Basics for sensorimotor information processing: some implications for learning.
In sensorimotor activities, learning requires efficient information processing, whether in car driving, sport activities or human-machine interactions. Several factors may affect the efficiency of such processing: they may be extrinsic (i.e., task-related) or intrinsic (i.e., subjects-related). The effects of these factors are intimately related to the structure of human information processing. In the present article we will focus on some of them, which are poorly taken into account, even when minimizing errors or their consequences is an essential issue at stake. Among the extrinsic factors, we will discuss, first, the effects of the quantity and quality of information, secondly, the effects of instruction and thirdly motor program learning. Among the intrinsic factors, we will discuss first the influence of prior information, secondly how individual strategies affect performance and, thirdly, we will stress the fact that although the human brain is not structured to function errorless (which is not new) humans are able to detect their errors very quickly and (in most of the cases), fast enough to correct them before they result in an overt failure. Extrinsic and intrinsic factors are important to take into account for learning because (1) they strongly affect performance, either in terms of speed or accuracy, which facilitates or impairs learning, (2) the effect of certain extrinsic factors may be strongly modified by learning and (3) certain intrinsic factors might be exploited for learning strategies.


Effect of thioxopeptide bonds on alpha-helix structure and stability.
Thioxoamide (thioamide) bonds are nearly isosteric substitutions for amides but have altered hydrogen-bonding and photophysical properties. They are thus well-suited backbone modifications for physicochemical studies on peptides and proteins. The effect of thioxoamides on protein structure and stability has not been subject to detailed experimental investigations up to date. We used alanine-based model peptides to test the influence of single thioxoamide bonds on alpha-helix structure and stability. The results from circular dichroism measurements show that thioxoamides are strongly helix-destabilizing. The effect of an oxo-to-thioxoamide backbone substitution is of similar magnitude as an alanine-to-glycine substitution resulting in a helix destabilization of about 7 kJ/mol. NMR characterization of a helical peptide with a thioxopeptide bond near the N-terminus indicates that the thioxopeptide moiety is tolerated in helical structures. The thioxoamide group is engaged in an i, i+4 hydrogen bond, arguing against the formation of a 3(10)-helical structure as suggested for the N-termini of alpha-helices in general and for thioxopeptides in particular.


Fragment-based screening by protein crystallography: successes and pitfalls.
Fragment-based drug discovery (FBDD) concerns the screening of low-molecular weight compounds against macromolecular targets of clinical relevance. These compounds act as starting points for the development of drugs. FBDD has evolved and grown in popularity over the past 15 years. In this paper, the rationale and technology behind the use of X-ray crystallography in fragment based screening (FBS) will be described, including fragment library design and use of synchrotron radiation and robotics for high-throughput X-ray data collection. Some recent uses of crystallography in FBS will be described in detail, including interrogation of the drug targets β-secretase, phenylethanolamine N-methyltransferase, phosphodiesterase 4A and Hsp90. These examples provide illustrations of projects where crystallography is straightforward or difficult, and where other screening methods can help overcome the limitations of crystallography necessitated by diffraction quality.


RNA-mediated gene regulation is less evolvable than transcriptional regulation.
Much of gene regulation is carried out by proteins that bind DNA or RNA molecules at specific sequences. One class of such proteins is transcription factors, which bind short DNA sequences to regulate transcription. Another class is RNA binding proteins, which bind short RNA sequences to regulate RNA maturation, transport, and stability. Here, we study the robustness and evolvability of these regulatory mechanisms. To this end, we use experimental binding data from 172 human and fruit fly transcription factors and RNA binding proteins as well as human polymorphism data to study the evolution of binding sites in vivo. We find little difference between the robustness of regulatory protein-RNA interactions and transcription factor-DNA interactions to DNA mutations. In contrast, we find that RNA-mediated regulation is less evolvable than transcriptional regulation, because mutations are less likely to create interactions of an RNA molecule with a new RNA binding protein than they are to create interactions of a gene regulatory region with a new transcription factor. Our observations are consistent with the high level of conservation observed for interactions between RNA binding proteins and their target molecules as well as the evolutionary plasticity of regulatory regions bound by transcription factors. They may help explain why transcriptional regulation is implicated in many more evolutionary adaptations and innovations than RNA-mediated gene regulation.


Identification of glutathione conjugates of the dimethyl ester of bilirubin in the bile of Gunn rats.
The Gunn rat, which is deficient in the UDP-glucuronosyltransferase for bilirubin, promptly excreted polar conjugates of the dimethyl ester of bilirubin in bile after intravenous infusion of this ester. The conjugates proved to be monoglutathione thioether adducts of the vinyl groups of the parent tetrapyrrole. High performance liquid chromatographic analysis of the conjugates as their dipyrrolic azosulfanilates demonstrated that only one of the dipyrroles of each tetrapyrrole was conjugated. The nonconjugated dipyrrole eluted as either the methyl endo- or exovinyl azodipyrrole. The amino acid composition of the pigments was consistent with that of a monoglutathione conjugate. NMR spectroscopy of the two major pigments demonstrated the loss of the proton signals of the C-18 vinyl group, indicating it to be the site of conjugation. Cation fast atomic bombardment tandem mass spectrometry demonstrated a molecular ion, [M + H]+, of m/z 937, which fragmented with a loss of 307 atomic mass units, consistent with glutathione. A molecular ion of m/z 807 was observed for the conjugate treated with gamma-glutamyltranspeptidase, consistent with the loss of glutamate. The mass spectrometry data indicated that the conjugates also contained a functional group whose mass was equivalent to hydroxyl, suggesting initial formation of an epoxide, which then reacts with glutathione. Pretreatment of the rat with 2,3,7,8-tetrachlorodibenzo-p-dioxin to induce cytochrome P-450 resulted in a 6-fold increase of the biliary excretion of the glutathione conjugates. Such induction also resulted in the excretion of a glutathione conjugate of bilirubin itself.


Types of headache and those remedies in traditional persian medicine.
The history of headache, as a common neurological complication, goes back to almost 9000 years ago. Many ancient civilizations present references to headaches and the coherent treatment strategies. Accordingly, several documents comprising headache complications embodying precise medical information stem from Traditional Persian Medicine (TPM) that can provide useful opportunities for more comprehensive treatment. We conducted a survey on headache through original important pharmacopeias and other important medical manuscripts of TPM which were written during 9(th) to 19(th) centuries and have derived all headache categories and herbal remedies. An extensive search of scientific data banks, such as Medline and Scopus, has also been exercised to find results relating to the anti-inflammatory, anti-nociceptive, and analgesic effects of denoted medicinal herbs. The concept of headache and treatments in TPM covers over 20 various types of headache and more than 160 different medicinal plants administered for oral, topical, and nasal application according to 1000 years of the subject documents. Nearly, 60% of remarked medicinal herbs have related anti-inflammatory or analgesic effects and some current headache types have similarities and conformities to those of traditional types. Beside historical approaches, there are many possible and available strategies that can lead to development of new and effective headache treatment from medicinal plants so that this study can provide beneficial information on clinical remedies based on centuries of experience in the field of headache which can stand as a new candidate for further investigations.


