation, oxidative stress, and gut dysbiosis. The induction of immune tolerance via endotoxin priming reverses these effects and protects high-fat diet dams from spontaneous preterm birth. Based on this work, the role of immunomodulation as a novel therapeutic approach to prevent preterm birth among women who consume high-fat diets should be explored.


Stream microbial communities and ecosystem functioning show complex responses to multiple stressors in wastewater.
Multiple anthropogenic drivers are changing ecosystems globally, with a disproportionate and intensifying impact on freshwater habitats. A major impact of urbanization are inputs from wastewater treatment plants (WWTPs). Initially designed to reduce eutrophication and improve water quality, WWTPs increasingly release a multitude of micropollutants (MPs; i.e., synthetic chemicals) and microbes (including antibiotic-resistant bacteria) to receiving environments. This pollution may have pervasive impacts on biodiversity and ecosystem services. Viewed through multiple lenses of macroecological and ecotoxicological theory, we combined field, flume, and laboratory experiments to determine the effects of wastewater (WW) on microbial communities and organic-matter processing using a standardized decomposition assay. First, we conducted a mensurative experiment sampling 60 locations above and below WWTP discharges in 20 Swiss streams. Microbial respiration and decomposition rates were positively influenced by WW inputs via warming and nutrient enrichment, but with a notable exception: WW decreased the activation energy of decomposition, indicating a "slowing" of this fundamental ecosystem process in response to temperature. Second, next-generation sequencing indicated that microbial community structure below WWTPs was altered, with significant compositional turnover, reduced richness, and evidence of negative MP influences. Third, a series of flume experiments confirmed that although diluted WW generally has positive influences on microbial-mediated processes, the negative effects of MPs are "masked" by nutrient enrichment. Finally, transplant experiments suggested that WW-borne microbes enhance decomposition rates. Taken together, our results affirm the multiple stressor paradigm by showing that different aspects of WW (warming, nutrients, microbes, and MPs) jointly influence ecosystem functioning in complex ways. Increased respiration rates below WWTPs potentially generate ecosystem "disservices" via greater carbon evasion from streams and rivers. However, toxic MP effects may fundamentally alter ecological scaling relationships, indicating the need for a rapprochement between ecotoxicological and macroecological perspectives.


Clinical and Molecular Assessment in a Female with Fragile X Syndrome and Tuberous Sclerosis.
Fragile X syndrome (FXS) and tuberous sclerosis (TSC) are genetic disorders that result in intellectual disability and an increased prevalence of autism spectrum disorders (ASD). While the clinical presentation of each disorder is distinct, the molecular causes are linked to a disruption in the mTORC1 (mammalian Target of Rapamycin Complex 1) and ERK1/2 (Extracellular signal-Regulated Kinase) signaling pathways. We assessed the clinical and molecular characteristics of an individual seen at the UC Davis MIND Institute with a diagnosis of FXS and TSC. Clinical evaluation of physical, behavioral, and cognitive impairments were performed. Additionally, total and phosphorylated proteins along the mTORC1 and ERK1/2 pathways were measured in primary fibroblast cell lines from the proband. In this case the phenotypic effects that result in a human with both FXS and TSC are shown to be severe. Changes in mTORC1 and ERK1/2 signaling proteins and global protein synthesis were not found to be noticeably different between four cohorts (typically developing, FMR1 full mutation, FMR1 full mutation and TSC1 loss of function mutation, and TSC1 loss of function mutation); however cohort sizes prevented stringent comparisons. It has previously been suggested that disruption of the mTORC1 pathway was reciprocal in TSC and FXS double knock-out mouse models so that the regulation of these pathways were more similar to wild-type mice compared to mice harboring a Fmr1-/y or Tsc2-/+ mutation alone. However, in this first reported case of a human with a diagnosis of both FXS and TSC, substantial clinical impairments, as a result of these two disorders were observed. Differences in the mTORC and ERK1/2 pathways were not clearly established when compared between individuals with either disorder, or both.


Audiological deficits after closed head injury.
Damage to the peripheral auditory structures has long been recognized as a common component of head injury. It is estimated that a majority of patients with skull trauma have resultant hearing impairment. Damage to the peripheral and/or central auditory pathways can occur as a primary or secondary injury. Considering the high incidence of hearing loss, it was considered worthwhile to conduct an in-depth investigation by administering a comprehensive audiological test battery on head-injured patients. The sample population consisted of 290 subjects with closed head injury (study group) and 50 subjects with otologically normal subjects (control group). The subjects in the study group were further divided into mild (n = 150), moderate (n = 100), and severe (n = 40) category on the basis of Glasgow Coma Scale score. The audiological assessment consisted of pure tone audiometry, speech audiometry, tympanometry, acoustic reflex testing, auditory brain stem response audiometry, and middle latency response audiometry. It is concluded that there is higher prevalence of hearing impairment in the study group compared with control group. Majority of the patients who incur hearing loss after closed head injury have mild degree of hearing impairment. A significant difference between the study and control group observed on majority of the auditory brain stem response and middle latency response parameters studied.


Medications prescribed in emergency departments for nontraumatic dental condition visits in the United States.
Prior research has documented factors associated with nontraumatic dental condition (NTDC) visits to emergency departments (EDs), but little is known about the care received by patients in EDs for NTDC visits. We examined national trends in prescription of analgesics and antibiotics in EDs for NTDC visits in the United States. We analyzed data from the National Hospital Ambulatory Medical Care survey from 1997 to 2007. We used a multivariable logistic regression model to examine factors associated with receiving analgesics and antibiotics for NTDC visits in EDs. Overall 74% received at least 1 analgesic, 56% received at least 1 antibiotic, and 13% received no medication at all during NTDC visits to EDs. The prescription of medications at EDs for NTDC visits steadily increased over time for analgesics (odds ratio=1.11/y, P<0.0001) and antibiotics (odds ratio=1.06/y, P<0.0001). In the multivariable analysis, self-pay patients had significantly higher adjusted odds of receiving antibiotics, whereas those with nondental reasons for visits and children (0-4 y) had significantly lower adjusted odds of receiving a prescription for antibiotics in EDs for NTDC visits. Children (0-4 y), adults (53-72 y), and older adults (73 y and older) had lower adjusted odds (P<0.001) of receiving analgesics. Nationally, analgesic and antibiotic prescriptions for NTDC visits to EDs have increased substantially over time. Self-pay patients had significantly higher odds of being prescribed antibiotics. Adults over 53 years and especially those 73 years and older had significantly lower odds of receiving analgesics in EDs for NTDC visits.


The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy.
Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post-partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome-wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper-polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU590 as well as novel derivative compounds induces profound, long-lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility.


Protein kinase G1 α overexpression increases stem cell survival and cardiac function after myocardial infarction.
We hypothesized that overexpression of cGMP-dependent protein kinase type 1α (PKG1α) could mimic the effect of tadalafil on the survival of bone marrow derived mesenchymal stem cells (MSCs) contributing to regeneration of the ischemic heart. MSCs from male rats were transduced with adenoviral vector encoding for PKG1α ((PKG1α)MSCs).Controls included native MSCs ((Nat)MSCs) and MSCs transduced with an empty vector ((Null)MSCs). PKG1α activity was increased approximately 20, 5 and 16 fold respectively in (PKG1α)MSCs. (PKG1α)MSCs showed improved survival under oxygen and glucose deprivation (OGD) which was evidenced by lower LDH release, caspase-3/7 activity and number of positive TUNEL cells. Anti-apoptotic proteins pAkt, pGSK3β, and Bcl-2 were significantly increased in (PKG1α)MSCs compared to (Nat)MSCs and (Null)MSCs. Higher release of multiple prosurvival and angiogenic factors such as HGF, bFGF, SDF-1 and Ang-1 was observed in (PKG1α)MSCs before and after OGD. In a female rat model of acute myocardial infarction, (PKG1α)MSCs group showed higher survival compared with (Null)MSCs group at 3 and 7 days after transplantation as determined by TUNEL staining and sry-gene quantitation by real-time PCR. Increased anti-apoptotic proteins and paracrine factors in vitro were also identified. Immunostaining for cardiac troponin I combined with GFP showed increased myogenic differentiation of (PKG1α)MSCs. At 4 weeks after transplantation, compared to DMEM group and (Null)MSCs group, (PKG1α)MSCs group showed increased blood vessel density in infarct and peri-infarct areas (62.5±7.7; 68.8±7.3 per microscopic view, p<0.05) and attenuated infarct size (27.2±2.5%, p<0.01). Heart function indices including ejection fraction (52.1±2.2%, p<0.01) and fractional shortening (24.8%±1.3%, p<0.01) were improved significantly in (PKG1α)MSCs group. Overexpression of PKG1α transgene could be a powerful approach to improve MSCs survival and their angiomyogenic potential in the infarcted heart.


