Functional small-molecules & polymers containing P[double bond, length as m-dash]C and As[double bond, length as m-dash]C bonds as hybrid π-conjugated materials.
Stable phospha- and arsaalkenes were used to synthesize polymers containing unsaturated P[double bond, length as m-dash]C and As[double bond, length as m-dash]C moieties. The composition, chemical environment, structure, optical, and electronic properties of the monomers and polymers were elucidated. The incorporation of the heteroatom-carbon double bonded units efficiently perturbs the optoelectronics and solid state features of both monomeric and polymeric scaffolds. Proof-of principle work supports their responsive character through post-functionalisation and electrochromic behaviour. To the best of our knowledge, this is the first example of a polymer containing arsenic-carbon double bonds.


Phenology of Trichodesmium spp. blooms in the Great Barrier Reef lagoon, Australia, from the ESA-MERIS 10-year mission.
Trichodesmium, a filamentous bloom-forming marine cyanobacterium, plays a key role in the biogeochemistry of oligotrophic ocean regions because of the ability to fix nitrogen. Naturally occurring in the Great Barrier Reef (GBR), the contribution of Trichodesmium to the nutrient budget may be of the same order as that entering the system via catchment runoff. However, the cyclicity of Trichodesmium in the GBR is poorly understood and sparsely documented because of the lack of sufficient observations. This study provides the first systematic analysis of Trichodesmium spatial and temporal occurrences in the GBR over the decade-long MERIS ocean color mission (2002-2012). Trichodesmium surface expressions were detected using the Maximum Chlorophyll Index (MCI) applied to MERIS satellite imagery of the GBR lagoonal waters. The MCI performed well (76%), albeit tested on a limited set of images (N = 25) coincident with field measurements. A north (Cape York) to south (Fitzroy) increase in the extent, frequency and timing of the surface expressions characterized the GBR, with surface expressions extending over several hundreds of kilometers. The two southernmost subregions Mackay and Fitzroy accounted for the most (70%) bloom events. The bloom timing of Trichodesmium varied from May in the north to November in the south, with wet season conditions less favorable to Trichodesmium aggregations. MODIS-Aqua Sea Surface Temperature (SST) datasets, wind speed and field measurements of nutrient concentrations were used in combination with MCI positive instances to assess the blooms' driving factors. Low wind speed (<6 m.s-1) and SST > 24°C were associated with the largest surface aggregations. Generalized additive models (GAM) indicated an increase in bloom occurrences over the 10-year period with seasonal bloom patterns regionally distinct. Interannual variability in SST partially (14%) explained bloom occurrences, and other drivers, such as the subregion and the nutrient budget, likely regulate Trichodesmium surface aggregations in the GBR.


In silico validation of the Autoinflammatory Disease Damage Index.
Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha. The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.


Interactive effects of the tumor necrosis factor promoter and 3'-untranslated regions.
The tumor necrosis factor (TNF) promoter and 3'-untranslated region (3'-UTR) each contain sequence elements that mediate a response to bacterial endotoxin. Although the promoter contains sequences that permit augmented TNF gene transcription in response to LPS, the 3'-UTR contains sequences that normally confer translational repression, but which allow "derepression" to occur after cell contact with endotoxin. We now show that both genetic elements act in concert during activation of TNF gene expression in macrophages. In order to do so, we have made use of chloramphenicol acetyltransferase reporter constructs in which the TNF promoter and 3'-UTR are represented either independently or in combination with one another. Suppression of chloramphenicol acetyltransferase and TNF mRNA synthesis, observed after treatment of the macrophages with dexamethasone, 2-aminopurine, pentoxifylline, or dibutyryl cAMP, has also been studied in detail. Each class of inhibitor suppresses TNF biosynthesis through a separate mechanism. Interestingly, suppression by pentoxifylline is manifested partly (but not entirely) at the level of transcription, and depends upon the presence of both the TNF promoter and 3'-UTR. The data suggest that other sequences within the TNF gene could also be required for the full effect of pentoxifylline, which may act to prevent processing of the primary transcript. The suppressive effect of dexamethasone is manifested both at the level of transcription and at the level of translation, and is mediated both by sequences present in the TNF promoter and by sequences present in the 3'-UTR. Suppression by 2-aminopurine is solely dependent upon promoter sequences.


Plague, pox and the physician in Aberdeen, 1495-1516.
This article discusses responses to disease in Aberdeen during a formative period in the provision of healthcare within the city. The foundation of King's College was followed, in 1497, by the establishment of the first royally endowed university Chair of Medicine in the British Isles, and its first incumbent, James Cumming, was employed by the local government as the first city doctor in 1503. His appointment had been preceded in 1497 by another legislative innovation in Aberdeen, when its council became the first civic body in the British Isles to implement regulations against the threat of the Great Pox (usually considered to be syphilis). It had subsequently to pass measures to prevent the spread of plague to the city, and these were typical of those already imposed elsewhere in Scotland and on the continent. Their apparent success in staving off plague lasted until 1514, when the city was struck by a severe outbreak which lasted two years.


The LN54 radiation hybrid map of zebrafish expressed sequences.
To increase the density of a gene map of the zebrafish, Danio rerio, we have placed 3119 expressed sequence tags (ESTs) and cDNA sequences on the LN54 radiation hybrid (RH) panel. The ESTs and genes mapped here join 748 SSLp markers and 459 previously mapped genes and ESTs, bringing the total number of markers on the LN54 RH panel to 4226. Addition of these new markers brings the total LN54 map size to 14,372 cR, with 118 kb/cR. The distribution of ESTs according to linkage groups shows relatively little variation (minimum, 73; maximum, 201). This observation, combined with a relatively uniform size for zebrafish chromosomes, as previously indicated by karyotyping, indicates that there are no especially gene-rich or gene-poor chromosomes in this species. We developed an algorithm to provide a semiautomatic method for the selection of additional framework markers for the LN54 map. This algorithm increased the total number of framework markers to 1150 and permitted the mapping of a high percentage of sequences that could not be placed on a previous version of the LN54 map. The increased concentration of expressed sequences on the LN54 map of the zebrafish genome will facilitate the molecular characterization of mutations in this species.


Probable positive effects of the photobiomodulation as an adjunctive treatment in COVID-19: A systematic review.
COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS) in up to one -third of the cases. Pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. The anti-inflammatory effect of the photobiomodulation (PBM) has been confirmed in many previous studies. Therefore, this review study was conducted to evaluate the direct effect of PBM on the acute lung inflammation or ARDS and also accelerating the regeneration of the damaged tissues. The indirect effects of PBM on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered. The databases of PubMed, Cochrane library, and Google Scholar were searched to find the relevant studies. Keywords included the PBM and related terms, lung inflammation, and COVID-19 -related signs. Studies were categorized with respect to the target tissue, laser parameters, and their results. Seventeen related papers were included in this review. All of them were in animal models. They showed that the PBM could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), intracellular adhesion molecule (ICAM), reactive oxygen species (ROS), isoform of nitric oxide synthase (iNOS), and macrophage inflammatory protein 2 (MIP-2)). Our findings revealed that the PBM could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. PBM can increase the oxygenation indirectly in order to rehabilitate the affected organs. Thus, the infra-red lasers or light-emitting diodes (LEDs) are recommended in this regard.


Cheiradone: a vascular endothelial cell growth factor receptor antagonist.
Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing) and pathological conditions (tumour development). Vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) are the major angiogenic regulators. We have identified a natural product (cheiradone) isolated from a Euphorbia species which inhibited in vivo and in vitro VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in in vitro (proliferation, wound healing, invasion in Matrigel and tube formation) and in vivo (the chick chorioallantoic membrane) models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC50) was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated. Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC50 values in the range 5.20-7.50 microM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC50 values of 2.9 and 0.61 microM respectively. Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.


The influence of exposure to violence on adolescents' physical aggression: The protective influence of peers.
This study examined the degree to which peers can serve as a protective factor to mitigate the negative effects of exposure to violence (i.e., victimization, witnessing violence) on adolescents' physical aggression. Four specific dimensions of peer influence were examined - friends' support for nonviolence, friends' support for fighting, peer pressure for fighting, and friends' delinquent behavior. Analyses were conducted on four waves of data collected every 3 months (i.e., fall, winter, spring, summer) from a predominantly African-American (78%) sample of 2575 sixth, seventh, and eighth graders attending three public middle schools in the United States. The sample was 52% female, with a mean age of 12.3 years (SD = 1.00). Findings for relations with victimization differed by sex. For boys, low levels of friends' delinquent behavior attenuated the relation between victimization and changes in physical aggression across all three waves. The protective effect of low levels of peer pressure for fighting was only evident in the winter for boys, whereas the protective effect of friends' support for nonviolence was only evident in the summer. For girls, high levels of friends' support for nonviolence attenuated the relation between victimization in the winter and changes in physical aggression in the spring. In contrast, none of the peer factors moderated the relation between witnessing violence and physical aggression. Findings suggest that prevention and interventions that increase positive peer influences and decrease negative peer influences may benefit adolescents by reducing risks associated with victimization.