[Evaluation of egressing students of the specialization course on Family Care Health in Espírito Santo State, Brazil].
The purpose of this study was to evaluate the contribution of the specialization course on Family Health Care (PG-PSF), in Espírito Santo State, for the reorientation of the practices in health. It is a cross-sectional study with a population of 47 egressing students of the PG-PSF course in 2007. It was used a semi-structured questionnaire for data collection data. The analysis of the generated contributions showed some reports regarding the changes in the work actions after the acquired knowledge during the course. The majority of the students declared that the acquired knowledge have applicability in their daily work. They also declared that can plan their actions based in the epidemic profile of the area where worked. The relevance of this course was verified for the egressing students, with the perspective of a constant adaptation of the contents and improvement of the didactic-pedagogic process, through a system of continuous education or permanent education, as well as the attendance processes and supervision in service.


Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma.
Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.


Polybrominated Diphenyl Ethers and Gut Microbiome Modulate Metabolic Syndrome-Related Aqueous Metabolites in Mice.
Polybrominated diphenyl ethers (PBDEs) are persistent environmental toxicants associated with increased risk for metabolic syndrome. Intermediary metabolism is influenced by the intestinal microbiome. To test the hypothesis that PBDEs reduce host-beneficial intermediary metabolites in an intestinal microbiome-dependent manner, 9-week old male conventional (CV) and germ-free (GF) C57BL/6 mice were orally gavaged once daily with vehicle, BDE-47, or BDE-99 (100 μmol/kg) for 4 days. Intestinal microbiome (16S rDNA sequencing), liver transcriptome (RNA-Seq), and intermediary metabolites in serum, liver, as well as small and large intestinal contents (SIC and LIC; LC-MS) were examined. Changes in intermediary metabolite abundances in serum, liver, and SIC, were observed under basal conditions (CV vs. GF mice) and by PBDE exposure. PBDEs altered the largest number of metabolites in the LIC; most were regulated by PBDEs in GF conditions. Importantly, intestinal microbiome was necessary for PBDE-mediated decreases in branched-chain and aromatic amino acid metabolites, including 3-indolepropionic acid, a tryptophan metabolite recently shown to be protective against inflammation and diabetes. Gene-metabolite networks revealed a positive association between the hepatic glycan synthesis gene α-1,6-mannosyltransferase (Alg12) mRNA and mannose, which are important for protein glycosylation. Glycome changes have been observed in patients with metabolic syndrome. In LIC of CV mice, 23 bacterial taxa were regulated by PBDEs. Correlations of certain taxa with distinct serum metabolites further highlight a modulatory role of the microbiome in mediating PBDE effects. In summary, PBDEs impact intermediary metabolism in an intestinal microbiome-dependent manner, suggesting that dysbiosis may contribute to PBDE-mediated toxicities that include metabolic syndrome.


Gray-matter volume in methamphetamine dependence: cigarette smoking and changes with abstinence from methamphetamine.
Group differences in brain structure between methamphetamine-dependent and healthy research participants have been reported, but findings in the literature present discrepancies. Although most methamphetamine-abusing individuals also smoke cigarettes, the effects of smoking on brain structure have not been distinguished from those of methamphetamine. Changes with abstinence from methamphetamine have also been relatively unexplored. This study, therefore, attempted to account for effects of smoking and brief abstinence from methamphetamine on gray-matter measures in methamphetamine-dependent research participants. Gray matter was measured using voxel-based morphometry in three groups: 18 control nonsmokers, 25 control smokers, and 39 methamphetamine-dependent smokers (methamphetamine-abstinent 4-7 days). Subgroups of methamphetamine-dependent and control participants (n=12/group) were scanned twice to determine change in gray matter over the first month of methamphetamine abstinence. Compared with Control Nonsmokers, Control Smokers and Methamphetamine-dependent Smokers had smaller gray-matter volume in the orbitofrontal cortex and caudate nucleus. Methamphetamine-dependent Smokers also had smaller gray-matter volumes in frontal, parietal and temporal cortices than Control Nonsmokers or Smokers, and smaller gray-matter volume in insula than control nonsmokers. Longitudinal assessment revealed gray matter increases in cortical regions (inferior frontal, angular, and superior temporal gyri, precuneus, insula, occipital pole) in methamphetamine-dependent but not control participants; the cerebellum showed a decrease. Gray-matter volume deficits in the orbitofrontal cortex and caudate of methamphetamine-dependent individuals may be in part attributable to cigarette smoking or pre-morbid conditions. Increase in gray matter with methamphetamine abstinence suggests that some gray-matter deficits are partially attributable to methamphetamine abuse.


Transient Receptor Potential Vanilloid 4 Channel Deficiency Aggravates Tubular Damage after Acute Renal Ischaemia Reperfusion.
Transient receptor potential vanilloid 4 (TRPV4) cation channels are functional in all renal vascular segments and mediate endothelium-dependent vasorelaxation. Moreover, they are expressed in distinct parts of the tubular system and activated by cell swelling. Ischaemia/reperfusion injury (IRI) is characterized by tubular injury and endothelial dysfunction. Therefore, we hypothesised a putative organ protective role of TRPV4 in acute renal IRI. IRI was induced in TRPV4 deficient (Trpv4 KO) and wild-type (WT) control mice by clipping the left renal pedicle after right-sided nephrectomy. Serum creatinine level was higher in Trpv4 KO mice 6 and 24 hours after ischaemia compared to WT mice. Detailed histological analysis revealed that IRI caused aggravated renal tubular damage in Trpv4 KO mice, especially in the renal cortex. Immunohistological and functional assessment confirmed TRPV4 expression in proximal tubular cells. Furthermore, the tubular damage could be attributed to enhanced necrosis rather than apoptosis. Surprisingly, the percentage of infiltrating granulocytes and macrophages were comparable in IRI-damaged kidneys of Trpv4 KO and WT mice. The present results suggest a renoprotective role of TRPV4 during acute renal IRI. Further studies using cell-specific TRPV4 deficient mice are needed to clarify cellular mechanisms of TRPV4 in IRI.


Ultrasound-triggered, flight-gated evasive maneuvers in the praying mantis Parasphendale agrionina. II. Tethered flight.
In tethered flight, Parasphendale agrionina (Gerst.) males respond to ultrasonic stimuli with a unique suite of behaviors that includes full extension of the forelegs, strong dorsiflexion of the abdomen, a head roll, a 5% decrease in wingbeat frequency and a 33% increase in forewing excursion. Latency for the foreleg extension averages 66 ms while the latency to onset of yaw is 174 ms. The direction of the turn is unrelated to the location of the speaker. Yaw magnitude and latency are only weakly related to sound pressure level, and variability in these and other parameters is high. The behavior shows moderately sharp tuning to 40-60 kHz with a lowest mean threshold of 60 dB SPL. A male will not respond to ultrasound unless in flight, and the context-gating is independent of sensory input from the tarsi. Several components of the in-flight evasive behavior resemble defensive displays on the ground, and we suggest that this mantis has responded to predation pressure from bats with both flight-derived maneuvers and an aerial deimatic display.