Plasma cholesterol concentration and death from coronary heart disease: 10 year results of the Whitehall study.
Ten year mortality from coronary heart disease in 17,718 middle aged men was related to their initial plasma cholesterol concentrations. The relative risk of death from coronary heart disease declined with age, but the absolute excess risk did not. The risk gradient was continuous over the whole range of cholesterol concentrations, the lowest mortality being among men with concentrations below the lowest decile. It seems that, as with blood pressure, the average cholesterol concentration in the blood pressure, the average cholesterol concentration in the population is too high: lowest concentrations are prognostically the best. A quarter of all deaths from coronary heart disease related to cholesterol occurred among men with concentrations above the top decile, but 55% occurred among men with concentrations in the middle three fifths of the distribution; this figure of 55% could be reduced only by a policy aimed at lowering concentrations in the whole population.


Detecting causality in complex ecosystems.
Identifying causal networks is important for effective policy and management recommendations on climate, epidemiology, financial regulation, and much else. We introduce a method, based on nonlinear state space reconstruction, that can distinguish causality from correlation. It extends to nonseparable weakly connected dynamic systems (cases not covered by the current Granger causality paradigm). The approach is illustrated both by simple models (where, in contrast to the real world, we know the underlying equations/relations and so can check the validity of our method) and by application to real ecological systems, including the controversial sardine-anchovy-temperature problem.


Abundances of demersal sharks and chimaera from 1994-2009 scientific surveys in the central Mediterranean Sea.
Bibliographic and data gathered in scientific bottom trawl surveys carried out off the Southern Coasts of Sicily (Mediterranean Sea), from 1994 to 2009 and between a depth of 10 and 800 m, were analysed in order to prepare a checklist of demersal sharks and chimaera, which are species sensitive to fisheries exploitation. Out of the 27 previously reported demersal shark and chimaera taxa in the Mediterranean, only 23 were found in literature and 20 sampled during the surveys in the investigated area. Among the species sampled in the surveys, only 2 ubiquitous (Squalusblainville and Scyliorhinuscanicula) and 3 deep-water (Chimaeramonstrosa , Centrophorusgranulosus and Galeusmelastomus) species showed a wide geographical distribution with a consistent abundance. Excluding the rare (such as Oxynotuscentrina) or uncommon shark (e.g. Squalusacanthias), the estimated frequencies of occurrence and abundance indexes show a possible risk of local extinction for the almost exclusively (e.g. angelshark, Squatina spp.) or preferential (e.g. Scyliorhinusstellaris) neritic species.


Topoisomerase I function during Escherichia coli response to antibiotics and stress enhances cell killing from stabilization of its cleavage complex.
To explore the role of topoisomerase I in gene activation and increased RecA levels during the bacterial SOS response, as well as the effect of antibiotic treatment and stress challenge on cell killing initiated by trapped topoisomerase I cleavage complex. A mutant Escherichia coli strain with a ΔtopA mutation was used to investigate the role of topoisomerase I function in the SOS response to trimethoprim and mitomycin C. Induction of the recA and dinD1 promoters was measured using luciferase reporters of these promoters fused to luxCDABE. An increase in the RecA level following trimethoprim treatment was quantified directly by western blotting. The effect of stress challenge from trimethoprim and acidified nitrite treatments on cell killing by topoisomerase I cleavage complex accumulation was measured by the decrease in viability following induction of recombinant mutant topoisomerase I that forms a stabilized cleavage complex. Topoisomerase I function was found to be required for efficient transcriptional activation of the recA and dinD1 promoters during the E. coli SOS response to trimethoprim and mitomycin C. The role of topoisomerase I in the SOS response was confirmed with quantitative western blot analysis of RecA following trimethoprim treatment. The bactericidal effect from topoisomerase I cleavage complex accumulation was shown to be enhanced by stress challenge from trimethoprim and acidified nitrite. Bacterial topoisomerase I function is actively involved in the SOS response to antibiotics and stress challenge. Cell killing initiated by the topoisomerase I cleavage complex would be enhanced by antibiotics and the host response. These findings provide further support for bacterial topoisomerase I as a therapeutic target.


"If It Feels Right, Do It": Intuitive Decision Making in a Sample of High-Level Sport Coaches.
Comprehensive understanding and application of decision making is important for the professional practice and status of sports coaches. Accordingly, building on a strong work base exploring the use of professional judgment and decision making (PJDM) in sport, we report a preliminary investigation into uses of intuition by high-level coaches. Two contrasting groups of high-level coaches from adventure sports (n = 10) and rugby union (n = 8), were interviewed on their experiences of using intuitive and deliberative decision making styles, the source of these skills, and the interaction between the two. Participants reported similarly high levels of usage to other professions. Interaction between the two styles was apparent to varying degrees, while the role of experience was seen as an important precursor to greater intuitive practice and employment. Initially intuitive then deliberate decision making was a particular feature, offering participants an immediate check on the accuracy and validity of the decision. Integration of these data with the extant literature and implications for practice are discussed.


Retrospective Inference as a Form of Bounded Rationality, and Its Beneficial Influence on Learning.
Probabilistic models of cognition typically assume that agents make inferences about current states by combining new sensory information with fixed beliefs about the past, an approach known as Bayesian filtering. This is computationally parsimonious, but, in general, leads to suboptimal beliefs about past states, since it ignores the fact that new observations typically contain information about the past as well as the present. This is disadvantageous both because knowledge of past states may be intrinsically valuable, and because it impairs learning about fixed or slowly changing parameters of the environment. For these reasons, in offline data analysis it is usual to infer on every set of states using the entire time series of observations, an approach known as (fixed-interval) Bayesian smoothing. Unfortunately, however, this is impractical for real agents, since it requires the maintenance and updating of beliefs about an ever-growing set of states. We propose an intermediate approach, finite retrospective inference (FRI), in which agents perform update beliefs about a limited number of past states (Formally, this represents online fixed-lag smoothing with a sliding window). This can be seen as a form of bounded rationality in which agents seek to optimize the accuracy of their beliefs subject to computational and other resource costs. We show through simulation that this approach has the capacity to significantly increase the accuracy of both inference and learning, using a simple variational scheme applied to both randomly generated Hidden Markov models (HMMs), and a specific application of the HMM, in the form of the widely used probabilistic reversal task. Our proposal thus constitutes a theoretical contribution to normative accounts of bounded rationality, which makes testable empirical predictions that can be explored in future work.


INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells.
Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, occurs in human breast cancers, but how INT6 relates to carcinogenesis remains unestablished. Here, we show that INT6 is involved in the DNA damage response. INT6 was required for cell survival following γ-irradiation and G(2)-M checkpoint control. RNA interference-mediated silencing of INT6 reduced phosphorylation of the checkpoint kinases CHK1 and CHK2 after DNA damage. In addition, INT6 silencing prevented sustained accumulation of ataxia telangiectasia mutated (ATM) at DNA damage sites in cells treated with γ-radiation or the radiomimetic drug neocarzinostatin. Mechanistically, this result could be explained by interaction of INT6 with ATM, which together with INT6 was recruited to the sites of DNA damage. Finally, INT6 silencing also reduced ubiquitylation events that promote retention of repair proteins at DNA lesions. Accordingly, accumulation of the repair factor BRCA1 was defective in the absence of INT6. Our findings reveal unexpected and striking connections of INT6 with ATM and BRCA1 and suggest that the protective action of INT6 in the onset of breast cancers relies on its involvement in the DNA damage response.


What do predators really want? The role of gerbil energetic state in determining prey choice by Barn Owls.
In predator-prey foraging games, predators should respond to variations in prey state. The value of energy for the prey changes depending on season. Prey in a low energetic state and/or in a reproductive state should invest more in foraging and tolerate higher predation risk. This should make the prey more catchable, and thereby, more preferable to predators. We ask, can predators respond to prey state? How does season and state affect the foraging game from the predator's perspective? By letting owls choose between gerbils whose states we experimentally manipulated, we could demonstrate predator sensitivity to prey state and predator selectivity that otherwise may be obscured by the foraging game. During spring, owls invested more time and attacks in the patch with well-fed gerbils. During summer, owls attacked both patches equally, yet allocated more time to the patch with hungry gerbils. Energetic state per se does not seem to be the basis of owl choice. The owls strongly responded to these subtle differences. In summer, gerbils managed their behavior primarily for survival, and the owls equalized capture opportunities by attacking both patches equally.


Ten year transitions in children's experience of living in a workless household: variations by ethnic group.
Over the last few decades, there has been an increase in the proportion of children growing up in workless households, that is households in which no adult member is in paid work. This proportion has stabilised, and has declined slightly in recent years. Worklessness among households with children is viewed as a cause for concern for two reasons: firstly, because children in workless households are much more likely to be growing up in poverty; secondly, because of concern that worklessness in families with children may be subject to intergenerational transmission.We know surprisingly little about children's experience of household worklessness over time, particularly over their childhood as a whole, even though worklessness is heavily implicated in higher poverty risks. Children from most minority ethnic groups are at substantially higher risk of household worklessness than those from the majority. For some ethnic groups, children's rates of living in a workless household are associated with high rates of lone parenthood. For others it is worklessness in couple parent families that predominates. This article uses the Office for National Statistics (ONS) Longitudinal Study to explore differences in risks of worklessness over time, among ethnic groups within a single cohort of children who are observed at two time points, 10 years apart.List of tables, 71.