Computationally designed GPCR quaternary structures bias signaling pathway activation.
Communication across membranes controls critical cellular processes and is achieved by receptors translating extracellular signals into selective cytoplasmic responses. While receptor tertiary structures can be readily characterized, receptor associations into quaternary structures are challenging to study and their implications in signal transduction remain poorly understood. Here, we report a computational approach for predicting receptor self-associations, and designing receptor oligomers with various quaternary structures and signaling properties. Using this approach, we designed chemokine receptor CXCR4 dimers with reprogrammed binding interactions, conformations, and abilities to activate distinct intracellular signaling proteins. In agreement with our predictions, the designed CXCR4s dimerized through distinct conformations and displayed different quaternary structural changes upon activation. Consistent with the active state models, all engineered CXCR4 oligomers activated the G protein Gi, but only specific dimer structures also recruited β-arrestins. Overall, we demonstrate that quaternary structures represent an important unforeseen mechanism of receptor biased signaling and reveal the existence of a bias switch at the dimer interface of several G protein-coupled receptors including CXCR4, mu-Opioid and type-2 Vasopressin receptors that selectively control the activation of G proteins vs β-arrestin-mediated pathways. The approach should prove useful for predicting and designing receptor associations to uncover and reprogram selective cellular signaling functions.


The paranoid optimist: an integrative evolutionary model of cognitive biases.
Human cognition is often biased, from judgments of the time of impact of approaching objects all the way through to estimations of social outcomes in the future. We propose these effects and a host of others may all be understood from an evolutionary psychological perspective. In this article, we elaborate error management theory (EMT; Haselton & Buss, 2000). EMT predicts that if judgments are made under uncertainty, and the costs of false positive and false negative errors have been asymmetric over evolutionary history, selection should have favored a bias toward making the least costly error. This perspective integrates a diverse array of effects under a single explanatory umbrella, and it yields new content-specific predictions.


Lifetime and current prevalence of specific psychiatric disorders among Vietnam veterans and controls.
To determine if Vietnam theater veterans were more likely than controls to have a specific psychiatric disorder other than posttraumatic stress disorder, the rates of specific psychiatric disorders were estimated using the Diagnostic Interview Schedule for national samples of veterans who served in Vietnam, other veterans of the Vietnam era, and matched civilian controls. Overall, there were few differences in rates of disorder between theater and other veterans; there were somewhat more differences between theater veterans and civilians. There were striking differences, however, in rates for most disorders, both lifetime and current, between male theater veterans with high levels of exposure to war zone stress and other male veterans or civilians. Female veterans exposed to high levels of war zone stress also had higher rates than other female respondents for several disorders.


The Paracondylar Skull Base: Anatomical Variants and Their Clinical Implications.
The knowledge of the vasculature around the paracondylar region is important in neurosurgical procedures such as the paracondylar and lateral supracondylar approaches. The objectives of the present study were to determine the prevalence of paracondylar emissary foramina in the adult skull bases and to study the morphology of condylar canals and hypoglossal canals. The present study included 48 adult human skulls that were obtained from the gross anatomy laboratory of our institution. The paracondylar region was macroscopically observed for the variant foramina, canals and grooves. It was observed that the paracondylar emissary foramen was present in 16 skulls (33.3%). The foramen was found bilaterally in 7 skulls (14.6%) and unilaterally in 9 skulls (18.7%). The hypoglossal canal was single in 35 (72.9%) skulls, double in 11 skulls (22.9%), and triple in 2 skulls (4.2%). The paracondylar process (2.1%) and the paracondylar groove (2.1%) were seen in 1 skull each. The posterior condylar canal was found to be patent in 19 (39.6%) skulls. The present study observed that, the paracondylar emissary vein is not rare in occurrence as it is observed in 33.3% of cases. The identification of the paracondylar emissary veins and accessory vessels is important to avoid dangerous bleeding during the surgery. The morphological knowledge of the foramina around the paracondylar region is enlightening to the chiropractors, neurosurgeons and radiologists.


Twin pregnancy: not only a medical event.
Twin pregnancies are at greater risk of obstetrical and perinatal adverse outcome compared to singletons. In addition, expecting twins can have particular psychological consequences on both parents. The aim of our study was to interview women with a twin pregnancy and their partners in order to assess their feelings and emotions related to the twins and to evaluate the opportunity to activate an information group about the theme of twin pregnancy, and a development of twins and family management. Twenty patients with an uncomplicated twin pregnancy and their partners answered 9 questions in a semistructured interview, set on the basis of the psychological and social issues reported in the literature on couples expecting twins. Emerging themes and key words were extracted from the interviews and analysed. Quantitative analysis showed that women were, in most cases, shocked at the time of the diagnosis of twinning, while men tried to minimize the worries of their partners. Women reported some fears related to the practical management of the future life, but they declared to feel not different from women expecting singleton, confirming the data reported in the literature. Seventy percent of the women were interested in meeting other parents with twins. Qualitative analysis frequently indicated the defence mechanism of rationalisation and negation of the worries concerning the pregnancy risks and the future care of their babies. Their answers seem to hide fears and doubts that are confessed with difficulty. Our study suggests the importance for hospital staff to create an atmosphere of calm and to demonstrate empathy and understanding, with the aim to help and allow the mothers to express their fears.


Investigating the neural basis of the auditory continuity illusion.
In this study, we investigated one type of auditory perceptual grouping phenomena--the auditory continuity illusion (also called temporal induction). We employed a previously developed, neurobiologically realistic, large-scale neural network model of the auditory processing pathway in the cortex, ranging from the primary auditory cortex to the prefrontal cortex, and simulated temporal induction without changing any model parameters. The model processes tonal contour stimuli, composed of combinations of upward and downward FM sweeps and tones, in a delayed match-to-sample task. The local electrical activities of the neuronal units of the model simulated accurately the experimentally observed electrophysiological data, where available, and the model's simulated BOLD-fMRI data were quantitatively matched with experimental fMRI data. In the present simulations, intact stimuli were matched with fragmented versions (i.e., with inserted silent gaps). The ability of the model to match fragmented stimuli declined as the duration of the gaps increased. However, when simulated broadband noise was inserted into these gaps, the matching response was restored, indicating that a continuous stimulus was perceived. The electrical activities of the neuronal units of the model agreed with electrophysiological data, and the behavioral activity of the model matched human behavioral data. In the model, the predominant mechanism implementing temporal induction is the divergence of the feedforward connections along the auditory processing pathway in the temporal cortex. These simulation results not only attest to the robustness of the model, but further predict the primary role of the anatomical connectivity of the auditory processing areas in mediating the continuity illusion.


Relationship between hypertension, hypertrophy, and opening angle of zero-stress state of arteries following aortic constriction.
Examination of changes occurring in the zero-stress state of an organ provides a way to study cellular growth in the organ due to change of physical stresses. The zero-stress state of the aorta is not a tube. It is a sector with an opening angle that varies with the location on the aorta and changes with cellular remodeling. Blood vessel remodeling can be induced by imposing a constriction on the abdominal aorta by a metal clip (aortic banding), which causes an increase of blood pressure, hypertrophy of the aortic wall, and large change of opening angle. The correlation of the opening angle with the blood vessel wall thickness and blood pressure changes in rat's aorta due to aortic banding is presented in this report. The opening angle changes daily following the aortic banding. Blood pressure rises in vessels of the upper body, but that in the lower body decreases at first and then rises to an asymptotic value. Blood vessel wall thickness increases in rough proportion to blood pressure. Vessel diameter changes also. But the most dramatic is the course of change of the zero-stress state. Typically, the time to reach 50 percent of asymptotic hypertrophy of blood vessel wall thickness is about 3-5 days. The corresponding time for blood pressure is about 7 days. The opening angle of the zero-stress state, however, increases rapidly at first, reaches a peak in about 2 to 4 days, then decreases gradually to a reduced asymptote. The exact values of the time constants depend on the location along the aortic tree. In general, the course of change of residual strain is very different from those of the blood pressure and the blood vessel wall thickness.


Cycle training induces muscle hypertrophy and strength gain: strategies and mechanisms.
Cycle training is widely performed as a major part of any exercise program seeking to improve aerobic capacity and cardiovascular health. However, the effect of cycle training on muscle size and strength gain still requires further insight, even though it is known that professional cyclists display larger muscle size compared to controls. Therefore, the purpose of this review is to discuss the effects of cycle training on muscle size and strength of the lower extremity and the possible mechanisms for increasing muscle size with cycle training. It is plausible that cycle training requires a longer period to significantly increase muscle size compared to typical resistance training due to a much slower hypertrophy rate. Cycle training induces muscle hypertrophy similarly between young and older age groups, while strength gain seems to favor older adults, which suggests that the probability for improving in muscle quality appears to be higher in older adults compared to young adults. For young adults, higher-intensity intermittent cycling may be required to achieve strength gains. It also appears that muscle hypertrophy induced by cycle training results from the positive changes in muscle protein net balance.