Cost effectiveness of screen-and-treat strategies for low bone mineral density: how do we screen, who do we screen and who do we treat?
Bone densitometry is currently widely recommended for, and considered central to, identifying post-menopausal women and older men at high risk of fracture and establishing an indication for pharmacological fracture-prevention therapy. The purpose of this article is to comprehensively review cost-effectiveness modelling studies published to date of bone mass measurement technologies (primarily dual energy x-ray absorptiometry [DXA]) designed to identify those individuals at sufficiently high risk of fracture to warrant pharmacological fracture-prevention therapy.Based on older paradigms of the pharmacological treatment of those with a bone density value below a specific threshold, bone densitometry appears to be cost effective for post-menopausal women aged > or =65 years, regardless of the presence or absence of other clinical risk factors. For younger post-menopausal women, bone densitometry is likely to be cost effective only for those with specific clinical risk factors, such as prior fracture or low bodyweight. For older men, bone densitometry may be cost effective for those who have had a prior fracture and/or are aged > or =80 years, but the subset of men for whom bone densitometry is likely to be cost effective may vary from country to country depending on societal willingness to pay for health benefits, fracture rates in the population and the costs of bone densitometry and drug treatment. The cost effectiveness of other technologies such as heel ultrasound, peripheral DXA and quantitative CT remains uncertain.However, in the context of the new WHO paradigm of directing treatment based on absolute fracture risk rather than bone density, a new generation of cost-effectiveness modelling studies will be required to define the most cost-effective way bone densitometry can be used to identify those who are likely to benefit sufficiently from pharmacological fracture-prevention therapies.


Solution structure, dynamics, and thermodynamics of the native state ensemble of the Sem-5 C-terminal SH3 domain.
Although the high-resolution structure of a protein may provide significant insight into which regions are important for function, it is well-known that proteins undergo significant conformational fluctuations, even under native conditions. This suggests that the static structure alone may not provide sufficient information for elucidation of the thermodynamic determinants of biological function and that an accurate molecular-level description of function requires knowledge of the nature and energetics of the conformational states that constitute the native state ensemble. Here the native state ensemble of the C-terminal src homology domain-3 (C-SH3) from Caenorhabditis elegans Sem-5 has been studied using a variety of high-resolution biophysical techniques. In addition to determining the first solution structure of the unliganded protein, we have performed (15)N relaxation and native state hydrogen-deuterium exchange. It is observed that the regions of greatest structural variabilility also show low protection and order parameters, suggesting a higher degree of conformational diversity. These flexible regions also coincide with those regions of Sem-5 that have been predicted by the COREX algorithm to be unfolded in many of the most probable conformational states within the native state ensemble. The implications of this agreement and the potential role of conformational heterogeneity of the observed biophysical properties are discussed.


Prevalence of tobacco use among young adults in Palestine.
Smoking tobacco is a worldwide public health issue. Over the last few decades, smoking patterns have been changing, reflected by increasing rates among young people and females in particular. This study aimed to determine the prevalence and modalities of smoking and to assess the factors, habits and beliefs that might encourage or discourage smoking among young adults in Palestine. A cross-sectional study was conducted in the West Bank in 2014 among Palestinians aged 18-25 years old. Subjects were recruited from six Palestinian universities (n=1997). Participants were asked to complete a questionnaire focusing on sociodemographics, knowledge and beliefs towards tobacco smoking, and the reasons that motivate or hinder smokers to quit. The prevalence of tobacco smoking was found to be 47.7%. Males had higher smoking rates, consumption levels, and initiated smoking at younger ages (74.4% started at ≤18 years old). Smoking cigarettes and waterpipe were the most common forms among both sexes. Smokers were also found to consume higher amounts of caffeinated drinks and fast food, showed lower scores towards anti-smoking beliefs, and reported significantly higher prevalence of smoking-related symptoms and diseases, primarily shortness of breath (20.5%) and cough (16.6%). The majority of smokers reported attempting and willingness to quit smoking. Health and financial costs were the strongest factors encouraging quitting while mood changes and lack of self-control were the most reported discouraging factors. Moreover, smoking among family members and peers increased the odds of smoking. Increasing rates of smoking among young Palestinians and a growing popularity of waterpipe use should alert stakeholders to the necessity for the implementation of smoking prevention and awareness policies and programmes.


Childhood obesity and adult cardiovascular disease risk: a systematic review.
Although the relationship between adult obesity and cardiovascular disease (CVD) has been shown, the relationship with childhood obesity remains unclear. Given the evidence of tracking of body mass index (BMI) from childhood to adulthood, this systematic review investigated the independent relationship between childhood BMI and adult CVD risk. To investigate the association between childhood BMI and adult CVD risk, and whether the associations observed are independent of adult BMI. Electronic databases were searched from inception until July 2008 for studies investigating the association between childhood BMI and adult CVD risk. Two investigators independently reviewed studies for eligibility according to inclusion/exclusion criteria, extracted the data and assessed study quality using the Newcastle-Ottawa Scale. Positive associations between childhood BMI and adult blood pressure or carotid intima-media thickness were generally attenuated once adjusted for adult BMI. Associations between childhood BMI and CVD morbidity/mortality had not been adjusted and do not provide evidence of an independent relationship. Negative associations between childhood BMI and blood pressure were observed in several adjusted data sets. Little evidence was found to suggest that childhood obesity is an independent risk factor for CVD risk. Instead, the data suggest that relationships observed are dependent on the tracking of BMI from childhood to adulthood. Importantly, evidence suggests that risk of raised blood pressure is highest in those who are at the lower end of the BMI scale in childhood and overweight in adulthood. The findings challenge the widely accepted view that the presence of childhood obesity is an independent risk factor for CVD and that this period should be a priority for public health intervention. Although interventions during childhood may be important in prevention of adult obesity, it is important to avoid the potential for negative consequences when the timing coincides with critical stages of neurological, behavioural and physical development.


Small bowel endoscopic enteral access.
Small bowel endoscopic enteral access is perceived as difficult. However, small bowel access is necessary for patients who are unable to tolerate gastric feedings. This review discusses the successes and challenges involved with endoscopic small bowel tube placement in various populations using a variety of placement techniques. In general, direct percutaneous endoscopic jejunostomy (DPEJ) is becoming a more common procedure performed to obtain small bowel enteral access. BMI may be a useful predictor of DPEJ tube placement success and complication rates. A retrospective review determined that DPEJ tube placement significantly decreased the incidence of aspiration pneumonia in patients with previous recurrent aspiration pneumonia episodes. DPEJ is an effective method of providing enteral nutrition for patients when percutaneous endoscopic gastrostomy is not indicated because of anatomical or gastric function abnormalities. However, there are known complications of DPEJ, including small bowel volvulus. Nasojejunal tubes also can provide enteral access to the small intestine. Endoscopic insertion of nasojejunal tubes promotes decreased length of hospital stay and early initiation of enteral feedings as compared with bedside self-migrating jejunal tubes in patients with severe acute pancreatitis. Endoscopically placed small bowel feeding tubes can safely deliver enteral nutrition to patients when gastric feedings are not indicated. Continued evaluation of endoscopic jejunal tube placement methods and associated clinical outcomes in assorted populations is necessary to determine the safest and most effective technique.