Sex differences in left-handedness: a meta-analysis of 144 studies.
Human handedness, a marker for language lateralization in the brain, continues to attract great research interest. A widely reported but not universal finding is a greater male tendency toward left-handedness. Here the authors present a meta-analysis of k = 144 studies, totaling N = 1,787,629 participants, the results of which demonstrate that the sex difference is both significant and robust. The overall best estimate for the male to female odds ratio was 1.23 (95% confidence interval = 1.19, 1.27). The widespread observation of this sex difference is consistent with it being related to innate characteristics of sexual differentiation, and its observed magnitude places an important constraint on current theories of handedness. In addition, the size of the sex difference was significantly moderated by the way in which handedness was assessed (by writing hand or by other means), the location of testing, and the year of publication of the study, implicating additional influences on its development.


Hyperkalemia-induced acute flaccid paralysis: a case report.
Acute flaccid paralysis is a medical emergency that may be caused by primary neuro-muscular disorders, metabolic alterations, and iatrogenic effects. Severe hyperkalemia is also a potential cause, especially in elderly patients with impaired renal function. Early diagnosis is essential for appropriate management. Here, we report the case of a 78-year-old woman with hypertension and diabetes presenting to the emergency department because of pronounced asthenia, rapidly evolving in quadriparesis. Laboratory examinations showed severe hyperkalemia of 9.9 mmol/L, metabolic acidosis, kidney failure (creatinine 1.6 mg/dl), and hyperglycemia (501 mg/dl). The electrocardiography showed absent P-wave, widening QRS, and tall T-waves. The patient was immediately treated with medical therapy and a hemodialysis session, presenting a rapid resolution of electrocardiographic and neurological abnormalities. This case offers the opportunity to discuss the pathogenesis, the clinical presentation, and the management of hyperkalemia-induced acute flaccid paralysis.


Genetic Variation in Pattern Recognition Receptors and Adaptor Proteins Associated With Development of Chronic Q Fever.
Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptors or adaptors would result in an increased likelihood to develop chronic Q fever. Twenty-four single-nucleotide polymorphisms in genes encoding Toll-like receptors, nucleotide-binding oligomerization domain-like receptor-2, αvβ3 integrin, CR3, and adaptors myeloid differentiation primary response protein 88 (MyD88), and Toll interleukin 1 receptor domain-containing adaptor protein (TIRAP) were genotyped in 139 patients with chronic Q fever and in 220 controls with cardiovascular risk-factors and previous exposure to C. burnetii. Associations between these single-nucleotide polymorphisms and chronic Q fever were assessed by means of univariate logistic regression models. Cytokine production in whole-blood stimulation assays was correlated with relevant genotypes. Polymorphisms in TLR1 (R80T), NOD2 (1007fsX1), and MYD88 (-938C>A) were associated with chronic Q fever. No association was observed for polymorphisms in TLR2, TLR4, TLR6, TLR8, ITGAV, ITGB3, ITGAM, and TIRAP. No correction for multiple testing was performed because only genes with a known role in initial recognition of C. burnetii were included. In the whole-blood assays, individuals carrying the TLR1 80R-allele showed increased interleukin 10 production with C. burnetii exposure. Polymorphisms in TLR1 (R80T), NOD2 (L1007fsX1), and MYD88 (-938C>A) are associated with predisposition to development of chronic Q fever. For TLR1, increased interleukin 10 responses to C. burnetii in individuals carrying the risk allele may contribute to the increased risk of chronic Q fever.


Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative.
To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA). A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008-09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice. A total of 49,242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice. Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice.


Longitudinal mapping of protective CD4+ T cell responses against HCV: analysis of fluctuating dominant and subdominant HLA-DR11 restricted epitopes.
Cellular immunity plays an important role in the control of persistent virus infections such as hepatitis C virus (HCV). Antiviral CD4(+) T cell responses have been shown to accompany resolution of acute disease and there is also a consistent association between HLA Class II genes, notably HLADRB1*1101 (and the closely linked HLADQB1*0301) and disease resolution. We initially mapped longitudinal CD4(+) T cell responses in an individual after spontaneous resolution of acute HCV, and identified three HLA-DR11-restricted responses which vary in immunodominance over time. Functional assays and HLA Class II tetramer staining revealed one to be a response to a commonly recognized epitope, NS3(1248-1261), although cytokine capture assays showed these specific cells to be at a very low frequency. In this patient, and in others reported, this most frequently recognized HLA-DR11 restricted epitope is not immunodominant. We analysed whether sequence variability within and between genotypes might account for differences in recognition of HLA-DR11 restricted epitopes. We found that a limited number, including NS3(1248-1261), showed extreme sequence conservation. Within NS3, the ability of peptides to accept amino acid substitutions was clearly related to the structure of the protein. Overall the data provide a deeper understanding of the relationship between protein structure and variability of HLA-DR11 restricted peptides and may explain the apparent dominance of responses to NS3(1248-1261) across studies but not within an individual immune response.


Nutritional risk in the urban population of Ouro Preto, southeastern region of Brazil: the Ouro Preto heart study.
To estimate the prevalence of combined nutritional risk according to sociodemographic and sedentarism characteristics of the urban population of Ouro Preto, state of Minas Gerais, Brazil. This cross-sectional study was conducted with a probability sampling of 768 subjects aged 15 years or older. Nutritional risk (NR) was defined according to the BMI and WC classification criteria adopted by the National Institutes of Health. Isolated NR (INR) was defined as women with WC > 80 cm and men with WC > 94 cm, and the combined nutritional risk (CNR) as the same WC values mentioned above and/or BMI > 25 kg/m(2). Binary logistic regression and the Hosmer & Lemeshow test were used to construct and adjust these models. INR was observed in several BMI categories for both women and men, with the following results: 19.1% and 1.4% among those with normal weight, 91.7% and 56% in overweight patients, and 98.5% and 80% in obese patients, respectively. Age and level of education were independently associated with the CNR. Odds ratios (OR) for CNR in women and men over 60 years of age were 9.94 and 14.35, respectively, when compared to younger patients. For women with < 4 years of schooling, the OR was 1.83 compared to patients with more than 4 years of school attendance, while among men with an average number of years of school attendance, the OR was 2.55 relative to those with more years of schooling. These findings show that age and education have an independent effect on the probability of CNR occurrence, and also that a joint analysis of BMI and WC is important in screening groups for nutritional risk.


Pain management and symptoms of substance dependence among patients with sickle cell disease.
Concerns about dependence on prescribed analgesia may compromise pain management, but there was previously little reliable evidence about substance dependence among patients with sickle cell disease (SCD). We conducted in-depth, semi-structured interviews with SCD patients in London, UK, to assess DSM-IV symptoms of substance dependence and abuse. Criteria were applied to differentiate between pain-related symptoms, which corresponded to the DSM-IV symptoms but involved analgesics used to control pain, and non-pain-related symptoms, which involved analgesic use beyond pain management. Pain-related symptoms are informative about how the pattern of recurrent acute pain in SCD may make patients vulnerable to perceptions of drug dependence. Non-pain-related symptoms are informative about more stringently defined dependence on analgesia in SCD. Inter-rater reliability was high, with mean Kappa coefficients of 0.67-0.88. The criteria could be used to assess analgesic dependence in other painful conditions. Pain-related symptoms were more frequent, accounting for 88% of all symptoms reported. When pain-related symptoms were included in the assessment, 31% of the sample met the DSM-IV criteria for substance dependence, compared with only 2% when the assessment was restricted to non-pain-related symptoms. Qualitative analysis of participants' descriptions of analgesic use showed that active coping attempts (attempts to anticipate pain and avoid hospital admissions) and awareness of dependence were themes in descriptions of both pain-related and non-pain-related symptoms. Seeking a more normal lifestyle and impaired activities were themes associated with pain-related symptoms. Psychological disturbance was a theme associated with non-pain-related symptoms. The implications are for more responsive treatment of pain in SCD and greater awareness of how patients' pain coping may be perceived as analgesic dependence. Further research could examine ways that pain-related and non-pain-related symptoms of dependence may be associated with other pain coping strategies and with the outcomes of treatment for painful episodes in hospital.


Perceptions of resident physicians about management of inpatient hyperglycemia in an urban hospital.
Information regarding practitioner beliefs about inpatient diabetes care is limited. To assess resident physician attitudes about inpatient hyperglycemia and determine perceived barriers to optimal glycemic control in an urban hospital setting. A previously developed questionnaire was modified and administered. Residents were asked about the importance of inpatient glucose control, desirable glucose ranges, and problems encountered when managing hyperglycemia. Urban teaching hospital. Of 85 resident physicians, 66 completed the survey (mean age, 31 years; 47% men; 33% in first residency year). Most respondents categorized glucose control as "very important" in critically-ill and perioperative patients but only "somewhat important" in non-critically-ill patients. Most residents said they would target a therapeutic glucose range within the recommended levels. Most residents (88%) also said they felt "very comfortable" or "somewhat comfortable" using subcutaneous insulin therapy, whereas some were "not at all comfortable" with either subcutaneous (11%) or intravenous (18%) administration. In general, respondents were not very familiar with existing institutional policies and preprinted order sets. The most commonly reported barrier to management of inpatient hyperglycemia was lack of knowledge about appropriate insulin regimens and their use. Anxiety about hypoglycemia was only the third most frequent concern. Most residents acknowledged the importance of good glucose control in hospitalized patients and chose target glucose ranges consistent with existing guidelines. Lack of knowledge about insulin treatment options was the most commonly cited barrier to ideal management. Educational programs should emphasize inpatient treatment strategies for glycemic control.