Comparison of the activities of variant forms of eIF-4D. The requirement for hypusine or deoxyhypusine.
Eukaryotic protein synthesis initiation factor 4D (eIF-4D) (current nomenclature, eIF-5A) contains the unique amino acid hypusine (N epsilon-(4-amino-2-hydroxybutyl)lysine). The first step in hypusine biosynthesis, i.e. the formation of the intermediate, deoxyhypusine (N epsilon-(4-aminobutyl)lysine), was carried out in vitro using spermidine, deoxyhypusine synthase, and ec-eIF-4D(Lys), an eIF-4D precursor prepared by over-expression of human eIF-4D cDNA in Escherichia coli. In a parallel reaction, using N-(3-aminopropyl)cadaverine in place of spermidine, a variant form of eIF-4D containing homodeoxyhypusine (N epsilon-(5-aminopentyl)lysine) was prepared. Evidence that N-(3-aminopropyl)cadaverine can also act as the amine substrate for deoxyhypusine synthase in intact cells was obtained by incubating putrescine- and spermidine-depleted Chinese hamster ovary cells with [3H]cadaverine. In these cells, in which [3H]cadaverine is readily converted to N-(3-aminopropyl) [3H]cadaverine, small amounts of [3H]homodeoxyhypusine and another 3H-labeled compound, presumed to be N epsilon-(5-amino-2-hydroxy[3H]pentyl)lysine, were found. eIF-4D stimulates methionyl-puromycin synthesis, an in vitro model assay for translation initiation. Whereas the unmodified precursor ec-eIF-4D(Lys) appeared inactive, the deoxyhypusine-containing form provided a significant degree of stimulation. The variant form containing homodeoxyhypusine, on the other hand, showed little or no activity. These findings emphasize the importance of hypusine or deoxyhypusine for the biological activity of eIF-4D and demonstrate the influence of both the length and chemical nature of its amino alkyl side chain.


Genetic mosaic analysis based on Cre recombinase and navigated laser capture microdissection.
Defining molecular interactions that occur at the interface between "normal" and "abnormal" cell populations represents an important but often underexplored aspect of the pathogenesis of diseases with focal origins. Here, we illustrate an approach for conducting such analyses based on mosaic patterns of Cre recombinase expression in the adult mouse intestinal epithelium. Transgenic mice were generated that express Cre in the stem cell niche of crypts located in specified regions of their intestine. Some of these mice were engineered to allow for doxycycline-inducible Cre expression. Recombination in all pedigrees was mosaic: Cre-expressing crypts that supported recombination in all of their active multipotent stem cells were located adjacent to "control" crypts that did not express Cre at detectable levels. Cre-mediated recombination of a floxed LacZ reporter provided direct evidence that adult small-intestinal crypts contain more than one active multipotent stem cell, and that these cells can be retained in both small-intestinal and colonic crypts for at least 80 d. A method was developed to recover epithelial cells from crypts with or without recombination for subsequent gene expression profiling. Stained sections of intestine were used to create electronic image templates to guide laser capture microdissection (LCM) of adjacent frozen sections. This navigated form of LCM overcomes problems with mRNA degradation encountered when cells are marked directly by immunohistochemical methods. Combining Cre-engineered genetic mosaic mice with navigated-LCM will allow biology and pathobiology to be explored at the junction between normal and perturbed cellular cohorts.


Diagnostic implications of detection of proteinase K-resistant protein in spleen, lymph nodes, and brain of sheep.
Brain, spleen, and selected lymph nodes from sheep with clinical signs of scrapie were analyzed for presence of proteinase K-resistant protein (PrP-res). Diagnosis of scrapie on the basis of detection of PrP-res was compared with diagnosis on the basis of histologic evaluation of the brain from clinically affected or exposed sheep. Proteinase K-resistant protein was found in every brain that was histologically positive for scrapie, and in addition, was found in the brain of several clinically positive sheep that were not diagnosed as scrapie-positive by histologic evaluation. Proteinase K-resistant protein was also found in 87% of the spleens and lymph nodes from sheep that had PrP-res detected in brain homogenates. Therefore, analysis of sheep brain, spleen, or lymph nodes for PrP-res provided a diagnostic approach that was superior to histologic examination alone for detection of naturally scrapie agent-infected sheep.


Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis.
This meta-analysis systematically reviewed randomized controlled trials comparing aspirin plus dipyridamole with aspirin alone in patients with stroke and TIA to determine the efficacy of these agents in preventing recurrent cerebral and systemic vascular events. We performed separate analyses of the incidences of stroke alone and composite outcome of stroke, myocardial infarction, or vascular death. We also performed two subset analyses, planned a priori, to examine effect size based on trials using (1) exclusively immediate-release and (2) predominantly extended-release dipyridamole. The summary results indicate a significant reduction in the overall risk ratio in favor of aspirin plus dipyridamole for stroke alone with relative risk 0.77 (0.67 to 0.89) and the composite end point with relative risk 0.85 (0.76 to 0.94). Studies using immediate-release dipyridamole showed a nonstatistically significant trend in favor of the combination for stroke alone with relative risk 0.83 (0.59 to 1.15) and for the composite outcome with relative risk 0.95 (0.75 to 1.19). Studies using predominantly extended-release dipyridamole showed a statistically significant difference in favor of the combination for stroke alone with relative risk 0.76 (0.65 to 0.89) and for the composite outcome with relative risk 0.82 (0.73 to 0.92). The combination of aspirin plus dipyridamole is more effective than aspirin alone in preventing stroke and other serious vascular events in patients with minor stroke and TIAs. The risk reduction was greater and statistically significant for studies using primarily extended release dipyridamole, which may reflect a true pharmacological effect or lack of statistical power in studies using immediate release dipyridamole.


Economic Impact of Hospitalizations in US Adults with Sarcopenia.
Sarcopenia is characterized by progressive loss of muscle mass with corresponding decline in strength and/or physical function. The economic burden of sarcopenia-associated disability is considerable in the US. To estimate the cost of hospitalizations in US adults with sarcopenia categorized by age, sex, and race/ethnicity. A retrospective, prevalence based, economic burden study, consisting of 4011 adults aged ≥40 years with and without sarcopenia. Data on prevalence of low lean mass, functional limitations, and hospitalizations were obtained from the National Health and Nutrition Examination Survey (1999-2004); cost of hospitalizations was obtained from the Healthcare Cost and Utilization Project - National Inpatient Sample (2014), and population estimates were obtained from the US Census (2014). Probability and cost of hospitalizations were estimated by multiple logistic regression and negative binomial regression models, respectively. The total estimated cost of hospitalizations in individuals with sarcopenia was USD $40.4 billion with an average per person cost of USD $260. Within this category, average per person cost was highest for Hispanic women (USD $548) and lowest for Non-Hispanic Black women (USD $25); average per person cost was higher for older adults (≥65 years) (USD $375) than younger adults (40-64 years) (USD $204) with sarcopenia. The total cost of hospitalizations in individuals with sarcopenia (≥65 years) was USD $19.12 billion. Individuals with sarcopenia had greater odds of hospitalization (OR, 1.95; p<.001) compared to those without and had an annual marginal increase in cost of USD $2315.7 per person compared to individuals without sarcopenia. Sarcopenia places considerable economic burden on the US healthcare system. The ethnic disparity and economic burden associated with sarcopenia warrant further investigation.


High-precision method of binocular camera calibration with a distortion model.
A high-precision camera calibration method for binocular stereo vision system based on a multi-view template and alternative bundle adjustment is presented in this paper. The proposed method could be achieved by taking several photos on a specially designed calibration template that has diverse encoded points in different orientations. In this paper, the method utilized the existing algorithm used for monocular camera calibration to obtain the initialization, which involves a camera model, including radial lens distortion and tangential distortion. We created a reference coordinate system based on the left camera coordinate to optimize the intrinsic parameters of left camera through alternative bundle adjustment to obtain optimal values. Then, optimal intrinsic parameters of the right camera can be obtained through alternative bundle adjustment when we create a reference coordinate system based on the right camera coordinate. We also used all intrinsic parameters that were acquired to optimize extrinsic parameters. Thus, the optimal lens distortion parameters and intrinsic and extrinsic parameters were obtained. Synthetic and real data were used to test the method. The simulation results demonstrate that the maximum mean absolute relative calibration errors are about 3.5e-6 and 1.2e-6 for the focal length and the principal point, respectively, under zero-mean Gaussian noise with 0.05 pixels standard deviation. The real result shows that the reprojection error of our model is about 0.045 pixels with the relative standard deviation of 1.0e-6 over the intrinsic parameters. The proposed method is convenient, cost-efficient, highly precise, and simple to carry out.


Brief report: information processing speed is intact in autism but not correlated with measured intelligence.
Speed of information processing, as measured by inspection time (IT), is a robust predictor of intellectual functioning. However, among individuals with autism and low IQ scores, IT has been reported to be discrepantly fast, and equal to that of high IQ typically developing children (Scheuffgen et al. in Dev Psychopathol 12: 83-90, 2000). The present investigation replicates and extends this study by examining IT and its relationship to IQ in a higher functioning (average range mean IQ) group of children with autism spectrum disorders (ASD) versus matched controls. Though IT was not significantly faster in the ASD group than in the matched control group, the relationship between IT and IQ was uniquely discrepant for the ASD group, partially corroborating and extending previous findings.