UGT1A1*28 genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan.
Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting. Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m(2), twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects. No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carrying two copies of UGT1A1*28 (p = 0.04; OR: 14; 95% CI: 1.1-185) or c.-3156G>A (p = 0.03) had a significantly increased risk of diarrhea over all cycles. Our findings indicate that UGT1A1 genotyping is not a good predictor of hematological toxicity in patients treated with intermediate irinotecan doses. However, it may be useful in the identification of patients at risk of severe diarrhea.


Plastic debris increases circadian temperature extremes in beach sediments.
Plastic pollution is the focus of substantial scientific and public interest, leading many to believe the issue is well documented and managed, with effective mitigation in place. However, many aspects are poorly understood, including fundamental questions relating to the scope and severity of impacts (e.g., demographic consequences at the population level). Plastics accumulate in significant quantities on beaches globally, yet the consequences for these terrestrial environments are largely unknown. Using real world, in situ measurements of circadian thermal fluctuations of beach sediment on Henderson Island and Cocos (Keeling) Islands, we demonstrate that plastics increase circadian temperature extremes. Particular plastic levels were associated with increases in daily maximum temperatures of 2.45°C and decreases of daily minimum by - 1.50°C at 5 cm depth below the accumulated plastic. Mass of surface plastic was high on both islands (Henderson: 571 ± 197 g/m2; Cocos: 3164 ± 1989 g/m2), but did not affect thermal conductivity, specific heat capacity, thermal diffusivity, or moisture content of beach sediments. Therefore, we suggest plastic effects sediment temperatures by altering thermal inputs and outputs (e.g., infrared radiation absorption). The resulting circadian temperature fluctuations have potentially significant implications for terrestrial ectotherms, many of which have narrow thermal tolerance limits and are functionally important in beach habitats.


Dietary factors regulate cytokines in murine models of systemic lupus erythematosus.
Cytokines play the active roles in the pathogenesis of systemic lupus erythematosus (SLE) and contribute significantly to the immune imbalance in this disease. Conservative therapeutic approaches, such as dietary modifications have been shown to have some beneficial impact on the disease activity of the SLE. Over the past years, accumulating evidences have supported a major role for specific dietary factors, including calorie restriction, n-3/n-6 fatty acids, vitamin A, vitamin D, vitamin E, phytoestrogens or herbal medicine in the regulation of cytokines involved in SLE development. Although there are many reviews that discuss the issue of nutrition and immunity, there are relatively few articles that focus on the regulation of cytokines by dietary factors. This concise review will summarize those animal studies that investigated not only the outcome of autoantibody production and proteinuria, but also cytokines production. However, the field of dietary factors in the immunomodulation of SLE is still in its infancy. More clinical studies are needed to confirm the preliminary results and advance the knowledge in this field. Lifestyle modification and adjustments in diet are important and encouraged to be suggested as an adjuvant therapy for SLE.


Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies.
Novel cancer therapies are often approved with evidence from a single pivotal trial alone. There are concerns about the credibility of this evidence. Higher validity may be indicated by five methodological and statistical characteristics of pivotal trial evidence that were described by the U.S. Food and Drug Administration (FDA), which may corroborate the reliance on a single trial alone for approval decisions. We did a metaepidemiologic evaluation of all single pivotal trials supporting FDA approval of novel drugs and therapeutic biologicals for cancers between 2000 and 2016. For each trial, we determined the presence of these five characteristics, which we operationalized as (1) large and multicenter trial (≥200 patients; more than one center); consistent treatment benefits across (2) multiple patient subgroups (in view of FDA reviewers), (3) multiple endpoints (including overall survival, progression-free survival, response rate, health related quality of life), and (4) multiple treatment comparisons (e.g., multi-arm studies); and (5) "statistically very persuasive" results (P-values <0.00125). Thirty-five of 100 approvals were based on evidence from a single pivotal trial without any further supporting evidence on beneficial effects (20 randomized controlled trials and 15 single-arm trials). The number increased substantially from one approval before 2006 to 23 after 2011. Sixty-six percent (23/35) of the trials were large multicenter trials (median 301 patients and 63 centers). Consistent effects were demonstrated across subgroups in 66% (23/35), across endpoints in 43% (15/35), and across multiple comparisons in 3% (1/35). Very low P-values for the primary endpoint were seen in 34% (12/35). At least one of the corroborating characteristics was present in 94% (33/35) of all approvals, two or more were present in 54% (19/35), and none had all characteristics. Single pivotal trials typically have some of the corroborating characteristics, but often only one or two. These characteristics need to be better operationalized, defined, and reported and whether single trials with such characteristics provide similar evidence about benefits and harms of novel treatments as multiple trials would do needs to be shown.


Reproductive strategy, clonal structure and genetic diversity in populations of the aquatic macrophyte Sparganium emersum in river systems.
Many aquatic and riparian plant species are characterized by the ability to reproduce both sexually and asexually. Yet, little is known about how spatial variation in sexual and asexual reproduction affects the genotypic diversity within populations of aquatic and riparian plants. We used six polymorphic microsatellites to examine the genetic diversity within and differentiation among 17 populations (606 individuals) of Sparganium emersum, in two Dutch-German rivers. Our study revealed a striking difference between rivers in the mode of reproduction (sexual vs. asexual) within S. emersum populations. The mode of reproduction was strongly related to locally reigning hydrodynamic conditions. Sexually reproducing populations exhibited a greater number of multilocus genotypes compared to asexual populations. The regional population structure suggested higher levels of gene flow among sexually reproducing populations compared to clonal populations. Gene flow was mainly mediated via hydrochoric dispersal of generative propagules (seeds), impeding genetic differentiation among populations even over river distances up to 50 km. Although evidence for hydrochoric dispersal of vegetative propagules (clonal plant fragments) was found, this mechanism appeared to be relatively less important. Bayesian-based assignment procedures revealed a number of immigrants, originating from outside our study area, suggesting intercatchment plant dispersal, possibly the result of waterfowl-mediated seed dispersal. This study demonstrates how variation in local environmental conditions in river systems, resulting in shifting balances of sexual vs. asexual reproduction within populations, will affect the genotypic diversity within populations. This study furthermore cautions against generalizations about dispersal of riparian plant species in river systems.