Analysis in vitro and in vivo of the transcriptional regulator CrgA of Neisseria meningitidis upon contact with target cells.
Contact between CrgA, a LysR-like regulatory protein in Neisseria meningitidis, and DNA is involved in the repression of several bacterial genes upon contact with epithelial cells. We used a defined in vitro system containing crgA promoter, purified RNA polymerase (RNAP) and purified CrgA protein to demonstrate that CrgA was directly responsible for this transcriptional repression. Interaction between the C-terminal domain of CrgA and the RNAP led to the production of short abortive transcripts, suggesting that CrgA may act by preventing RNAP from clearing the promoter. We probed the regulation by CrgA of its own production by analysing CrgA-DNA contacts during cell-bacteria interaction by assaying in vivo protection against dimethyl sulphate (DMS) methylation. Comparison of DMS footprints in vitro and in vivo suggested that CrgA repressed transcription through specific base contacts, probably in the major groove of the DNA double helix, resulting in DNA looping. Upon contact with target cells, CrgA was released from the DNA, allowing transcription of the target gene to proceed to elongation and facilitating tight control of the expression of genes regulated by CrgA.


The Tagging Procedure of Visible Implant Elastomers Influences Zebrafish Individual and Social Behavior.
One commonly used method to preserve individual identity in the study of social behavior of zebrafish is through silicone-based visible implant elastomers (VIEs), which represent a safe and durable tagging procedure. While the effects of VIE tagging on welfare and general health have been addressed in detail, whether this procedure influences social behavior remains unclear. In this study, we compared individual and group behaviors exhibited by shoals composed of three individuals: two nontagged and one (focal subject) that was either nontagged (control condition) or sham-, purple-, blue-, or yellow tagged. Traditional behavioral parameters of activity, shoaling, and schooling (speed, polarization, and interindividual distances), along with an information-theoretic measure of social interaction (transfer entropy), were used to study the effect of tagging. Our findings indicate that tagging procedure per se significantly increased individual speed of the tagged subjects and of the group. The tagging procedure also altered the level of interaction between individuals, measured by transfer entropy. Conversely, tagging procedure did not influence shoaling and schooling tendencies. These findings suggest that VIE tagging may elicit some level of stress, which may affect some behavioral responses more than others. We recommend use of alternative methods such as multitracking systems when possible.


[Prognosis of surgically treated thymic epithelial tumors].
This study was performed to clarify the prognosis of patients with surgically treated thymic epithelial tumors. The records of 131 patients who underwent surgical treatment during 1985-2005 were retrospectively reviewed. Pathologic review was done according to the WHO classification of tumors of the thymus. Patients characteristics were: 76 male and 55 fimale; average age 53 (range 20-80) years; tumor stage was stage I in 42, stage II in 43, stage III in 23, stage IVa in 15, stage IVb in 1, and thymic carcinoma (squamous cell carcinoma) in 7 based on Masaoka's staging. There were 7 cases of type A, 23 of type AB, 30 of type B1, 27 of type B2, 29 of type B3, and 15 of type C. Surgical procedures performed were 5 partial resections, 5 tumoretomies, 5 thymectomies, 65 extended thymectomies, 4 tumorectomies plus adjunctive resections of surrounding tissue, and 51 extended thymectomies plus tumorectomies plus adjunctive resections of surrounding tissue including the pleura, pericardium, lung, and great vessels. Five-, 10-, and 15-year survival rates by Masaoka stage were 100%, 100%, and 100% in stage I; 100%, 100%, and 87.5% in stage II; 100%, 87.5%, and 87.5% in stage III; 71.1%, 53.3%, and 53.3% in stage IVa; and 42.9%, 42.9%, and 0% in thymic carcinoma. The prognosis of patients with stage IVa and thymic carcinoma was thus significantly poorer compared with that in the other groups. According to the WHO classification, the 5-year survival rate of type A was 100%, and the 5-, 10-, and 15-year survival rates were 100%, 100%, and 100% in type AB; 100%, 100%, and 75.0% in type B1; 92.6%, 86.4%, and 86.4% in type B2; 95.5%, 95.5%, and 81.8% in type B3; and 57.1%, 42.9%, and 0% in type C. The survival rate of patients with type C was the poorest and there was a significant difference between type C and all other groups. The prognosis of patients with thymic epithelial tumors after resection is thought to be determined by histologic classification and clinical invasiveness. In particular, patients with type B3 and type C thymomas should be considered for multidisciplinary treatment.


A general reinforcement learning algorithm that masters chess, shogi, and Go through self-play.
The game of chess is the longest-studied domain in the history of artificial intelligence. The strongest programs are based on a combination of sophisticated search techniques, domain-specific adaptations, and handcrafted evaluation functions that have been refined by human experts over several decades. By contrast, the AlphaGo Zero program recently achieved superhuman performance in the game of Go by reinforcement learning from self-play. In this paper, we generalize this approach into a single AlphaZero algorithm that can achieve superhuman performance in many challenging games. Starting from random play and given no domain knowledge except the game rules, AlphaZero convincingly defeated a world champion program in the games of chess and shogi (Japanese chess), as well as Go.


Comparison of 99mTc-DMSA renal scintigraphy with biochemical and histopathological findings in animal models of acute kidney injury.
Biochemical and histological assays are currently used for the diagnosis and characterization of kidney injury. The purpose of this study was to compare technetium-99m-labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy, as a non-invasive method, with common biochemical and histopathological methods in two animal models of acute kidney injury. Nephrotoxicity was induced either by gentamicin (100 mg/kg/day for one week) or unilateral ureteral ligation (UUO). Renal scintigraphy was performed 1 h after intravenous injection of 99mTc-DMSA (3 mCi). Furthermore, plasma levels of blood urea nitrogen (BUN), creatinine, sodium, and potassium were determined using an autoanalyzer. At the end of experiments, kidneys were excised for the measurement of activity uptake (mCi/gr) using a dose calibrator as well as histopathological examinations with hematoxylin and eosin (H&E) staining. There was a significant decrease in 99mTc-DMSA uptake in both gentamicin (P value = 0.049) and UUO (P value = 0.034) groups, and it was more significant in the former. The levels of BUN and creatinine increased in both gentamicin and UUO groups, while the levels of sodium and potassium remained unchanged. Furthermore, a strong correlation was found between DMSA uptake and histopathological findings. Scintigraphy with 99mTc-DMSA is capable of detection of kidney injury in both gentamicin and UUO groups. Moreover, a significant correlation was found between scintigraphy parameters and histopathological findings. This suggests 99mTc-DMSA as a non-invasive method for the evaluation of kidney injury induced by drugs or anatomical disorders.


The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK.
Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been implicated in β-cell death in type 1 and type 2 diabetes. However, the UPR is also a fundamental mechanism required for β-cell adaptation and survival. The mechanisms regulating the transition from adaptive to apoptotic UPR remain to be clarified. Here, we investigated the relationships between XBP1, CHOP and JNK in the transition from adaptive to apoptotic UPR and β-cell death in models of type 1 and type 2 diabetes. XBP1 inhibition potentiated cell death induced by pro-inflammatory cytokines or the saturated fatty acid palmitate in MIN6 β-cells. This response was prevented by CHOP inhibition. IRE1/XBP1 inhibition led to alterations in islets from diabetes-resistant ob/ob mice that resemble those found in diabetes, including increases in cell death and inflammation and antioxidant gene expression. Similarly, IRE1/XBP1 inhibition increased cell death in islets from NOD mice. On the other hand, JNK inhibition: 1) increased adaptive UPR and reduced cell death in islets from diabetic db/db mice, and 2) restored adaptive UPR while protecting against apoptotic UPR gene expression and β-cell death and dysfunction following cytokine exposure. These findings suggest that the balance between XBP1-mediated adaptive and CHOP-dependent apoptotic UPR is critically important for β-cell survival during ER stress. JNK activation regulates the transition from adaptive to apoptotic UPR, thus providing a mechanism for β-cell propensity to cell death rather than ER stress adaptation in type 1 and type 2 diabetes.


Remote health diagnosis and monitoring in the time of COVID-19.
Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. The clinical spectrum of SARS-CoV-2 pneumonia requires early detection and monitoring, within a clinical environment for critical cases and remotely for mild cases, with a large spectrum of symptoms. The fear of contamination in clinical environments has led to a dramatic reduction in on-site referrals for routine care. There has also been a perceived need to continuously monitor non-severe COVID-19 patients, either from their quarantine site at home, or dedicated quarantine locations (e.g. hotels). In particular, facilitating contact tracing with proximity and location tracing apps was adopted in many countries very rapidly. Thus, the pandemic has driven incentives to innovate and enhance or create new routes for providing healthcare services at distance. In particular, this has created a dramatic impetus to find innovative ways to remotely and effectively monitor patient health status. In this paper, we present a review of remote health monitoring initiatives taken in 20 states during the time of the pandemic. We emphasize in the discussion particular aspects that are common ground for the reviewed states, in particular the future impact of the pandemic on remote health monitoring and consideration on data privacy.