Assessment of a New Lower-Cost Real-Time PCR Assay for Detection of High-Risk Human Papillomavirus: Useful for Cervical Screening in Limited-Resource Settings?
Inexpensive and easy-to-perform human papillomavirus (HPV) tests are needed for primary cervical cancer screening in lower-resource regions. In a convenience sample of 516 residual exfoliative cervical specimens from the Kaiser Permanente Northern California and U.S. National Cancer Institute Persistence and Progression Study, we assessed the agreement and clinical performance of a simple, inexpensive real-time PCR assay for the detection of 13 carcinogenic HPV types (the H13 assay; Hybribio, Hong Kong) that is marketed in limited-resource settings compared to previous testing by the Hybrid Capture 2 assay (HC2; Qiagen, Germantown, MD) and the Onclarity assay (BD Diagnostics, Sparks, MD). The test set was chosen to include many HPV-positive specimens. The reference standard was a combination of HC2 and Onclarity results for HPV detection and histologic diagnosis of controls (less than cervical intraepithelial neoplasia grade 2 [<CIN2]) or cases (cervical intraepithelial neoplasia grade 2 or higher [CIN2+]) for disease status. In this enriched convenience sample, H13 tested positive for 94.4% of the 108 HC2- and Onclarity-positive CIN2+ specimens and negative for 88.2% of the 51 HC2- and Onclarity-negative <CIN2 specimens. H13 positivity was significantly lower than that of HC2 among women with CIN2+ (89.9% versus 98.7%, respectively) (P < 0.001) and <CIN2 (53.5% versus 72.4%, respectively) (P < 0.001). In conclusion, H13 corresponds well to the combination of HC2 and Onclarity and has good clinical accuracy compared to histologic diagnosis, with less cross-reactivity with untargeted HPV types than HC2. H13 is a lower-cost HPV DNA test that might be useful for primary screening in limited-resource settings.


Generalization of the Tolman electronic parameter: the metal-ligand electronic parameter and the intrinsic strength of the metal-ligand bond.
The catalytic activity of transition metal complexes (R)nM-L can be predicted utilizing the metal-ligand electronic parameter (MLEP) that is based on the local stretching force constant of the M-L bond. Vibrational spectroscopy is an excellent tool to accurately determine vibrational mode properties such as stretching frequencies. These correspond, because of mode-mode coupling, to delocalized vibrational modes, which have to be first converted into local vibrational modes, and their properties. Each bond of a molecule can be uniquely characterized by the local stretching force constant and frequency. The former is ideally suited to set up a scale of bond strength orders, which identifies weak M-L bonds with promising catalytic activity. It is shown how the MLEP replaces the TEP (Tolman Electronic Parameter), which is based on the CO stretching frequencies of a (CO)nM-L complex and which is now exclusively used in hundreds of investigations. However, the TEP is at best a qualitative parameter that suffers from relatively large mode-mode coupling errors and the basic deficiency of most indirect descriptors: They cannot correctly describe the intrinsic M-L bond strength via the CO stretching frequencies.


Inhibition of CD26/DPP IV attenuates ischemia/reperfusion injury in orthotopic mouse lung transplants: the pivotal role of vasoactive intestinal peptide.
The T cell activation Ag CD26/dipeptidylpeptidase IV (DPP IV) combines co-stimulatory and enzymatic properties. Catalytically, it functions as an exopeptidase, modulating biological activity of key chemokines and peptides. Here we investigated the effect of organ-specific inhibition of DPP IV catalytic activity on ischemia/reperfusion injury after extended ischemia in the mouse model of orthotopic single lung transplantation. C57BL/6 mice were syngeneically, transplanted, grafts were perfused and stored in Perfadex with (treated) or without (control) a DPP IV enzymatic activity inhibitor (AB192). Transplantation was performed after 18h cold ischemia time; following 2-h reperfusion, grafts were analyzed for oxygenation, thiobarbituric acid-reactive substances, histomorphology, and immunohistochemistry was performed for leukocyte Ag 6, myeloperoxidase, hemoxygenase 1, vasoactive intestinal protein (VIP), and real-time PCR for VIP. Treatment with the DPP IV inhibitor AB192 resulted in significant improvement of gas exchange, less lipid oxidation, preservation of parenchymal ultrastructure, reduced neutrophil infiltration, reduced myeloperoxidase expression, increased hemoxygenase 1 expression, pronounced expression of VIP in alveolar macrophages and increased mRNA expression of VIP. Inhibition of intragraft DPP IV catalytic activity with AB192 strikingly ameliorates ischemia/reperfusion injury after extended ischemia. Furthermore, preservation of endogenous intragraft VIP levels correlate with maintaining lung function and structural integrity.


Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories.
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.


Classification of nucleic acids structures by means of the chemometric analysis of circular dichroism spectra.
DNA can adopt structures in solution apart from the well-known Watson-Crick double helix, ranging from disordered single strands to high-order structures such as triplexes or quadruplexes. Moreover, different topologies can be adopted depending on the polarity of the DNA strands. The elucidation of the structure and topology adopted by a DNA sequence is usually carried out by means of spectroscopic techniques, such as circular dichroism. In this work, the ability of several chemometric methods to efficiently classify DNA structures from circular dichroism data is tested. With this objective in mind, a dataset including 50 experimental spectra corresponding to different DNA structures (random coil, duplex, hairpin, reversed and normal triplex, parallel and antiparallel G-quadruplex, and i-motif) has been analyzed by means of unsupervised hierarchical clustering analysis, principal component analysis and partial least squares discriminant analysis. The results have shown than those methods allow efficiently the classification of DNA structures from circular dichroism spectra. Moreover, these classification methods also provided the most characteristic wavelengths used in the classification procedures.


UBE2C-mediated Autophagy Inhibition via Ubiquitination of SIRT1 Contributes to Endometrial Cancer Progression.
Recent studies have shown that autophagy plays an important role in gynecologic tumors, and ubiquitin modification of autophagy regulatory components is essential to regulate autophagic flux. In this study, we found that the ubiquitin-conjugating enzyme E2C (UBE2C) affects endometrial cancer cell apoptosis and proliferation by inhibiting autophagy. Electron microscopy observation of cell ultrastructure and experimental biochemical analysis showed that endometrial cancer cells with UBE2C expression knocked down display typical autophagic characteristics. Cells were cotreated with the autophagy pharmacologic inhibitors chloroquine and/or bafilomycin A1, and mRFP-GFP-LC3 assays were performed to monitor autophagic flux and determine whether UBE2C suppresses the autophagy program. Investigation of the corresponding mechanism by which UBE2C inhibits autophagy revealed that UBE2C induces K48-linked SIRT1 ubiquitination and promotes ubiquitination-dependent degradation of SIRT1, subsequently reducing H4K16 deacetylation levels and epigenetically inhibiting the expression of autophagy-related genes. The results of cell counting kit-8, Hoechst staining, and immunofluorescence assays further indicated that deletion of the autophagy-related gene BECN1 significantly attenuates UBE2C knockdown-induced cell apoptosis. Moreover, overexpression of UBE2C promoted tumor growth in the xenograft mice model. While, the introduction of rapamycin, an agonist of autophagy, successfully reversed tumor growth and apoptosis inhibition mediated by UBE2C overexpression in vitro and in vivo. Taken together, our results suggested that UBE2C-mediated ubiquitination and degradation of SIRT1 contribute to the malignant progression of endometrial cancer through epigenetic inhibition of autophagy. Our study highlights the tumorigenic role and regulatory mechanism of UBE2C in endometrial cancer; UBE2C inhibits endometrial cancer cell apoptosis through autophagy-related mechanisms and our findings provide new insights into the treatment of endometrial cancer.


Examining quality of life in an Australian cohort of people with epilepsy over six years - Understanding the role of stigma and mood.
Research examining quality of life (QoL) among people living with epilepsy (PWE) consistently highlights the detrimental impact of stigma, anxiety, and depression, as well as the dynamic and changing nature of QoL over time. This paper represents the first panel study of the Australian Epilepsy Longitudinal Survey (AELS), examining factors that influence the QoL of PWE over a six-year interval, particularly focusing on experiences of stigma, depression, and anxiety. Ninety-two adults participated in both Wave 2 (T1; 2010) and Wave 4 (T2; 2016/17) of the AELS. Average age at T2 was 53.4 years [standard deviation (SD) = 15.3; range: 22-82; 55% female]. Over the study interval, there was a shift towards more younger participants moving out of high school and older participants moving into retirement. We explored the impact of (i) experiences of stigma, (ii) mood, and (iii) sociodemographic factors on QoL at both T1 and T2 via the use of correlation analyses. Hierarchical regression was used to determine the strongest predictors of QoL at T2. Occurrence of recent seizures, stigma, anxiety, and depression measured at T1 were all significantly correlated with total QoL at both T1 and T2. Sociodemographic factors including years of education, and weekly income before tax were not significantly correlated with QoL at either T1 or T2. QoL and depression at T1 were identified as the strongest predictors of QoL at T2 (six years later). The current study supports previous research highlighting the importance of psychological factors in understating QoL in PWE, particularly stigma, anxiety, and depression. In particular, it highlights the impact of depression on QoL over a 6-year interval, providing evident for the long-term nature of this relationship.


Giardiasis as a re-emerging infectious disease and its zoonotic potential.
The reasons for considering giardiasis as a re-emerging infectious disease are presented, with emphasis on Giardia infections in child care centres, livestock and pets, and the role of zoonotic transmission. However, the aetiology and control of giardiasis is complicated by the genetic and phenotypic variability of Giardia species infective to mammals. Of particular significance has been the uncertainty about host specificity and the question of zoonotic transmission. The recent application of molecular characterisation procedures based on PCR has made an enormous contribution to an understanding of the genetic structure of Giardia populations, and this is reviewed in the context of the zoonotic transmission and molecular epidemiology of Giardia infections.