Surround suppression and facilitation in the fovea: very long-range spatial interactions in contrast perception.
Surround modulation of perceived contrast has been almost exclusively studied in short-range conditions, i.e., in situations where a tiny gap, at most, separates center from surround. Existing long-range studies suggest that suppression extends to 12-cycle distance, whereas facilitation of perceived contrast is suggested to arise from visual field regions enclosing the center. In V1 neurons, however, long-range surround modulation involves both suppression and facilitation. Thus, we investigated short- and long-range surround modulation by measuring the perceived contrast of a center in the presence of a surround either near (0.3 cycles, 0.1 degree) or far (19.8 cycles, 6.6 degrees) from the center. This study demonstrates that in addition to the well-known suppression, surround modulation involves remarkably long-range facilitation of perceived contrast. At low center contrasts, the long-range facilitation was stronger than the long-range suppression, whereas at high center contrast we found mainly long-range suppression. Because the current models of perceived contrast could not account for our data, we considered our results in the context of models developed for surround modulation in V1 neurons. However, neither mechanistic nor phenomenological models proved satisfactory. Moreover, with the current knowledge, it seems that straightforward pooling of V1 neurons' responses cannot account for surround modulation of perceived contrast.


Permissive influence of stress in the expression of a U-shaped relationship between serum corticosterone levels and spatial memory errors in rats.
The relationship between glucocorticoids (GCs) and memory is complex, in that memory impairments can occur in response to manipulations that either increase or decrease GC levels. We investigated this issue by assessing the relationship between serum corticosterone (the primary rodent GC) and memory in rats trained in the radial arm water maze, a hippocampus-dependent spatial memory task. Each day, rats learned a new location of the hidden escape platform and then 30 min later their memory of the location of the platform was tested. Under control conditions, well-trained rats had excellent spatial memory and moderately elevated corticosterone levels (approximately 26 microg/dl versus a baseline of approximately 2 microg/dl). Their memory was impaired when corticosterone levels were either reduced by metyrapone (a corticosterone synthesis inhibitor) or increased by acute stress (predator exposure), forming an overall U-shaped relationship between corticosterone levels and memory. We then addressed whether there was a causal relationship between elevated corticosterone levels and impaired memory. If elevated corticosterone levels were a sufficient condition to impair memory, then exogenously administered corticosterone, alone, should have impaired performance. However, we found that spatial memory was not impaired in corticosterone-injected rats that were not exposed to the cat. This work demonstrates that an intermediate level of corticosterone correlated with optimal memory, and either a decrease or an increase in corticosterone levels, in conjunction with strong emotionality, impaired spatial memory. These findings indicate that fear-provoking conditions, which are known to engage the amygdala, interact with stress levels of corticosterone to influence hippocampal functioning.


Synthesis of platelet activating factor by ocular tissue from inflamed eyes.
Platelet activating factors (PAFs) are a family of ether lipids with properties that suggest a major role in inflammation. We have previously implicated PAFs in ocular inflammation based on the inhibition of several rabbit models of iritis with a specific PAF receptor antagonist. We have tested ocular tissues for the ability to synthesize PAF. Iris, ciliary body, cornea, and/or retina were carefully dissected from New Zealand white rabbits, and tissue from four eyes was pooled. Tissues were stimulated with calcium ionophore (10 mumol/L), and supernatants were extracted with chloroform-methanol. Platelet-aggregating activity was found in the chloroform phase in 2 of 9, 1 of 8, 0 of 9, and 3 of 9 studies involving iris, retina, ciliary body, or cornea, respectively. Twenty-four hours after the intravitreal injection of 125 ng of endotoxin, aggregating activity was consistently detectable from supernatants of stimulated iris and ciliary body, occasionally present from stimulated retina but not detectable from cornea. The shape of the aggregation curve resembled that produced by 0.5 to 2.0 ng of authentic PAF. Moreover, the aggregation could be completely inhibited by a PAF receptor antagonist and the aggregating activity chromatographed identically on high-performance liquid chromatography to a PAF standard. These studies indicate that PAF-like activity could be detected from several ocular tissues subsequent to inflammation. Iris, ciliary body, retina, vascular endothelium, and/or leukocytes could each contribute to the presence of this inflammatory mediator.


Neurally evoked calcium transients in terminal Schwann cells at the neuromuscular junction.
We examined the effects of motor-nerve stimulation on the intracellular Ca2+ levels of Schwann cells, the glial cells at the frog neuromuscular junction. Schwann cells, which were loaded with the fluorescent Ca2+ indicator fluo-3 and examined by confocal microscopy, showed a transient increase in free Ca2+ within a few seconds of the onset of tetanic stimulation of the motor nerve. The Ca2+ response was specific to the synapse in that it was found in the terminal Schwann cells at the junction but not in the myelinating Schwann cells along the axon. The Ca2+ transients occurred in the presence of d-tubocurare, indicating that they were not mediated by nicotinic acetylcholine receptors and recurred when the stimulus was repeated. The Ca2+ response persisted after degeneration of the postsynaptic muscle fiber, demonstrating that the terminal Schwann cell was stimulated directly by presynaptic activity. The finding that terminal Schwann cells at the neuromuscular junction respond to presynaptic activity suggests that glial-cell function is modulated by synaptic transmission.


Prevalence of Anisakis spp. and Hysterothylacium spp. larvae in teleosts and cephalopods sampled from waters off Sardinia.
A study was carried out on the presence of Anisakis and Hysterothylacium larvae in fish and cephalopods caught in Sardinian waters. A total of 369 specimens of 24 different species of teleosts and 5 species of cephalopods were collected from different fishing areas of Sardinia. Larvae were detected and isolated by both visual inspection and enzymatic digestion. These methods allowed Anisakis type I and type II third-stage larvae and Hysterothylacium third- and fourth-stage larvae to be detected. The prevalence, mean intensity, and mean abundance were calculated. The results obtained showed the highest prevalence of Anisakidae in Zeus faber (100%) and of Anisakis in Micromesistius poutassou (87.5%). The highest prevalence of Anisakis type I larvae was in M. poutassou (81.2%), and that of Anisakis type II larvae was in Todarodes sagittatus (20%). The highest values for prevalence, mean intensity, and mean abundance for Hysterothylacium were found in Z. faber. These prevalences and the mean intensity and abundance were higher than those reported by different authors in other Mediterranean areas. This may be because the enzymatic digestive method used in this research resulted in higher recovery levels. The data suggest that Sardinia may be a high-risk area for zoonotic diseases and that measures such as information campaigns, aimed at both sanitary service personnel and consumers, should be employed to limit the spread of such zoonosis.


A qualitative exploration of the experiences of adoptive parents attending 'Nurturing Attachments', a dyadic developmental psychotherapy informed group.
Children who are adopted have frequently experienced a range of aversive experience which impact on their ability to form secure attachments. Dyadic Developmental Psychotherapy (DDP) is an intervention designed to develop and promote secure attachments with children who have experienced developmental trauma. Eight adoptive parents participated in semi-structured interviews regarding their experiences of attending the 'Nurturing Attachment' group informed by DDP. The transcripts of their interviews were explored using Interpretative Phenomenological Analysis. The analysis revealed five inter-connected superordinate themes which were as follows: A supportive group, A shift in perspective, 'Turning trauma into secure attachment', 'Am I doing it right?' and Continuing the adoption journey. Themes are considered in relation to the theoretical underpinnings and practice of DDP. Some further implications for clinical and research practice are also discussed.