Protection of p(+)-n-Si Photoanodes by Sputter-Deposited Ir/IrOx Thin Films.
Sputter deposition of Ir/IrOx on p(+)-n-Si without interfacial corrosion protection layers yielded photoanodes capable of efficient water oxidation (OER) in acidic media (1 M H2SO4). Stability of at least 18 h was shown by chronoamperomety at 1.23 V versus RHE (reversible hydrogen electrode) under 38.6 mW/cm(2) simulated sunlight irradiation (λ > 635 nm, AM 1.5G) and measurements with quartz crystal microbalances. Films exceeding a thickness of 4 nm were shown to be highly active though metastable due to an amorphous character. By contrast, 2 nm IrOx films were stable, enabling OER at a current density of 1 mA/cm(2) at 1.05 V vs. RHE. Further improvement by heat treatment resulted in a cathodic shift of 40 mV and enabled a current density of 10 mA/cm(2) (requirements for a 10% efficient tandem device) at 1.12 V vs. RHS under irradiation. Thus, the simple IrOx/Ir/p(+)-n-Si structures not only provide the necessary overpotential for OER at realistic device current, but also harvest ∼100 mV of free energy (voltage) which makes them among the best-performing Si-based photoanodes in low-pH media.


Ebola virus disease: An update on current prevention and management strategies.
Ebola virus disease (EVD) is characterised by systemic viral replication, immuno-suppression, abnormal inflammatory responses, large volume fluid and electrolyte losses, and high mortality in under-resourced settings. There are various therapeutic strategies targeting EVD including vaccines utilizing different antigen delivery methods, antibody-based therapies and antiviral drugs. These therapies remain experimental, but received attention following their use particularly in cases treated outside West Africa during the 2014-15 outbreak, in which 20 (80%) out of 25 patients survived. Emerging data from current trials look promising and are undergoing further study, however optimised supportive care remains the key to reducing mortality from EVD.


Quality assurance of computer-aided detection and diagnosis in colonoscopy.
Recent breakthroughs in artificial intelligence (AI), specifically via its emerging sub-field "deep learning," have direct implications for computer-aided detection and diagnosis (CADe and/or CADx) for colonoscopy. AI is expected to have at least 2 major roles in colonoscopy practice-polyp detection (CADe) and polyp characterization (CADx). CADe has the potential to decrease the polyp miss rate, contributing to improving adenoma detection, whereas CADx can improve the accuracy of colorectal polyp optical diagnosis, leading to reduction of unnecessary polypectomy of non-neoplastic lesions, potential implementation of a resect-and-discard paradigm, and proper application of advanced resection techniques. A growing number of medical-engineering researchers are developing both CADe and CADx systems, some of which allow real-time recognition of polyps or in vivo identification of adenomas, with over 90% accuracy. However, the quality of the developed AI systems as well as that of the study designs vary significantly, hence raising some concerns regarding the generalization of the proposed AI systems. Initial studies were conducted in an exploratory or retrospective fashion by using stored images and likely overestimating the results. These drawbacks potentially hinder smooth implementation of this novel technology into colonoscopy practice. The aim of this article is to review both contributions and limitations in recent machine-learning-based CADe and/or CADx colonoscopy studies and propose some principles that should underlie system development and clinical testing.


Introduction to the special issue: Tree invasions: towards a better understanding of their complex evolutionary dynamics.
Many invasive plants show evidence of trait-based evolutionary change, but these remain largely unexplored for invasive trees. The increasing number of invasive trees and their tremendous impacts worldwide, however, illustrates the urgent need to bridge this knowledge gap to apply efficient management. Consequently, an interdisciplinary workshop, held in 2015 at Stellenbosch University in Stellenbosch, South Africa, brought together international researchers to discuss our understanding of evolutionary dynamics in invasive trees. The main outcome of this workshop is this Special Issue of AoB PLANTS. The collection of papers in this issue has helped to identify and assess the evolutionary mechanisms that are likely to influence tree invasions. It also facilitated expansion of the unified framework for biological invasions to incorporate key evolutionary processes. The papers cover a wide range of evolutionary mechanisms in tree genomes (adaptation), epigenomes (phenotypic plasticity) and their second genomes (mutualists), and show how such mechanisms can impact tree invasion processes and management. The special issue provides a comprehensive overview of the factors that promote and mitigate the invasive success of tree species in many parts of the world. It also shows that incorporating evolutionary concepts is crucial for understanding the complex drivers of tree invasions and has much potential to improve management. The contributions of the special issue also highlight many priorities for further work in the face of ever-increasing tree invasions; the complexity of this research needs calls for expanded interdisciplinary research collaborations.


Enhancing the enzymatic digestibility of sugarcane bagasse through the application of an ionic liquid in combination with an acid catalyst.
Various ionic liquids have been identified as effective pretreatment solvents that can enhance the cellulose digestibility of lignocellulose by removing lignin, one of the main factors contributing to the recalcitrant nature of lignocellulose. 1-Butyl-3-methylimidazolium methylsulfate ([BMiM]MeSO(4)) is a potential delignification reagent, hence its application as a pretreatment solvent for sugarcane bagasse (SB) was investigated. The study also evaluated the benefit of an acid catalyst (i.e., H(2) SO(4)) and the effect of pretreatment conditions, which varied within a time and temperature range of 0-240 min and 50-150°C, respectively. The use of an acid catalyst contributed to a more digestible solid and a higher degree of delignification. However, the [BMiM]MeSO(4)-H(2) SO(4) combination failed to produce a fully digestible solid, as a maximum cellulose digestibility of 77% (w/w) was obtained at the optimum pretreatment condition of 125°C for 120 min. Furthermore, up to half of the lignin content could be extracted during pretreatment, while simultaneously extensive, sometimes complete, removal of xylan, the presence of which, also hampers cellulose digestibility. Hence, [BMiM]MeSO(4) has been identified an effective pretreatment solvent for SB as the application thereof both significantly improved digestibility, and simultaneously removed two of the main factors contributing to the recalcitrant nature of lignocellulose. As xylan and lignin have potential value as precursor chemicals, the existing process may in future be extended toward substrate fractionation, a biorefinery concept where value is added to all feedstock constituents.


Suicidal ideation among surgeons in Italy and Sweden - a cross-sectional study.
Suicidal ideation is more prevalent among physicians, compared to the population in general, but little is known about the factors behind surgeons' suicidal ideation. A surgeon's work environment can be competitive and characterised by degrading experiences, which could contribute to burnout, depression and even thoughts of suicide. Being a surgeon has been reported to be predictor for not seeking help when psychological distressed. The aim of the present study was to investigate to what extent surgeons in Italy and Sweden are affected by suicidal ideation, and how suicidal ideation can be associated with psychosocial work conditions. A cross-sectional study of surgeons was performed in Italy (N = 149) and Sweden (N = 272), where having suicidal ideation was the outcome variable. Work-related factors, such as harassment, depression and social support, were also measured. Suicidal ideation within the previous twelve months was affirmatively reported by 18% of the Italian surgeons, and by 12% of the Swedish surgeons in the present study. The strongest association with having recent suicidal ideation for both countries was being subjected to degrading experiences/harassment at work by a senior physician. Sickness presenteeism, exhaustion and disengagement were related to recent suicidal ideation among Italian surgeons, while role conflicts and sickness presenteeism were associated with recent suicidal ideation in the Swedish group. For both countries, regular meetings to discuss situations at work were found to be protective. A high percentage of surgeons at two university hospitals in Italy and Sweden reported suicidal ideation during the year before the investigation. This reflects a tough workload, including sickness presenteeism, harassment at work, exhaustion/disengagement and role conflicts. Regular meetings to discuss work situations might be protective.


Functionalized bis(thiosemicarbazonato) complexes of zinc and copper: synthetic platforms toward site-specific radiopharmaceuticals.
Two new types of unsymmetrical bis(thiosemicarbazone) proligands and their neutral zinc(II) and copper(II) complexes have been synthesized. These bifunctional ligands both chelate the metal ions and provide pendent amino groups that can be readily functionalized with biologically active molecules. Functionalization has been demonstrated by the synthesis of three water-soluble glucose conjugates of the new zinc(II) bis(thiosemicarbazonato) complexes, and their copper(II) analogues have been prepared in aqueous solution via transmetalation. A range of techniques including NMR, electron paramagnetic resonance, cyclic voltammetry, high-performance liquid chromatography (HPLC), UV/vis, and fluorescence emission spectroscopy have been used to characterize the complexes. Four compounds, including two zinc(II) complexes, have been characterized by X-ray crystallography. The connectivity and conformation of the glucose conjugates have been assigned by NMR spectroscopy. Time-dependent density functional theory calculations have been used to assign the electronic transitions of the copper(II) bis(thiosemicarbazonato) chromophore. Two copper-64-radiolabeled complexes, including one glucose conjugate, have been prepared and characterized using radio-HPLC, and transmetalation is shown to be a viable method for radiolabeling compounds with copper radionuclides. Preliminary cell washout studies have been performed under normoxic conditions, and the uptake and intracellular distribution have been studied using confocal fluorescence microscopy.