Sense of humor and its association with psychological disturbances among dental students in India.
Although the health benefits of humor and the potential advantages of having a good Sense of Humor (SoH) have been long recognized, they have not been investigated in dental students. The aim of this study was to assess the extent and demographic correlates of SoH in dental students and its association with their self-reported level of psychological disturbances. Six hundred and five students (age 20.3±1.83 years, 250 males, 355 females) from two dental schools in India anonymously completed the Multidimensional Sense of Humor Scale (MSHS) and the Depression Anxiety Stress Scales-21. Independent samples t-test and one-way ANOVA were used to analyze the intergroup differences based on gender and year of study, respectively. The association between SoH and each of the three negative affective states was evaluated with multiple linear regressions. The mean MSHS score of the sample was 59.65±11.77. Male students showed a marginally higher SoH than females (60.78 vs. 58.86, p<0.05). The level of SoH steadily improved along the course duration, with statistically significant increases in the third and fifth years of study. SoH was negatively associated with all three negative affective states and explained nearly 3 to 5 percent of their variance. These results warrant further inquiry on the correlates of SoH in dental students, the psychosocial roles of humor, and their application in improving the psychological climate in dental schools.


Obesity intervention in persons with spinal cord injury.
A single group uncontrolled trial. Despite widespread emphasis on the obesity-related health risks in persons with spinal cord injury (SCI), limited research has been carried out to intervene in this problem. This study was conducted to assess the initial effectiveness of a weight loss program on various health outcomes in persons with SCI. A rehabilitation center in Birmingham, Alabama, United States. A total of 16 individuals with chronic SCI who were overweight or obese participated in a weight management program that consisted of 12 weekly classes, covering nutrition, exercise, and behavior modification. Various outcomes were examined over a 6-month period (baseline, week 12, and week 24), including body composition measured by dual energy X-ray absorptiometry, physiologic measures, diet behavior, and psychosocial and physical functioning. Of these, 13 participants returned for the week 24 follow-up. Weight loss averaged 3.5+/-3.1 kg (3.8% of the initial weight) at week 12 and 2.9+/-3.7 kg (3.0% of the initial weight) at week 24. There was a significant reduction from baseline values at weeks 12 and 24 in body mass index, anthropometric measurements, and fat mass and improvement in diet behavior and psychosocial and physical functioning, while lean mass and blood albumin and hemoglobin levels were maintained. A correlation analysis showed that a greater weight loss was importantly (r>0.4) associated with a greater reduction in total cholesterol at weeks 12 and 24 and in systolic and diastolic blood pressure at week 24. Several factors were important (r>0.4 or r<-0.4) in determining the success in weight loss, including age, race, marital and employment status, family history of overweight/obesity, level and duration of injury, and cholesterol level at baseline. This is the first demonstration that a carefully planned program with time-calorie displacement diet is effective for overweight/obese individuals with SCI to lose weight without compromising total lean mass and overall health. It provides foundation for a future large clinical trial for weight loss of persons with SCI or other spinal cord dysfunction.


Ultra-low-field NMR relaxation and diffusion measurements using an optical magnetometer.
Nuclear magnetic resonance (NMR) relaxometry and diffusometry are important tools for the characterization of heterogeneous materials and porous media, with applications including medical imaging, food characterization and oil-well logging. These methods can be extremely effective in applications where high-resolution NMR is either unnecessary, impractical, or both, as is the case in the emerging field of portable chemical characterization. Here, we present a proof-of-concept experiment demonstrating the use of high-sensitivity optical magnetometers as detectors for ultra-low-field NMR relaxation and diffusion measurements.


Self-reported experiences of racial discrimination and Black-White differences in preterm and low-birthweight deliveries: the CARDIA Study.
We examined the effects of self-reported experiences of racial discrimination on Black-White differences in preterm (less than 37 weeks gestation) and low-birthweight (less than 2500 g) deliveries. Using logistic regression models, we analyzed data on 352 births among women enrolled in the Coronary Artery Risk Development in Young Adults Study. Among Black women, 50% of those with preterm deliveries and 61% of those with low-birthweight infants reported having experienced racial discrimination in at least 3 situations; among White women, the corresponding percentages were 5% and 0%. The unadjusted odds ratio for preterm delivery among Black versus White women was 2.54 (95% confidence interval [CI]=1.33, 4.85), but this value decreased to 1.88 (95% CI=0.85, 4.12) after adjustment for experiences of racial discrimination and to 1.11 (95% CI=0.51, 2.41) after additional adjustment for alcohol and tobacco use, depression, education, and income. The corresponding odds ratios for low birthweight were 4.24 (95% CI=1.31, 13.67), 2.11 (95% CI=0.75, 5.93), and 2.43 (95% CI=0.79, 7.42). Self-reported experiences of racial discrimination were associated with preterm and low-birthweight deliveries, and such experiences may contribute to Black-White disparities in perinatal outcomes.


Regulation and Functions of the Renin-Angiotensin System in White and Brown Adipose Tissue.
The renin angiotensin system (RAS) is a major regulator of blood pressure, fluid, and electrolyte homeostasis. RAS precursor angiotensinogen (Agt) is cleaved into angiotensin I (Ang I) and II (Ang II) by renin and angiotensin converting enzyme (ACE), respectively. Major effects of Ang II, the main bioactive peptide of this system, is mediated by G protein coupled receptors, Angiotensin Type 1 (AGTR1, AT1R) and Type 2 (AGTR2, AT2R) receptors. Further, the discovery of additional RAS peptides such as Ang 1-7 generated by the action of another enzyme ACE2 identified novel functions of this complex system. In addition to the systemic RAS, several local RAS exist in organs such as the brain, kidney, pancreas, and adipose tissue. The expression and regulation of various components of RAS in adipose tissue prompted extensive research into the role of adipose RAS in metabolic diseases. Indeed, animal studies have shown that adipose-derived Agt contributes to circulating RAS, kidney, and blood pressure regulation. Further, mice overexpressing Agt have high blood pressure and increased adiposity characterized by inflammation, adipocyte hypertrophy, and insulin resistance, which can be reversed at least in part by RAS inhibition. These findings highlight the importance of this system in energy homeostasis, especially in the context of obesity. This overview article discusses the depot-specific functions of adipose RAS, genetic and pharmacological manipulations of RAS, and its applications to adipogenesis, thermogenesis, and overall energy homeostasis. © 2017 American Physiological Society. Compr Physiol 7:1137-1150, 2017.


Serotonin increases DNA synthesis in rat proximal and distal pulmonary vascular smooth muscle cells in culture.
Cultured smooth muscle cells obtained from rat lung periphery (RPC) and proximal pulmonary artery (RSMC) expressed mRNA for serotonin (5-HT) type 2 receptor (5-HT2) and 5-HT transporter (by Northern blot analysis). Functional expression of these genes was evident since both cell types 1) bound 125I-labeled lysergic acid diethylamide (LSD; 5-HT2 receptor antagonist) that was equally effectively displaced by either ketanserin or mianserin; and 2) transported 5-[3H]HT in an imipramine-sensitive manner. Serotonin (10(-9)-10(-5) M) stimulated DNA synthesis (as measured by [3H]thymidine uptake) in RPC and RSMC. The 5-HT-induced increase in DNA synthesis was significantly inhibited in both cell types by the 5-HT2 receptor antagonist, ketanserin (10(-7)-10(-6) M), and by fluoxetine (10(-6) M), a putative 5-HT transport inhibitor. Acute exposure to 5-HT (1-100 microM) caused an abrupt rise in intracellular calcium ([Ca2+]i) in single pulmonary vascular smooth muscle cells as microspectrofluorometrically determined using the calcium-sensitive dye, fura 2. The 5-HT-induced change in [Ca2+]i was completely abolished in the presence of 10(-6) M ketanserin as well as imipramine or fluoxetine (10(-6) M). The calcium transients due to 5-HT persisted in a Na(+)-free condition (in which the transporter activity was completely abolished) and imipramine and fluoxetine (and ketanserin) were effective inhibitors of 5-HT under these conditions. Therefore, the 5-HT2 receptor, but not the transporter, is responsible for initiating the acute effects (e.g., calcium transients) of 5-HT in cultured rat pulmonary vascular smooth muscle cells and fluoxetine (1 microM) may have 5-HT2-receptor antagonist properties.(ABSTRACT TRUNCATED AT 250 WORDS)


S-adenosylmethionine decarboxylase of Bacillus subtilis is closely related to archaebacterial counterparts.
Bacillus subtilis synthesizes polyamines by decarboxylating arginine to agmatine, which is subsequently hydrolysed to putrescine. Spermidine is synthesized from putrescine and decarboxylated S-adenosylmethionine (dAdoMet). In Gram-negative bacteria and in eukaryotes, AdoMet is decarboxylated by an unusual 'pyruvoyl' AdoMet decarboxylase (SpeD), the catalytic pyruvoyl moiety of which is generated by serinolysis of an internal serine with self-cleavage of the protein at the upstream peptide bond. Neither the Gram-positive bacterial nor the archaeal counterpart of the Escherichia coli SpeD enzyme were known. We have identified the corresponding B. subtilis speD gene (formely ytcF). Heterologous expression of the cognate Methanococcus jannaschii protein, MJ0315, demonstrated that it displays the same activity as B. subtilis SpeD, indicating that spermidine biosynthesis in Gram-positive bacteria and in archaea follows a pathway very similar to that of Gram-negatives and eukarya. In B. subtilis, transcription of speD is modulated by spermidine and methionine. Its expression is high under usual growth conditions. In contrast, the SpeD protein self-cleaves slowly in vitro, a noticeable difference with its archaeal counterpart. Under certain growth conditions (minimal medium containing succinate and glutamate as a carbon source), speD is co-transcribed with gapB, the gene encoding glyceraldehyde-3-phosphate dehydrogenase, an enzyme required for gluconeogenesis. This observation may couple polyamine metabolism to sulphur and carbon metabolism by a so far unknown mechanism.