Impaired holistic processing of left-right composite faces in congenital prosopagnosia.
Congenital prosopagnosia (CP) refers to a lifelong impairment in face processing despite normal visual and intellectual skills. Many studies have suggested that the key underlying deficit in CP is one of a failure to engage holistic processing. Moreover, there has been some suggestion that, in normal observers, there may be greater involvement of the right than left hemisphere in holistic processing. To examine the proposed deficit in holistic processing and its potential hemispheric atypicality in CP, we compared the performance of 8 CP individuals with both matched controls and a large group of non-matched controls on a novel, vertical composite task. In this task, participants judged whether a cued half of a face (either left or right half) was the same or different at study and test, and the two face halves could be either aligned or misaligned. The standard index of holistic processing is one in which the unattended face half influences performance on the cued half and this influence is greater in the aligned than in the misaligned condition. Relative to controls, the CP participants, both at a group and at an individual level, did not show holistic processing in the vertical composite task. There was also no difference in performance as a function of hemifield of the cued face half in the CP individuals, and this was true in the control participants, as well. The findings clearly confirm the deficit in holistic processing in CP and reveal the useful application of this novel experimental paradigm to this population and potentially to others as well.


Diffuse reflectance spectroscopy: Systemic and microvascular oxygen saturation is linearly correlated and hypoxia leads to increased spatial heterogeneity of microvascular saturation.
The microvascular oxygen saturation (SmvO(2)) in the skin and tongue (sublingual mucosa) in pigs (n=6) was characterised using diffuse reflectance spectroscopy (DRS). The correlation between arterial oxygen saturation (SaO(2)) and SmvO(2) as well as the spatial heterogeneity of SmvO(2) was examined during hypoxia. DRS uses shallow-penetrating visible light to assess microvascular oxygen saturation (SmvO(2)) in superficial tissue. Hypoxia was induced by gradual reduction in ventilation or reduction of the inspiratory oxygen fraction. The spatial heterogeneity of SmvO(2) was expressed as the coefficient of variation (CV) of repeated SmvO(2) measurements. Baseline SmvO(2) before interventions was 20.2% (10.3%-38.1%, median with range) in groin skin, 32.9% (13.0%-49.3%) in the ear and 42.2% (32.1%-51.5%) in the tongue. SmvO(2) in the groin was significantly lower than venous oxygen saturation (SvO(2)) (p<0.05) and SmvO(2) in the tongue (p=0.03). There was a significant linear correlation between SaO(2) and SmvO(2) in all measuring sites for both interventions (p<0.05). Similarly there was a significant correlation between CV of repeated SmvO(2) measurements and SmvO(2) in all measuring sites for both interventions (p<0.01). The results from baseline measurements indicate a surprisingly high oxygen extraction in the measurement volume of DRS, especially in the groin skin. A reduction of SmvO(2) with decreasing SaO(2) was found and additionally the results suggest that spatial heterogeneity of microvascular oxygen saturation increases during hypoxia. Microvascular disturbances have been demonstrated in both local vascular diseases and systemic conditions such as shock and sepsis, an assessment of microvascular oxygen saturation using DRS may be useful in the monitoring of the microcirculation in such patients. This study is a part of an ongoing characterization of the DRS technique.


Local Pyramidal Descriptors for Image Recognition.
In this paper, we present a novel method to improve the flexibility of descriptor matching for image recognition by using local multiresolution pyramids in feature space. We propose that image patches be represented at multiple levels of descriptor detail and that these levels be defined in terms of local spatial pooling resolution. Preserving multiple levels of detail in local descriptors is a way of hedging one's bets on which levels will most relevant for matching during learning and recognition. We introduce the Pyramid SIFT (P-SIFT) descriptor and show that its use in four state-of-the-art image recognition pipelines improves accuracy and yields state-of-the-art results. Our technique is applicable independently of spatial pyramid matching and we show that spatial pyramids can be combined with local pyramids to obtain further improvement. We achieve state-of-the-art results on Caltech-101 (80.1%) and Caltech-256 (52.6%) when compared to other approaches based on SIFT features over intensity images. Our technique is efficient and is extremely easy to integrate into image recognition pipelines.


[Reproducibility and validity of a semi-quantitative food frequency questionnaire].
The reproducibility and relative validity of a semi-quantitative food frequency questionnaire (FFQ) were evaluated. Subjects were 72 (36 men and 36 women) residents of N island, Shimane Prefecture in Japan, aged 50-76 years. The questionnaire was administered twice at an interval of one week (FFQ1, FFQ2), and 7-day weighing diet records were collected during that period. This protocol was conducted in summer and winter. The mean intakes for 11 nutrients calculated from the FFQ1 and FFQ2 were similar and, those from the FFQ1 were smaller than those from the diet records for all but fat and vitamin C. Pearson correlation coefficients assessing reproducibility between nutrient intakes from FFQ1 and FFQ2 ranged from 0.59 for vitamin C to 0.90 for carbohydrate. Validity was measured by comparing nutrient intakes from FFQ1 with those from the 7-day diet record, and Pearson correlation coefficients ranged from 0.15 for iron to more than 0.35 for total energy and macronutrients. These correlation coefficients showed slight difference by gender or age group, but did not vary materially between seasons. These data indicate that this questionnaire is reproducible but has some problems in validity.


Regression Convolutional Neural Network for Automated Pediatric Bone Age Assessment From Hand Radiograph.
Skeletal bone age assessment is a common clinical practice to investigate endocrinology, and genetic and growth disorders of children. However, clinical interpretation and bone age analyses are time-consuming, labor intensive, and often subject to inter-observer variability. This advocates the need of a fully automated method for bone age assessment. We propose a regression convolutional neural network (CNN) to automatically assess the pediatric bone age from hand radiograph. Our network is specifically trained to place more attention to those bone age related regions in the X-ray images. Specifically, we first adopt the attention module to process all images and generate the coarse/fine attention maps as inputs for the regression network. Then, the regression CNN follows the supervision of the dynamic attention loss during training; thus, it can estimate the bone age of the hard (or "outlier") images more accurately. The experimental results show that our method achieves an average discrepancy of 5.2-5.3 months between clinical and automatic bone age evaluations on two large datasets. In conclusion, we propose a fully automated deep learning solution to process X-ray images of the hand for bone age assessment, with the accuracy comparable to human experts but with much better efficiency.


Polarization-independent imaging with an acousto-optic tandem system.
We propose a method for filtering convergent light beams with arbitrary polarization. For this purpose, a tandem of similar acousto-optic tunable filters was applied. Owing to the special mutual orientation of the cells, two coincident beams with ordinary and extraordinary polarizations were diffracted by the first crystal and the second crystal, respectively.


On the futility of using familial sinistrality to subclassify handedness groups.
Annett's right shift model was used to show that presence of left-handedness in parents or grandparents is an extremely weak indicator of whether or not a person's handedness is influenced by genetic factors. Furthermore, where a genetic influence is present, familial sinistrality is only weakly related to underlying genotype. The usual rationale given for subdividing handedness groups according to familial sinistrality is logically indefensible.