The Effect of Digestive Capacity on the Intake Rate of Toxic and Non-Toxic Prey in an Ecological Context.
Digestive capacity often limits food intake rate in animals. Many species can flexibly adjust digestive organ mass, enabling them to increase intake rate in times of increased energy requirement and/or scarcity of high-quality prey. However, some prey species are defended by secondary compounds, thereby forcing a toxin limitation on the forager's intake rate, a constraint that potentially cannot be alleviated by enlarging digestive capacity. Hence, physiological flexibility may have a differential effect on intake of different prey types, and consequently on dietary preferences. We tested this effect in red knots (Calidris canutus canutus), medium-sized migratory shorebirds that feed on hard-shelled, usually mollusc, prey. Because they ingest their prey whole and crush the shell in their gizzard, the intake rate of red knots is generally constrained by digestive capacity. However, one of their main prey, the bivalve Loripes lucinalis, imposes a toxin constraint due to its symbiosis with sulphide-oxidizing bacteria. We manipulated gizzard sizes of red knots through prolonged exposure to hard-shelled or soft foods. We then measured maximum intake rates of toxic Loripes versus a non-toxic bivalve, Dosinia isocardia. We found that intake of Dosinia exponentially increased with gizzard mass, confirming earlier results with non-toxic prey, whereas intake of Loripes was independent of gizzard mass. Using linear programming, we show that this leads to markedly different expected diet preferences in red knots that try to maximize energy intake rate with a small versus a large gizzard. Intra- and inter-individual variation in digestive capacity is found in many animal species. Hence, the here proposed functional link with individual differences in foraging decisions may be general. We emphasize the potential relevance of individual variation in physiology when studying trophic interactions.


Coexistence of guanylate cyclase and atrial natriuretic factor receptor in a 180-kD protein.
Atrial natriuretic factor (ANF) is a peptide hormone that is released from atria and regulates a number of physiological processes, including steroidogenesis in adrenal cortex and testes. The parallel stimulation of membrane guanylate cyclase and corticosterone production in isolated fasciculata cells of rat adrenal cortex has supported the hypothesis of a mediatory role for cyclic guanosine monophosphate (cyclic GMP) in signal transduction. A novel particulate guanylate cyclase tightly coupled with ANF receptor was purified approximately 273,000-fold by two-step affinity chromatography. The enzyme had a molecular size of 180 kilodaltons and was acidic in nature with a pI of 4.7. Its specific activity was 1800 nanomoles of cyclic GMP formed per minute per milligram of protein. The purified enzyme bound ANF with a specific binding activity of 4.01 nanomoles per milligram of protein, a value that is close to the theoretical binding activity of 5.55 nanomoles per milligram of protein for 1 mole of the ligand binding 1 mole of the receptor protein. These results indicate that the guanylate cyclase-coupled ANF receptor exists in a 180-kilodalton protein of rat adrenocortical carcinoma and represent a step toward the elucidation of the basic mechanism of cyclic GMP-mediated transmembrane signal transduction in response to a hormone.


Evaluating the effects of white matter multiple sclerosis lesions on the volume estimation of 6 brain tissue segmentation methods.
The accuracy of automatic tissue segmentation methods can be affected by the presence of hypointense white matter lesions during the tissue segmentation process. Our aim was to evaluate the impact of MS white matter lesions on the brain tissue measurements of 6 well-known segmentation techniques. These include straightforward techniques such as Artificial Neural Network and fuzzy C-means as well as more advanced techniques such as the Fuzzy And Noise Tolerant Adaptive Segmentation Method, fMRI of the Brain Automated Segmentation Tool, SPM5, and SPM8. Thirty T1-weighted images from patients with MS from 3 different scanners were segmented twice, first including white matter lesions and then masking the lesions before segmentation and relabeling as WM afterward. The differences in total tissue volume and tissue volume outside the lesion regions were computed between the images by using the 2 methodologies. Total gray matter volume was overestimated by all methods when lesion volume increased. The tissue volume outside the lesion regions was also affected by white matter lesions with differences up to 20 cm(3) on images with a high lesion load (≈50 cm(3)). SPM8 and Fuzzy And Noise Tolerant Adaptive Segmentation Method were the methods less influenced by white matter lesions, whereas the effect of white matter lesions was more prominent on fuzzy C-means and the fMRI of the Brain Automated Segmentation Tool. Although lesions were removed after segmentation to avoid their impact on tissue segmentation, the methods still overestimated GM tissue in most cases. This finding is especially relevant because on images with high lesion load, this bias will most likely distort actual tissue atrophy measurements.


[Resistance mutation patterns of hepatitis B virus in patients with suboptimal response to adefovir dipivoxil therapy after lamivudine resistance].
To investigate the resistance mutation patterns of hepatitis B virus(HBV) during adefovir dipivoxil (ADV) monotherapy or combination therapy after lamivudine(LAM) resistance. Serum samples from fifteen patients with suboptimal viral response to ADV therapy after LAM resistance were collected. The RT region of HBV P gene was PCR-applied, cloned and sequenced, and the mutation patterns in relation to resistance were analyzed. The ADV resistance mutation patterns of A181T+N236T, A181V, A181T were selected in ADV monotherapy group. The LAM resistance mutation patterns of M204V+L180M, M204V+L180M+L229V, M204I+L80I, M204V+L180M+V207I were detected in the combination therapy group. 20% of clones from three serum samples were detected double resistance to LAM and entecavir (ETV) in the combination therapy group, the resistance patterns were M204I+L80I+T184I (2/10), M204V+L180M+T184S (2/10), and M204V+L180M+G173L+S202G (2/10) respectively. I269L clones were detected in two serum samples from both two groups and P109S clones also detected in the one from monotherapy group. In the patients with suboptimal viral response to ADV therapy after LAM resistance, the ADV resistance mutation patterns of A181T+N236T, A181V and A181T could easily be selected during ADV monotherapy; while in the patients with combination therapy, the LAM resistance mutation patterns of M204V+L180M, M204V+L180M+L229V, M204I+L80I, and M204V+L180M+V207I were predominant, the ETV resistance mutation T184I/S and S202G could be selected. The mutation patterns of I269L and P109S may impact the responses to ADV therapy in some patients.


Use of samarium Sm 153 lexidronam for the treatment of dogs with primary tumors of the skull: 20 cases (1986-2006).
To evaluate samarium Sm 153 lexidronam ((153)Sm-EDTMP) as a treatment option for dogs with bony tumors of the skull. Retrospective case series. Dogs with multilobular osteochondrosarcoma (MLO) or osteosarcoma (OSA) of the skull. Veterinary Medical Teaching Hospital records from the Universities of Missouri and Florida from 1986 to 2006 were searched for dogs with primary skull tumors treated with (153)Sm-EDTMP. 25 dogs were initially evaluated, with 5 dogs subsequently excluded because of inadequate follow-up or unrelated death. Seven OSAs and 13 MLOs were diagnosed. Tumors involved the occipital and frontal bones (n = 10), zygomatic arch and maxilla region (6), palate (3), and mandible (1). No clinically important adverse effects related to (153)Sm-EDTMP treatment were documented. Of the 20 dogs evaluated 21 days after injection with (153)Sm-EDTMP, 4 had subjective improvement, 13 had progressive disease, and 3 had insufficient follow-up. On the basis of radiographic findings, metastasis was suspected in 1 dog; 16 dogs had no metastasis evident, and medical records were insufficient for 3 dogs. Survival time, defined as the (153)Sm-EDTMP injection date to the date of death, ranged from 3 to 1,314 days (median, 144 days). The subjective improvement in 4 patients and lack of clinical evidence of adverse effects suggested that (153)Sm-EDTMP injection may be an option for the treatment of dogs with MLO or OSA of the skull when other treatments have failed or surgery is not possible.


Race/Ethnicity, nativity, and tobacco use among US young adults: results from a nationally representative survey.
A growing body of research documents racial/ethnic disparities in U.S. cigarette smoking. To date, however, few studies have examined the influence of nativity, in addition to race/ethnicity, on current and ever use of cigarettes as well as other tobacco products among young adults. Here, racial/ethnic and nativity disparities in tobacco use and self-identified smoking status are documented for U.S. women and men aged 18-34, both unadjusted and adjusted for socioeconomic status. The Legacy Young Adult Cohort Study (N = 3,696) was used to examine gender-specific tobacco use and smoking status differences among foreign-born Hispanics, U.S.-born Hispanics, U.S.-born non-Hispanic Blacks, and U.S.-born non-Hispanic Whites. Prevalence estimates and multivariable models of ever tobacco use, current tobacco use, and self-identified smoking status were calculated. U.S.-born Hispanics, Blacks, and Whites exhibit the highest levels of ever and current use across a range of tobacco products, whereas foreign-born Hispanics, particularly women, exhibit the lowest ever and current use of most products and are least likely to describe themselves as smokers. Controlling for socioeconomic covariates, current tobacco use is generally lower for most minority groups relative to Whites. Social or occasional smoking, however, is higher among U.S.-born Hispanics and Blacks. The high level of tobacco use among U.S.-born young adults foreshadows substantial tobacco-related morbidity and mortality in the coming decades. Foreign-born Hispanic young adults, particularly women, exhibit the lowest levels of tobacco use. Future studies of tobacco use must differentiate racial/ethnic groups by nativity to better understand patterns of tobacco use.