Estimating kinetic parameters for single channels with simulation. A general method that resolves the missed event problem and accounts for noise.
Analysis of currents recorded from single channels is complicated by the limited time resolution (filtering) of the data which can prevent the detection of brief intervals. Although a number of approaches have been used to correct for the undetected intervals (missed events) when identifying kinetic models and estimating parameters, none of them provide a general method which takes into account the true effects of noise and limited time resolution. This paper presents such a method. The approach is to use simulated single-channel currents to incorporate the true effects of filtering and noise on missed events and interval durations. The simulated currents are then analyzed in a manner identical to that used to analyze the experimental currents. An iterative search process using likelihood comparison of two-dimensional dwell-time distributions obtained from the simulated and experimental single-channel currents then allows the most likely rate constants to be determined. The large errors and false solutions that can result from the more typically applied assumptions of no noise and an absolute dead time (idealized filtering) are excluded by the iterative simulation method, and the correlation information contained in the two-dimensional distributions should increase the ability to distinguish among different gating mechanisms. The iterative simulation method is generally applicable to channels which typically open to a single conductance level. For these channels the method places no restrictions on the proposed gating mechanism or the form of the predicted dwell-time distributions.


Mapping condition-dependent regulation of lipid metabolism in Saccharomyces cerevisiae.
Lipids play a central role in cellular function as constituents of membranes, as signaling molecules, and as storage materials. Although much is known about the role of lipids in regulating specific steps of metabolism, comprehensive studies integrating genome-wide expression data, metabolite levels, and lipid levels are currently lacking. Here, we map condition-dependent regulation controlling lipid metabolism in Saccharomyces cerevisiae by measuring 5636 mRNAs, 50 metabolites, 97 lipids, and 57 (13)C-reaction fluxes in yeast using a three-factor full-factorial design. Correlation analysis across eight environmental conditions revealed 2279 gene expression level-metabolite/lipid relationships that characterize the extent of transcriptional regulation in lipid metabolism relative to major metabolic hubs within the cell. To query this network, we developed integrative methods for correlation of multi-omics datasets that elucidate global regulatory signatures. Our data highlight many characterized regulators of lipid metabolism and reveal that sterols are regulated more at the transcriptional level than are amino acids. Beyond providing insights into the systems-level organization of lipid metabolism, we anticipate that our dataset and approach can join an emerging number of studies to be widely used for interrogating cellular systems through the combination of mathematical modeling and experimental biology.


Composite microtubules of the axon: quantitative analysis of tyrosinated and acetylated tubulin along individual axonal microtubules.
We have shown previously, using immunoelectron microscopy, that axonal microtubules (MTs) are composite, consisting of distinct domains that differ in their content of tyrosinated alpha-tubulin (tyr-tubulin). Here, we extend these studies using a novel preparation that permits visualization of individual axonal MTs over distances of several tens of micrometers using conventional immunofluorescence procedures. Neurons are cultured on a substratum of poly-lysine and laminin and then extracted with a MT stabilizing solution containing Triton X-100 and NaCl. These extraction conditions cause a loosening of the axonal MT array so that individual MTs separate from each other for variable distances along their length. We call this phenomenon fraying. Within the axon shaft, individual MTs can often be traced for several tens of micrometers, but fraying is most extensive in the distal 100-200 microns of the axon, where individual MTs can frequently be traced for distances of 50 to 100 microns or more to their plus ends. In some cases MTs separate completely from the axon, permitting visualization of both of their ends. Double-staining of frayed preparations with various combinations of antibodies against tyr-tubulin, acetylated alpha-tubulin (Ac-tubulin) or beta-tubulin, clearly revealed the composite nature of axonal MTs. Composite MTs consisted of two distinct domains, one that was relatively rich in tyr-tubulin and poor in Ac-tubulin, and the other that was relatively poor in tyr-tubulin and rich in Ac-tubulin. The transition between these domains was relatively abrupt, with the tyr-tubulin-rich domain extending from the transition to the plus-end of the MT. Quantitative analyses of fluorescence intensity along individual MTs using digital image processing revealed that the relative amount of tyr-tubulin increased by approximately 800% across the transition, whereas the relative amount of Ac-tubulin decreased by approximately 60%. Within the tyr-tubulin-rich domains, the relative amount of tyr-tubulin was generally not constant, but increased from the transition to the plus-end of the MT in a nonlinear manner. We propose that the specific pattern of variation in the extent of post-translational modification along an individual MT represents a snapshot of that polymer's growth history.


Increasing Prevalence of HIV Pretreatment Drug Resistance in Women But Not Men in Rural Uganda During 2005-2013.
The prevalence of HIV pretreatment drug resistance (PDR) is increasing in sub-Saharan Africa. We sought to describe correlates of PDR and evaluate effects of PDR on clinical outcomes in rural Uganda. We analyzed data from the Uganda AIDS Rural Treatment Outcomes study, a cohort of antiretroviral therapy (ART)-naive adults with HIV (2005-2015). We performed resistance testing on pre-ART specimens. We defined PDR as any World Health Organization (WHO) 2009 surveillance drug resistance mutation and classified PDR level using the Stanford algorithm. We fit unadjusted and sex-stratified log binomial regression and Cox proportional hazard models to identify correlates of PDR and the impact of PDR on viral suppression, loss to follow-up (LTFU), and death. We analyzed data from 738 participants (median age 33 years, 69% female). Overall, prevalence of PDR was 3.5% (n = 26), owing mostly to resistance to non-nucleoside reverse transcriptase inhibitors. PDR increased over time in women (1.8% in those enrolling in clinic in 2001-2006, vs. 7.0% in 2007-2013; p = 0.006), but not in men (1.15% vs. 0.72%, p = 0.737). Lower pre-ART log10 HIV RNA was also associated with higher prevalence of PDR. We identified longer time to viral suppression among those with PDR compared with without PDR (0.5 and 0.3 years, respectively, p = 0.023), but there was no significant relationship with mortality or LTFU (p = 0.139). We observed increasing rates of PDR in women in southwestern Uganda. Implications of this trend, particularly to prevention of mother-to-child transmission programs in the region, require attention due to delayed viral suppression among those with PDR.


A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth.
The planar polarity and staircase-like pattern of the hair bundle are essential to the mechanoelectrical transduction function of inner ear sensory cells. Mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15 or sans cause Usher syndrome type I (USH1, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa leading to blindness) in humans and hair bundle disorganization in mice. Whether the USH1 proteins are involved in common hair bundle morphogenetic processes is unknown. Here, we show that mouse models for the five USH1 genetic forms share hair bundle morphological defects. Hair bundle fragmentation and misorientation (25-52 degrees mean kinociliary deviation, depending on the mutant) were detected as early as embryonic day 17. Abnormal differential elongation of stereocilia rows occurred in the first postnatal days. In the emerging hair bundles, myosin VIIa, the actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium lateral link components cadherin 23 and protocadherin 15, all concentrated at stereocilia tips, in accordance with their known in vitro interactions. Soon after birth, harmonin-b switched from the tip of the stereocilia to the upper end of the tip link, which also comprises cadherin 23 and protocadherin 15. This positional change did not occur in mice deficient for cadherin 23 or protocadherin 15. We suggest that tension forces applied to the early lateral links and to the tip link, both of which can be anchored to actin filaments via harmonin-b, play a key role in hair bundle cohesion and proper orientation for the former, and in stereociliary elongation for the latter.


Modeling the combined impacts of host plant resistance and biological control on the population dynamics of a major pest of wheat.
Single-tool approaches often fail to provide effective long-term suppression of pest populations, such that combining several tools into an integrated management strategy is critical. Yet studies that harness the power of population models to explore the relative efficacy of various management tools and their combinations remain rare. We constructed a Leslie matrix population model to evaluate the potential of crop resistance, acting alone or in combination with biological control, to reduce populations of the wheat stem sawfly, Cephus cinctus Norton, a major pest of wheat in North America. Our model projections indicated that crop resistance reduced, but did not stop, C. cinctus population growth, suggesting that implementing multiple management tools will be necessary for longer term control of this pest. The levels of parasitism needed to curtail population growth were much lower in model projections for resistant solid-stemmed compared with susceptible hollow-stemmed cultivars (22% versus 86%). Furthermore, even when accounting for the reduced levels of parasitism observed in resistant cultivars, projected population growth rates for C. cinctus were always lower in resistant compared with susceptible wheat cultivars. Despite some empirical evidence for antagonistic interactions between resistance and biological control, our models suggest that combining these two approaches will always reduce population growth rates to lower levels than implementing either strategy alone. More work focused on integrating biological control into crop resistance breeding programs, and determining how these approaches affect performance of limiting life stages, will be important to optimize sustainable approaches to integrated pest management in this system and more broadly. Published 2020. This article is a U.S. Government work and is in the public domain in the USA.