Decision-making conflict and the neural efficiency hypothesis of intelligence: a functional near-infrared spectroscopy investigation.
Research on the neural efficiency hypothesis of intelligence (NEH) has revealed that the brains of more intelligent individuals consume less energy when performing easy cognitive tasks but more energy when engaged in difficult mental operations. However, previous studies testing the NEH have relied on cognitive tasks that closely resemble psychometric tests of intelligence, potentially confounding efficiency during intelligence-test performance with neural efficiency per se. The present study sought to provide a novel test of the NEH by examining patterns of prefrontal activity while participants completed an experimental paradigm that is qualitatively distinct from the contents of psychometric tests of intelligence. Specifically, participants completed a personal decision-making task (e.g., which occupation would you prefer, dancer or chemist?) in which they made a series of forced choices according to their subjective preferences. The degree of decisional conflict (i.e., choice difficulty) between the available response options was manipulated on the basis of participants' unique preference ratings for the target stimuli, which were obtained prior to scanning. Evoked oxygenation of the prefrontal cortex was measured using 16-channel continuous-wave functional near-infrared spectroscopy. Consistent with the NEH, intelligence predicted decreased activation of the right inferior frontal gyrus (IFG) during low-conflict situations and increased activation of the right-IFG during high-conflict situations. This pattern of right-IFG activity among more intelligent individuals was complemented by faster reaction times in high-conflict situations. These results provide new support for the NEH and suggest that the neural efficiency of more intelligent individuals generalizes to the performance of cognitive tasks that are distinct from intelligence tests.


Global methylation state at base-pair resolution of the Caulobacter genome throughout the cell cycle.
The Caulobacter DNA methyltransferase CcrM is one of five master cell-cycle regulators. CcrM is transiently present near the end of DNA replication when it rapidly methylates the adenine in hemimethylated GANTC sequences. The timing of transcription of two master regulator genes and two cell division genes is controlled by the methylation state of GANTC sites in their promoters. To explore the global extent of this regulatory mechanism, we determined the methylation state of the entire chromosome at every base pair at five time points in the cell cycle using single-molecule, real-time sequencing. The methylation state of 4,515 GANTC sites, preferentially positioned in intergenic regions, changed progressively from full to hemimethylation as the replication forks advanced. However, 27 GANTC sites remained unmethylated throughout the cell cycle, suggesting that these protected sites could participate in epigenetic regulatory functions. An analysis of the time of activation of every cell-cycle regulatory transcription start site, coupled to both the position of a GANTC site in their promoter regions and the time in the cell cycle when the GANTC site transitions from full to hemimethylation, allowed the identification of 59 genes as candidates for epigenetic regulation. In addition, we identified two previously unidentified N(6)-methyladenine motifs and showed that they maintained a constant methylation state throughout the cell cycle. The cognate methyltransferase was identified for one of these motifs as well as for one of two 5-methylcytosine motifs.


Chronic otitis media with multiple complications.
Chronic otitis media (COM) is defined as persistent infection or inflammation of the middle ear and mastoid air cells. The proximity of the middle ear cleft and mastoid air cells to the intratemporal and intracranial compartments places structures located in these areas at increased risk of infectious complications. The complications of COM are divided into intracranial and extracranial complications. The development and appropriate use of antibiotics have led to a decrease in these potentially devastating complications. However, they continue to occur, and clinical vigilance is required for early detection and treatment. We reported a case with multiple complications, both intracranial and extracranial secondary to COM.


Detection of enzyme activities and their relation to serotypes of bovine and human group B streptococci.
Enzymatic properties of group B streptococci (GBS) serotypes from bovine milk and human routine vaginal specimens were investigated. Out of the 56 human and 66 bovine GBS, 35 and 30 could be classified serologically by a co-agglutination test with type-specific antisera, respectively. Hyaluronidase (HYAL), streptokinase (SK) and protease activities were detected using culture media. HYAL activity was observed mostly in typable human GBS, and serotypes Ia, Ic and II comprised 77.3% of the typable strains producing HYAL. Bovine GBS serotypes II, III and VII comprised 87.5% of typable bovine strains exhibiting HYAL activity. SK activity was detected only in three human GBS. Human GBS serotypes Ia, Ic, II, III, VII and almost all typable bovine GBS strains showed protease activity. β-D-glucosidase activity was frequently observed in human GBS, whereas N-acetyl-β-D-glucosaminidase activity was mostly detected in non-typable GBS from humans. These results indicate that different GBS serotypes could vary in their virulence properties, and bovine and human GBS isolates could not be differentiated by their enzyme activities. Use of the culture media appeared to be a simple-to-apply and useful method for the detection of extracellular enzyme activity such as HYAL, protease and SK.


A high performance photonic pulse processing device.
This paper presents an all optical fiber based implementation of a hybrid analog-digital computational primitive that provides a basis for complex processing on high bandwidth signals. A natural implementation of a hybrid analog/digital photonic processing primitive is achieved through the integration of new nonlinear fiber, and exploitation of the physics of semiconductor device to process signals in unique ways. Specifically, we describe the use of a semiconductor optical amplifier to implement leaky temporal integration of a signal and a highly Ge-doped nonlinear fiber for thresholding. A straightforward correspondence between our computational primitive and leaky-integrate-and-fire neurons permits leveraging of a large body of research characterizing the computational capabilities of these devices and the emerging pulse processing computational paradigm as a means to implement practical signal processing algorithms in hybrid computing platforms. An experimental demonstration of the behavior of the pulse processing primitive is presented.


The flash-lag effect and the flash-drag effect in the same display.
Visual motion distorts the perceived position of a stimulus. In the flash-drag effect (FDE), the perceived position of a flash appears to be shifted in the direction of nearby motion. In the flash-lag effect (FLE), a flash adjacent to a moving stimulus appears to lag behind. The FLE has been explained by several models, including the differential latency hypothesis, that a moving stimulus has a shorter processing latency than a flash does. The FDE even occurs when the flash is presented earlier than the moving stimulus, and it has been discussed whether this temporal property can be explained by the differential latency model. In the present study, we simultaneously quantified the FDE and FLE using the random jump technique (Murakami, 2001b) and compared their temporal properties. While the positional offset between a randomly jumping stimulus and a flashed stimulus determined the FLE, a drifting grating appeared next to the flash at various stimulus-onset asynchronies to induce the FDE. The grating presented up to 200 ms after the flash onset induced the FDE, whose temporal tuning was explained by a simple convolution model incorporating stochastic fluctuations of differential latency estimated from the FLE data and a transient-sustained temporal profile of motion signals. Thus, a common temporal mechanism to compute the stimulus position in reference to surrounding stimuli governs both the FDE and the FLE.


Population-based neuroimaging reveals traces of childbirth in the maternal brain.
Maternal brain adaptations have been found across pregnancy and postpartum, but little is known about the long-term effects of parity on the maternal brain. Using neuroimaging and machine learning, we investigated structural brain characteristics in 12,021 middle-aged women from the UK Biobank, demonstrating that parous women showed less evidence of brain aging compared to their nulliparous peers. The relationship between childbirths and a "younger-looking" brain could not be explained by common genetic variation or relevant confounders. Although prospective longitudinal studies are needed, the results suggest that parity may involve neural changes that could influence women's brain aging later in life.


Synthesis and properties of benzophenone-spiropyran and naphthalene-spiropyran conjugates.
We have designed and synthesized four compounds integrating luminescent and photochromic components in their molecular skeletons. Two of them combine a nitrospiropyran photochrome with either one or two naphthalene fluorophores and can be prepared in three synthetic steps. The other two consist of a nitrospiropyran photochrome and a benzophenone phosphore connected by either ether or ester linkages and can be prepared in six or five, respectively, synthetic steps. The luminescent components of these assemblies are expected to transfer energy intramolecularly to the photochromic species upon excitation and encourage their photoisomerization. Consistently, the phosphorescence of the benzophenone units and the fluorescence of the naphthalene components are effectively quenched when these species are connected covalently to a nitrospiropyran. Nonetheless, the photoisomerization of the photochrome becomes significantly less efficient after the covalent attachment to the luminescent partner. The fraction of incident radiations absorbed by either the benzophenone or the naphthalene fragment does not promote the isomerization of the photochromic appendage. Instead, irreversible transformations occur upon irradiation of the luminophore-photochrome assemblies. Thus, the covalent attachment of a benzophenone or a naphthalene to a nitrospiropyran is not a viable strategy to improve the photocoloration efficiency of the photochromic component. Even although the very same luminophores are known to sensitize intermolecularly the isomerization of nitrospiropyrans, the transition to covalent luminophore-photochrome assemblies tends to promote degradation, rather than sensitization, upon irradiation.


Foundations for a new science of learning.
Human learning is distinguished by the range and complexity of skills that can be learned and the degree of abstraction that can be achieved compared with those of other species. Homo sapiens is also the only species that has developed formal ways to enhance learning: teachers, schools, and curricula. Human infants have an intense interest in people and their behavior and possess powerful implicit learning mechanisms that are affected by social interaction. Neuroscientists are beginning to understand the brain mechanisms underlying learning and how shared brain systems for perception and action support social learning. Machine learning algorithms are being developed that allow robots and computers to learn autonomously. New insights from many different fields are converging to create a new science of learning that may transform educational practices.


Induction of hypothermia as a model of 5-hydroxytryptamine1A receptor-mediated activity in the rat: a pharmacological characterization of the actions of novel agonists and antagonists.
In this study, we examined the localization of the 5-hydroxytryptamine (5-HT)1A receptors mediating hypothermia in the rat, evaluated the pharmacological specificity of this response and examined the influence of a series of novel 5-HT1A receptor ligands upon core temperature. Administered s.c., 8-hydroxy-(2-di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), an agonist at both pre- and postsynaptic 5-HT1A receptors, elicited pronounced hypothermia. In contrast, BMY 7378, which shows low efficacy at postsynaptic 5-HT1A receptors but high efficacy at presynaptic 5-HT1A receptors, elicited only mild hypothermia. Similarly, 8-OH-DPAT was more efficacious than BMY 7378 in eliciting corticosterone secretion, a response mediated by postsynaptic 5-HT1A receptors, whereas BMY 7378 was as efficacious as 8-OH-DPAT in inhibiting striatal accumulation of 5-hydroxytryptophan, a response mediated by presynaptic 5-HT1A receptors. These data suggest, by analogy, that postsynaptic 5-HT1A receptors mediate hypothermia, an interpretation supported by the observation that destruction of central 5-HT neurons with 5,7-dihydroxytryptamine failed to reduce 8-OH-DPAT-induced hypothermia (DIH). Agonists at 5-HT1B, 5-HT1C, 5-HT2 and/or 5-HT3 receptors did not elicit hypothermia, and drugs releasing 5-HT elicited hyperthermia. In contrast, DIH was fully mimicked by the novel 5-HT1A receptors agonists, eltoprazine, WY 48,723, MDL 72832, tandospirone, S 14671, S 14506 and WY 50,324, whereas the novel partial agonist, zalospirone, was less efficacious. DIH was blocked by (-)-alprenolol, (+/-)-pindolol and the novel beta-blocker, (-)-tertatolol, which also has high affinity for 5-HT1A receptors; in distinction, betaxolol and ICI 118,551, antagonists at beta-1 and beta-2 adrenoceptors, respectively, were inactive. Spiperone, NAN-190 and BMY 7378 also inhibited DIH whereas ritanserin, SCH 39166, raclopride and prazosin, antagonists at 5-HT2 receptors, D1 and D2 dopamine receptors and alpha-1 adrenoceptors, respectively, were inactive. The novel 5-HT1A antagonists, WAY 100,135, MDL 73005 EF and (very potently) SDZ 216-525 all blocked DIH. Potency for induction of hypothermia and inhibition of DIH correlated well with affinity for 5-HT1A binding sites. In conclusion, hypothermia is a highly specific and sensitive response to activation of postsynaptic 5-HT1A receptors. Furthermore, DIH is inhibited by their selective blockade. At postsynaptic 5-HT1A receptors mediating hypothermia, eltoprazine, WY 48,723, MDL 72832 and tandospirone are agonists, zalospirone is a partial agonist and (-)-tertatolol, WAY 100,135, MDL 73005 EF and SDZ 216-525 are antagonists.


Zipping and unzipping of adenylate kinase: atomistic insights into the ensemble of open<-->closed transitions.
Adenylate kinase (AdK), a phosphotransferase enzyme, plays an important role in cellular energy homeostasis. It undergoes a large conformational change between an open and a closed state, even in the absence of substrate. We investigate the apo-AdK transition at the atomic level both with free-energy calculations and with our new dynamic importance sampling (DIMS) molecular dynamics method. DIMS is shown to sample biologically relevant conformations as verified by comparing an ensemble of hundreds of DIMS transitions to AdK crystal structure intermediates. The simulations reveal in atomic detail how hinge regions partially and intermittently unfold during the transition. Conserved salt bridges are seen to have important structural and dynamic roles; in particular, four ionic bonds that open in a sequential, zipper-like fashion and, thus, dominate the free-energy landscape of the transition are identified. Transitions between the closed and open conformations only have to overcome moderate free-energy barriers. Unexpectedly, the closed state and the open state encompass broad free-energy basins that contain conformations differing in domain hinge motions by up to 40 degrees . The significance of these extended states is discussed in relation to recent experimental Förster resonance energy transfer measurements. Taken together, these results demonstrate how a small number of cooperative key interactions can shape the overall dynamics of an enzyme and suggest an "all-or-nothing" mechanism for the opening and closing of AdK. Our efficient DIMS molecular dynamics computer simulation approach can provide a detailed picture of a functionally important macromolecular transition and thus help to interpret and suggest experiments to probe the conformational landscape of dynamic proteins such as AdK.


Vibration Therapy in Management of Delayed Onset Muscle Soreness (DOMS).
Both athletic and nonathletic population when subjected to any unaccustomed or unfamiliar exercise will experience pain 24-72 hours postexercise. This exercise especially eccentric in nature caused primarily by muscle damage is known as delayed-onset muscle soreness (DOMS). This damage is characterized by muscular pain, decreased muscle force production, reduce range of motion and discomfort experienced. DOMS is due to microscopic muscle fiber tears. The presence of DOMS increases risk of injury. A reduced range of motion may lead to the incapability to efficiently absorb the shock that affect physical activity. Alterations to mechanical motion may increase strain placed on soft tissue structures. Reduced force output may signal compensatory recruitment of muscles, thus leading to unaccustomed stress on musculature. Differences in strength ratios may also cause excessive strain on unaccustomed musculature. A range of interventions aimed at decreasing symptoms of DOMS have been proposed. Although voluminous research has been done in this regard, there is little consensus among the practitioners regarding the most effective way of treating DOMS. Mechanical oscillatory motion provided by vibration therapy. Vibration could represent an effective exercise intervention for enhancing neuromuscular performance in athletes. Vibration has shown effectiveness in flexibility and explosive power. Vibration can apply either local area or whole body vibration. Vibration therapy improves muscular strength, power development, kinesthetic awareness, decreased muscle sore, increased range of motion, and increased blood flow under the skin. VT was effective for reduction of DOMS and regaining full ROM. Application of whole body vibration therapy in postexercise demonstrates less pressure pain threshold, muscle soreness along with less reduction maximal isometric and isokinetic voluntary strength and lower creatine kinase levels in the blood.


Intracellular co-localization of SPLUNC1 protein with nanobacteria in nasopharyngeal carcinoma epithelia HNE1 cells depended on the bactericidal permeability increasing protein domain.
Epithelial surfaces constitute natural immunobarriers against environmental threats. These barriers are brimming with fluids that bind, transport, cleave or degrade bacterial cells and their endotoxic by-products. Saliva and the airway surface-lining fluid (ASL) comprise the important fluid constituents. Short palate, lung and nasal epithelium clone 1 (SPLUNC1) is a potential host defensive protein that is secreted from the submucosal gland to the saliva and nasal lavage fluid. However, its antimicrobial spectrum and antimicrobial mechanism is not clear. Through green fluorescence protein (GFP) mediated subcellular localization experiments in nasopharyngeal carcinoma (NPC) HNE1 cell line, we determined that the intracellular GFP-tagged SPLUNC1 protein binds to a miniscule microorganisms, approximately 50-400nm in size, after the bactericidal permeability increasing protein (BPI) domain was deleted, GFP-tagged truncated SPLUNC1 protein lost its function of binding to the miniscule microorganisms. We verified that these microorganisms are nanobacteria (NB) with a negative staining using transmitted electronic microscope (TEM) and immunofluorescent analysis using an NB-specific antibody. We isolated and cultured the NB from the cultured nasopharyngeal carcinoma epithelia HNE1 cell supernatant. We found that the NB did not absorb the Hoechst stain, even when we extended the staining time to 35min. However, with the time extension the larger sized NB (larger than 300nm) did stain positively. From the biopsy specimen of NPC, we also detected the NB, which can lead to the swelling of mitochondria in the infected host cells. We hypothesize that SPLUNC1 and NB co-localization is due to the GFP-tagged SPLUNC1 protein binding to the lipopolysaccharide (LPS) of the Gram-negative NB, which can play an important role in the host defense of nasopharyngeal epithelium. This research sheds new light on the mechanism of SPLUNC1 involvement in the host upper respiratory tract defense system.