First Report of Yellow Nutsedge (Cyperus esculentus) and Purple Nutsedge (C. rotundus) in Georgia Naturally Infected with Impatiens necrotic spot virus.
Impatiens necrotic spot virus (INSV), family Bunyaviridae, genus Tospovirus, is an emerging virus found mostly in ornamentals under greenhouse production. INSV has been detected in peanut (Arachis hypogaea L.) in Georgia and Texas (3) and recently in tobacco (Nicotiana tabacum L.) in the southeastern United States (2) but little is known about INSV distribution and impact on these crops. Noncrop plant hosts are likely to contribute to disease spread by serving as reservoirs for the virus and reproductive hosts for thrips (Frankliniella occidentalis Pergande), which transmit the virus. Yellow nutsedge, a native of North America, and purple nutsedge introduced from Eurasia, are considered serious weed problems in the southeastern United States. To date, there are no reports of natural INSV infections in these weeds. A survey was conducted at two research farms in Tift County, Georgia to determine if yellow and purple nutsedge plants were naturally infected with Tomato spotted wilt virus (TSWV) and INSV. The first field at the Black Shank Farm had been planted with flue-cured tobacco K-326 earlier in the year and fallow at the time of sampling. The second field at the Ponder Farm was planted at the time of sampling with yellow squash (Cucurbita pepo L.) and cabbage (Brassica oleracea L.). In early October 2002, 90 nutsedge plants were taken at random from each site. Leaf and root tissues of each of the nutsedge plants were tested for TSWV and INSV using double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) alkaline phosphatase antisera kits (Agdia Inc., Elkhart, IN). No visible symptoms of INSV or TSWV were observed. Samples from the field at the Black Shank Farm resulted in 2 of 26 positive for INSV in purple nutsedge plants and 6 of 64 in yellow nutsedge plants. At the Ponder Farm, 3 of 12 were positive for INSV in purple nutsedge plants and 14 of 78 in yellow nutsedge plants. None of the samples in either site tested positive for TSWV. The DAS-ELISA positive samples were verified for INSV using reverse transcription-polymerase chain reaction (RT-PCR) as previously described by Dewey et al. (1). Total RNA extracts were obtained from the DAS-ELISA positive nutsedge samples using RNeasy extraction kits (Qiagen Inc., Valencia, CA). The RT-PCR was carried out with primer 1F: 5'-TCAAG(C/T) CTTC(G/T)GAA(A/G)GTGAT 3' (1) and primer 2R: 5'-ATGAACAAAGCAAAGATTACC 3' specific to the 3' end of the INSV N gene open reading frame (GenBank Accession No. NC003624). DAS-ELISA negative tissues of Cyperus esculentus L. and Emilia sonchifolia (L.) DC and an E. sonchifolia DAS-ELISA positive for INSV were included in the reactions as controls. All of the DAS-ELISA positive nutsedge samples yielded an amplification product with the expected size of 298 bp when PCR products were resolved by agarose (0.7%) gel electrophoresis. The relatively high occurrence of INSV found in the sampled fields may explain the recent increase in incidence of INSV in susceptible field crops. Although yellow nutsedge is more common than purple nutsedge in North America, the potential for dispersal of INSV in both species could be significant because of the nature of nutsedge tuber survival and spreading capabilities. References: (1) R. A. Dewey et al. J. Virol. Methods 56:19, 1996. (2) N. Martínez-Ochoa et al. On-line publication. doi:10.1094/PHP-2003-0417-01-HN. Plant Health Progress, 2003. (3) S. S. Pappu et al. Plant Dis. 83:966,1999.


Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial.
Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. Alliance for Better Bone Health (Warner Chilcott and Sanofi).


LARP-1 promotes oogenesis by repressing fem-3 in the C. elegans germline.
LA-related protein 1 (LARP-1) belongs to an RNA-binding protein family containing a LA motif. Here, we identify LARP-1 as a regulator of sex determination. In C. elegans hermaphrodites, a complex regulatory network regulates the switch from sperm to oocyte production. We find that simultaneous depletion of larp-1 and the Nanos homologue nos-3 results in germline masculinization. This phenotype is accompanied by a strong reduction of the levels of TRA-1, a GLI-family transcription factor that promotes oogenesis. TRA-1 levels are regulated by CBC(FEM-1), a ubiquitin ligase consisting of the FEM proteins, FEM-1, FEM-2 and FEM-3 and the cullin CUL-2. We show that both the masculinization phenotype and the reduction of TRA-1 levels observed in nos-3;larp-1 mutants require fem-3 activity, suggesting that nos-3 and larp-1 regulate the sperm-oocyte switch by inhibiting the fem genes. Consistently, fem-3 mRNA levels are increased in larp-1 mutants. By contrast, levels of fem-3 mRNA are not affected in nos-3 mutants. Therefore, our data indicate that LARP-1 and NOS-3 promote oogenesis by regulating fem-3 expression through distinct mechanisms.


Do as I do: 7-month-old infants selectively reproduce others' goals.
In the current study, we tested whether 7-month-old infants would selectively imitate the goal-relevant aspects of an observed action. Infants saw an experimenter perform an action on one of two small toys and then were given the opportunity to act on the toys. Infants viewed actions that were either goal-directed or goal-ambiguous, and that represented either completed or uncompleted goals. Infants reproduced the goal of the experimenter only in those cases where the action was goal-directed, in both the complete and incomplete goal conditions. These results provide the first evidence that infants as young as 7 months of age selectively imitate actions based on their goal-directedness, and that they are able to analyze the goals of even uncompleted actions. Even during the first year of life, infants' sensitivity to goal-directed action is expressed not only in their responses in visual habituation procedures, but also in their overt actions.


How to handle speciose clades? Mass taxon-sampling as a strategy towards illuminating the natural history of Campanula (Campanuloideae).
Speciose clades usually harbor species with a broad spectrum of adaptive strategies and complex distribution patterns, and thus constitute ideal systems to disentangle biotic and abiotic causes underlying species diversification. The delimitation of such study systems to test evolutionary hypotheses is difficult because they often rely on artificial genus concepts as starting points. One of the most prominent examples is the bellflower genus Campanula with some 420 species, but up to 600 species when including all lineages to which Campanula is paraphyletic. We generated a large alignment of petD group II intron sequences to include more than 70% of described species as a reference. By comparison with partial data sets we could then assess the impact of selective taxon sampling strategies on phylogenetic reconstruction and subsequent evolutionary conclusions. Phylogenetic analyses based on maximum parsimony (PAUP, PRAP), Bayesian inference (MrBayes), and maximum likelihood (RAxML) were first carried out on the large reference data set (D680). Parameters including tree topology, branch support, and age estimates, were then compared to those obtained from smaller data sets resulting from "classification-guided" (D088) and "phylogeny-guided sampling" (D101). Analyses of D088 failed to fully recover the phylogenetic diversity in Campanula, whereas D101 inferred significantly different branch support and age estimates. A short genomic region with high phylogenetic utility allowed us to easily generate a comprehensive phylogenetic framework for the speciose Campanula clade. Our approach recovered 17 well-supported and circumscribed sub-lineages. Knowing these will be instrumental for developing more specific evolutionary hypotheses and guide future research, we highlight the predictive value of a mass taxon-sampling strategy as a first essential step towards illuminating the detailed evolutionary history of diverse clades.


Serum antibody does not account for differences in the severity of chronic respiratory disease caused by Mycoplasma pulmonis in LEW and F344 rats.
Chronic respiratory disease in rats, resulting from Mycoplasma pulmonis infection, is useful in the study of the immunological mechanisms in similar inflammatory diseases and provides a unique opportunity to study the interactions between systemic and mucosal immune systems in a naturally occurring infection. The present study examined the serum antibody responses to M. pulmonis in strains of rats which differ in disease progression and severity; LEW rats developed more severe disease than did F344 rats. Serum antibody responses were evaluated as to their levels, isotypes, and antigens recognized. Infected LEW rats produced greater or equal levels of the major classes of serum antibody to M. pulmonis than did infected F344 rats, suggesting that development of serum antibody responses alone does not resolve lesions and is not responsible for the difference in disease severity found in LEW and F344 rats. Although LEW rats produced higher responses in all subclasses of immunoglobulin G (IgG), the specific IgG response of LEW rats was composed predominately of IgG1 and IgG2a subclasses, while IgG2b was the major component of the IgG response in F344 rats. Finally, LEW rats responded more quickly to M. pulmonis antigens than did F344 rats, and there was no difference in the antigens eventually recognized by each strain, confirming previous work which suggested that LEW rats do not exhibit an unresponsiveness to a specific antigen(s) of M. pulmonis.


Increase in body weight is a non-motor side effect of deep brain stimulation of the subthalamic nucleus in Parkinson's disease.
Deep brain stimulation of the subthalamic nucleus (DBS STN) is an effective treatment method in advanced Parkinson's disease (PD) providing marked improvement of its major motor symptoms. In addition, non-motor effects have been reported including weight gain in PD patients after DBS STN. Using retrospective survey, we aimed to evaluate weight changes in our patients with advanced PD treated with DBS STN. We inquired 25 PD patients (16 men, 9 women), of mean age 55 (42-65) years, mean PD duration 15 (9-21) years, who previously received bilateral DBS STN. We obtained valid data from 23 patients. In the first survey, 1 to 45 months after DBS, weight gain was found in all patients comparing to pre-DBS period. The mean increase was 9.4 kg (from 1 to 25 kg). The patients' mean body mass index (BMI) increased from 23.7 to 27.0 kg/m2, i.e. by 3.3 kg/m2 (+2 to +6.1 kg/m2). In the repeated survey one year later, in 12 of the patients body weight moderately decreased, 3 did not change, and 6 patients further increased their weight. Possible explanations of body weight gain after DBS STN include a reduction of energy output related to elimination of dyskinesias, improved alimentation or direct influence on function of lateral hypothalamus by DBS STN.


Physicochemical and antioxidative characteristics of Iranian pomegranate (Punica granatum L. cv. Rabbab-e-Neyriz) juice and comparison of its antioxidative activity with Zataria multiflora Boiss essential oil.
Pomegranate juice (PJ) and its products are directly used in foods due to their pleasant taste and palatability as well as preservative effects. In spite of useful effects of essential oils such as zataria multiflora Boiss essential oil (ZEO) on prolonging shelf-life of foods, their application is restricted due to their vigorous taste and aroma. In the present study, physicochemical characteristics, chemical compositions and antioxidative activities of two Iranian native plants, PJ (Rabbab-e-Neyriz cultivar) and ZEO were investigated. 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and reducing power tests were used for measuring antioxidant activity. The level of total phenolic of them were also determined. Total soluble solids content, pH value, titratable acidity content and total anthocyanins content of PJ were also measured. Chemical compositions of ZEO were determined using gas-chromatography, mass-spectrometry (GC-MS). The results of antioxidative tests indicated that the ZEO was significantly more potent (p < 0.05) than PJ. Also the phenolic content in ZEO (262.52 mg per g) was significantly higher (p < 0.05) than PJ (154.90 mg per 100g). Chemical compositions analysis of ZEO indicated that its major components were carvacrol (59.17%), linalool (23.67%), trans-caryophyllene (3.07%) and carvacrol methyl ether (2.44%). In the present study, physicochemical and antioxidative characteristics of Rabbab-e-Neyriz PJ were determined for first time. It was aslo found that ZEO in comparison with PJ had higher antioxidative activity and total phenolic content.


A combined nanoplasmonic and electrodeless quartz crystal microbalance setup.
We have developed an instrument combining localized surface plasmon resonance (LSPR) sensing with electrodeless quartz crystal microbalance with dissipation monitoring (QCM-D). The two techniques can be run simultaneously, on the same sensor surface, and with the same time resolution and sensitivity as for the individual techniques. The electrodeless QCM eliminates the need to fabricate electrodes on the quartz crystal and gives a large flexibility in choosing the surface structure and coating for both QCM-D and LSPR. The performance is demonstrated for liquid phase measurements of lipid bilayer formation and biorecognition events, and for gas phase measurements of hydrogen uptake/release by palladium nanoparticles. Advantages of using the combined equipment for biomolecular adsorption studies include synchronized information about structural transformations and extraction of molecular (dry) mass and degree of hydration of the adlayer, which cannot be obtained with the individual techniques. In hydrogen storage studies the combined equipment, allows for synchronized measurements of uptake/release kinetics and quantification of stored hydrogen amounts in nanoparticles and films at practically interesting hydrogen pressures and temperatures.


Heaviside's dolphins (Cephalorhynchus heavisidii) relax acoustic crypsis to increase communication range.
The costs of predation may exert significant pressure on the mode of communication used by an animal, and many species balance the benefits of communication (e.g. mate attraction) against the potential risk of predation. Four groups of toothed whales have independently evolved narrowband high-frequency (NBHF) echolocation signals. These signals help NBHF species avoid predation through acoustic crypsis by echolocating and communicating at frequencies inaudible to predators such as mammal-eating killer whales. Heaviside's dolphins (Cephalorhynchus heavisidii) are thought to exclusively produce NBHF echolocation clicks with a centroid frequency around 125 kHz and little to no energy below 100 kHz. To test this, we recorded wild Heaviside's dolphins in a sheltered bay in Namibia. We demonstrate that Heaviside's dolphins produce a second type of click with lower frequency and broader bandwidth in a frequency range that is audible to killer whales. These clicks are used in burst-pulses and occasional click series but not foraging buzzes. We evaluate three different hypotheses and conclude that the most likely benefit of these clicks is to decrease transmission directivity and increase conspecific communication range. The expected increase in active space depends on background noise but ranges from 2.5 (Wenz Sea State 6) to 5 times (Wenz Sea State 1) the active space of NBHF signals. This dual click strategy therefore allows these social dolphins to maintain acoustic crypsis during navigation and foraging, and to selectively relax their crypsis to facilitate communication with conspecifics.


IL-1β suppresses innate IL-25 and IL-33 production and maintains helminth chronicity.
Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1β in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1β (IL-1β(-/-)), or treated with the soluble IL-1βR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1β acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1β that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity.


Are older adults up-to-date with cancer screening and vaccinations?
Public health organizations in the United States emphasize the importance of providing routine screening for breast cancer, cervical cancer, and colorectal cancer, as well as vaccinations against influenza and pneumococcal disease among older adults. We report a composite measure of adults aged 50 years and older who receive recommended cancer screening services and vaccinations. We analyzed state data from the 2002 Behavioral Risk Factor Surveillance System, which included 105,860 respondents aged 50 and older. We created a composite measure that included colonoscopy or sigmoidoscopy within 10 years or a fecal occult blood test in the past year, an influenza vaccination in the past year, a Papanicolaou test within 3 years for women with an intact cervix, a mammogram, and for adults aged 65 and older, a pneumonia vaccination during their lifetime. We performed separate analyses for four age and sex groups: men aged 50 to 64, women aged 50 to 64, men aged 65 and older, and women aged 65 and older. The percentage of each age and sex group that was up-to-date according to our composite measure ranged from 21.1% of women aged 50 to 64 (four tests) to 39.6% of men aged 65 and older (three tests). For each group, results varied by income, education, race/ethnicity, insurance status, and whether the respondent had a personal physician. These results suggest the need to improve the delivery of cancer screenings and vaccinations among adults aged 50 and older. We propose continued efforts to measure use of clinical preventive services.


Adiposity, mediating biomarkers and risk of colon cancer in the European prospective investigation into cancer and nutrition study.
Adiposity is a risk factor for colon cancer, but underlying mechanisms are not well understood. We evaluated the extent to which 11 biomarkers with inflammatory and metabolic actions mediate the association of adiposity measures, waist circumference (WC) and body mass index (BMI), with colon cancer in men and women. We analyzed data from a prospective nested case-control study among 662 incident colon cancer cases matched within risk sets to 662 controls. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. The percent effect change and corresponding CIs were estimated after adjusting for biomarkers shown to be associated with colon cancer risk. After multivariable adjustment, WC was associated with colon cancer risk in men (top vs. bottom tertile RR 1.68, 95% CI 1.06-2.65; ptrend = 0.02) and in women (RR 1.67, 95% CI 1.09-2.56; ptrend = 0.03). BMI was associated with risk only in men. The association of WC with colon cancer was accounted mostly for by three biomarkers, high-density lipoprotein cholesterol, non-high-molecular-weight adiponectin and soluble leptin receptor, which in combination explained 46% (95% CI 37-57%) of the association in men and 50% (95% CI 40-65%) of the association in women. Similar results were observed for the associations with BMI in men. These data suggest that alterations in levels of these metabolic biomarkers may represent a primary mechanism of action in the relation of adiposity with colon cancer. Further studies are warranted to determine whether altering their concentrations may reduce colon cancer risk.


The paretic pupil: its incidence and aetiology after keratoplasty for keratoconus.
The present study reveals that pupillary abnormalities are common after keratoplasty for keratoconus and that, in addition to the fixed dilated pupils which we have found in 7.8 per cent. of eyes, varying degrees of partially dilated pupil frequently occur after operation. In our experience, glaucoma is not a sequel to the simple paretic pupil, a finding which confirms the results of the smaller series of Alberth and Schnitzler (1971); glaucoma thus seems to be no more a special complication of keratoplasty for keratoconus than it is of keratoplasty for any other corneal pathology. The paretic pupils can be explained on the basis of ischaemic atrophy of the sphincter pupillae muscle secondary to an iris strangulation phenomenon occurring during surgery in the manner we have discussed. The relative frequency of a dilated pupil, together with the common finding of focal iris atrophy after minimal surgical trauma to the iris in cases of keratoconus, forces one to conclude that the pathology in this condition is not confined to the cornea but probably extends to the iris and possibly to the scleral envelope as well.


Deconstructing Methane Emissions from a Small Northern European River: Hydrodynamics and Temperature as Key Drivers.
Methane (CH4) emissions from small rivers and streams, particularly via ebullition, are currently under-represented in the literature. Here, we quantify the methane effluxes and drivers in a small, Northern European river. Methane fluxes are comparable to those from tropical aquatic systems, with average emissions of 320 mg CH4 m-2 d-1. Two important drivers of methane flux variations were identified in the studied system: 1) temperature-driven sediment methane ebullition and 2) flow-dependent contribution suspected to be hydraulic exchange with adjacent wetlands and small side-bays. This flow-dependent contribution to river methane loading is shown to be negligible for flows less than 4 m3 s-1 and greater than 50% as flows exceed 7 m3 s-1. While the temperature-ebullition relationship is comparable to other systems, the flow rate dependency has not been previously demonstrated. In general, we found that about 80% of the total emissions were due to methane bubbles. Applying ebullition rates to global estimates for fluvial systems, which currently are not considered, could dramatically increase emission rates to ranges from lakes or wetlands. This work illustrates that small rivers can emit significant methane and highlights the need for further studies on the link between hydrodynamics and connected wetlands.