Immune cell cooperation, viruses, and antibodies to nucleic acids in new zealand mice.
The development of autoimmunity in New Zealand mice is related to genetic, immunologic, and viral factors. Evidence is presented to suggest that thymus-dependent immune functions may be depressed and bone marrow-dependent functions augmented in these mice. Antibodies to RNA and DNA appear spontaneously and can also be induced by treatment with rI.rC. Antibodies binding rI.rC-(14)C in human lupus sera, in NZB/NZW F(1) (B/W) mice developing lupus, and in NZB, ALN, and ALN/NZB mice have greatest specificity for reovirus double-stranded RNA. Treatment of B/W mice with RNA and cyclophosphamide induces immunologic tolerance, and suppresses antibodies binding rI.rC-(14)C. During recovery, the specificity of the antibodies is unaltered. Induction of tolerance in this way prevents the accelerated formation of anti-RNA antibodies normally induced by MLV. This finding suggests that virus-accelerated and natural disease occur through a similar mechanism, and supports the hypothesis that viruses may act as antigenic stimuli for a genetically hyper-responsive antibody-producing system.


Design and implementation of the Competency Assessment Tool (CAT): user experience usability study.
The decision on patients' competency to manage their affairs and take care of themselves requires a rigorous evaluation process and consistency among practice settings. Research indicates there is a lack of resources to guide healthcare and social service professionals in the interprofessional decision-making process that such an evaluation requires. A web-based tool, the Competency Assessment Tool (CAT), was designed to assist professionals in that process. The authors conducted a usability study with a beta version of the CAT. The objectives of this study were to: (1) explore what is needed to support its use in community-based and specialized settings; and (2) identify barriers to and facilitators of implementation. A major concern was the perceived onerous nature of the tool. Participants indicated a need for different versions of the tool, depending on the complexity of the evaluation. They want to be directed to areas in the tool based on their field of expertise and want adjustments to functionalities related to collaborative work. This study highlights the importance of the awareness of User Experience (UX) considerations at the outset of the design process, to limit the impact of required modifications and facilitate implementation in the workplace.


The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate.
Numerous studies demonstrate that the rhesus monkey is an excellent species with which to investigate mechanisms underlying human emotion and psychopathology. To examine the role of the central nucleus of the amygdala (CeA) in mediating the behavioral and physiological responses associated with fear and anxiety, we used rhesus monkeys to assess the effects of excitotoxic lesions of the CeA. Behavioral and physiological responses of nine monkeys with bilateral CeA destruction (ranging from 46 to 98%) were compared with five animals with asymmetric lesions (42-86.5% destruction on the most affected side) and with 16 unoperated controls. Results suggest that similar to rodent species, the primate CeA plays a role in mediating fear- and anxiety-related behavioral and endocrine responses. Compared with controls and the asymmetric-lesion group, bilaterally lesioned monkeys displayed significantly less fear-related behavior when exposed to a snake and less freezing behavior when confronted by a human intruder. In addition, bilaterally lesioned monkeys had decreased levels of CSF corticotrophin-releasing factor (CRF), and both lesioned groups had decreased plasma ACTH concentrations. In contrast to these findings, patterns of asymmetric frontal brain electrical activity, as assessed by regional scalp EEG, did not significantly differ between control and lesioned monkeys. These findings suggest that in primates, the CeA is involved in mediating fear- and anxiety-related behavioral and pituitary-adrenal responses as well as in modulating brain CRF activity.


Residential proximity to major roads and preterm births.
Preterm births cause a large public-health burden, and air pollution is considered to be a potential risk factor. We evaluated the association between proximity to major roads (as an index for air pollution) and preterm births, classified by gestational age and specific clinical manifestations. Data on parental information and birth outcomes were extracted from the database maintained by the perinatal hospital in Shizuoka, Japan. We restricted the analysis to mothers who delivered liveborn single births from 1997 to 2008 (n = 14,226). Using the geocoded residential information, each birth was classified on its proximity to major roads. We estimated the multivariate-adjusted odds ratios and their 95% confidence intervals (CIs) for the association of proximity to major roads with preterm births, using logistic regression. We found positive associations between proximity to major roads and preterm births at all gestational ages. Living within 200 m increased the risk of births before 37 weeks by 1.5 times (95% CI = 1.2-1.8), birth before 32 weeks by 1.6 times (1.1-2.4), and births before 28 weeks by 1.8 times (1.0-3.2). Proximity specifically increased the risk of preterm births with preterm premature rupture of the membranes and with pregnancy hypertension. This study demonstrates that exposure to traffic-related air pollution increases even the risk of preterm births of less than 30 weeks' gestational age and proposes a possible mechanism.


Sleep intensity and the evolution of human cognition.
Over the past four decades, scientists have made substantial progress in understanding the evolution of sleep patterns across the Tree of Life. Remarkably, the specifics of sleep along the human lineage have been slow to emerge. This is surprising, given our unique mental and behavioral capacity and the importance of sleep for individual cognitive performance. One view is that our species' sleep architecture is in accord with patterns documented in other mammals. We promote an alternative view, that human sleep is highly derived relative to that of other primates. Based on new and existing evidence, we specifically propose that humans are more efficient in their sleep patterns than are other primates, and that human sleep is shorter, deeper, and exhibits a higher proportion of REM than expected. Thus, we propose the sleep intensity hypothesis: Early humans experienced selective pressure to fulfill sleep needs in the shortest time possible. Several factors likely served as selective pressures for more efficient sleep, including increased predation risk in terrestrial environments, threats from intergroup conflict, and benefits arising from increased social interaction. Less sleep would enable longer active periods in which to acquire and transmit new skills and knowledge, while deeper sleep may be critical for the consolidation of those skills, leading to enhanced cognitive abilities in early humans.


Risk Factors of HIV and Other Sexually Transmitted Infections in China: A Systematic Review of Reviews.
Sexually Transmitted Infections (STIs) are a global challenge. China, once said to have eradicated STIs, is now facing a rapid rise in the prevalence of HIV/STIs. This review of reviews aims to map HIV/STI risk factors among the Chinese population, with the objective of identifying risk factors to inform the formulation of effective prevention strategies. A systematic search using key terms related to HIV/STIs, risk factors and the Chinese population in both English and Chinese databases (PubMed, PsycINFO, the Cochrane Library; Wanfang data, CNKI, VIP and SINOMED) was conducted, and peer-reviewed systematic reviews on the topic from 1991 to 2014 were selected. Identified risk factors were grouped into different level determinants based on the HIV Social Epidemiology Model, and then evaluated and reported based on the PRISMA checklist. Of the twenty-eight reviews included, the majority were focused on well-established, individual level risk factors within key populations, with some highlighting the complexity of interacting factors (e.g., alcohol use and higher income in male migrants). While twenty-two reviews covered individual factors, only ten mentioned social factors and five had contents on structural factors. There are gaps in the evidence on social and structural level impacts of HIV/STIs, such as on stigma, discrimination, health policy, access to care, and illicit drug control policies. Migration and social expectation appear to pose a significant threat in aggravating the HIV/STI situation in China; for example, incarceration patterns indicated a significant risk of HIV/STIs for female sex workers. Since international guidelines recommend an integrated and multi-level approach to HIV/STI prevention, a comprehensive approach targeting interventions at all levels along the continuum of care is needed to effectively curtail HIV/STI transmission in China. More research is needed to better understand the impact of socio-political interventions within a Chinese context.


Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development.
Mutations in the transcription factor TBX20 (T-box 20) are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by embryonic day 9.5. Because Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type-specific requirement for TBX20 in early myocardial development remains to be explored. Here, we investigated roles of TBX20 in midgestation cardiomyocytes for heart development. Ablation of Tbx20 from developing cardiomyocytes using a doxycycline inducible cTnTCre transgene led to embryonic lethality. The circumference of developing ventricular and atrial chambers, and in particular that of prospective left atrium, was significantly reduced in Tbx20 conditional knockout mutants. Cell cycle analysis demonstrated reduced proliferation of Tbx20 mutant cardiomyocytes and their arrest at the G1-S phase transition. Genome-wide transcriptome analysis of mutant cardiomyocytes revealed differential expression of multiple genes critical for cell cycle regulation. Moreover, atrial and ventricular gene programs seemed to be aberrantly regulated. Putative direct TBX20 targets were identified using TBX20 ChIP-Seq (chromatin immunoprecipitation with high throughput sequencing) from embryonic heart and included key cell cycle genes and atrial and ventricular specific genes. Notably, TBX20 bound a conserved enhancer for a gene key to atrial development and identity, COUP-TFII/Nr2f2 (chicken ovalbumin upstream promoter transcription factor 2/nuclear receptor subfamily 2, group F, member 2). This enhancer interacted with the NR2F2 promoter in human cardiomyocytes and conferred atrial specific gene expression in a transgenic mouse in a TBX20-dependent manner. Myocardial TBX20 directly regulates a subset of genes required for fetal cardiomyocyte proliferation, including those required for the G1-S transition. TBX20 also directly downregulates progenitor-specific genes and, in addition to regulating genes that specify chamber versus nonchamber myocardium, directly activates genes required for establishment or maintenance of atrial and ventricular identity. TBX20 plays a previously unappreciated key role in atrial development through direct regulation of an evolutionarily conserved COUPT-FII enhancer.


The effect of mucoadhesive excipient on the nasal retention time of and the antibody responses induced by an intranasal influenza vaccine.
Recently, we reported that intranasal vaccination of humans with whole inactivated influenza vaccine in the absence of mucosal adjuvant induced neutralizing antibody responses in the serum and nasal mucus. The mucoadhesive excipient carboxy-vinyl polymer (CVP) increases the viscosity and therefore mucoadhesiveness of intranasal medicaments and is an authorized excipient in Japan. In the present study, we analyzed the effect of adding CVP on intranasal whole inactivated influenza vaccine antigen dynamics and antibody responses. Mice and nonhuman primates (NHPs) were intranasally administered the [(18)F]-radiolabeled vaccine and subjected to positron emission tomography analysis for 6h. Dendritic cells were stimulated in vitro with the vaccine mixed with or without a mucosal adjuvant (Ampligen) and/or CVP, after which the tumor necrosis factor (TNF)-α and interferon (IFN)-β levels in the supernatants were measured. Cynomolgus monkeys were immunized intranasally with the vaccine mixed with Ampligen and/or CVP and their vaccine-specific serum IgG and IgA titers were measured on days 0 and 33. The vaccine was retained significantly longer in the nasal cavity of both mice and NHPs when it was delivered with CVP rather than PBS. Accumulation of the radiolabeled vaccine in the central nervous system was not detected in either model regardless of whether CVP was used. CVP only very weakly increased the TNF-α production of vaccine-stimulated dendritic cells. IFN-β production was not observed regardless of the presence or absence of CVP. CVP increased the vaccine-specific IgA antibody responses of the intranasally vaccinated cynomolgus macaques. CVP increased intranasal retention of whole inactivated influenza vaccine, did not promote antigen redirection to the central nervous system, and improved mucosal antibody responses. The mechanism probably relates to its mucoadhesive properties rather than its ability to directly stimulate the immune system. Intranasal vaccines with CVP may be a promising candidate vaccine formulation for humans.


The effect of a multidisciplinary physical activity intervention on the body composition and physical fitness of obese children.
The aim was to determine the effect of a physical activity, diet, and behaviour modification intervention of 13 weeks, 3x per week for 60 minutes on the body composition and physical fitness of overweight and obese children. A convenience sample of 37 subjects with a mean age of 11 years (±0.99) was used, where 20 subjects (13 girls; seven boys) took part in the intervention and 17 (11 girls; six boys) formed part of the control group. Body composition (height, body mass, skinfolds, circumferences, body fat percentage, and body mass index) and health-promoting physical fitness (cardiorespiratory endurance, flexibility, muscular strength, and muscular endurance) were analysed using the Fitnessgram and the Bruininks-Oseretsky Test of Motor Proficiency-II during baseline, after the intervention programme, and after a follow-up period of three months. The results showed statistical (P<0.05) and practical significant (d>0.2) improvement in the body composition of the group, after participation in the intervention, with a sustainable effect, three months later on body fat percentage and the subscapular skinfold. Muscular strength and flexibility improved significantly after the intervention, but with no sustainable effect. It is concluded that a multi-disciplinary obesity intervention can improve the body composition profile and the health-related physical fitness of young obese children, although the effect will not be sustainable without ongoing, controlled intervention.


Conservation genetics of two threatened frogs from the Mambilla highlands, Nigeria.
Amphibians are the vertebrate group with the highest number of species threatened with extinction, and habitat loss and fragmentation are considered to be among the leading causes of their declines and extinctions. Little is known of the population biology of amphibian species inhabiting montane forests in Central and West Africa, where anthropogenic activities such as farming and cattle raising are major threats to native biodiversity. We used Amplified Fragment Length Polymorphisms (AFLPs) to assess the population genetic structure of two poorly known species, Cardioglossa schioetzi and Leptodactylodon bicolor (both in the Arthroleptidae), in and around Ngel Nyaki Forest Reserve on the Mambilla Plateau in eastern Nigeria. The landscape comprises continuous forest on steep slopes and small riparian forest fragments in a grassland matrix. While increased fragmentation is well documented for these and other forests in the mountains of Cameroon and Nigeria over the past century, there are no previous assessments of the impact of forest fragmentation on montane amphibian populations in this region. Our estimates of genetic diversity are similar across populations within each species with levels of heterozygosity values consistent with local population declines. Except for a pair of populations (C. schioetzi) we did not observe genetic differentiation between forest and riparian forest fragment populations, nor across sites within continuous forest (L. bicolor). Our results demonstrate recent gene flow between forest fragments and the adjacent protected forests and suggest that small forest corridors connecting these may lessen the genetic consequences of at least 30 years of intense and severe fragmentation in Ngel Nyaki.


Mass spectrometry of extracellular vesicles.
The review briefly summaries main features of extracellular vesicles, a joint terminology for exosomes, microvesicles, and apoptotic vesicles. These vesicles are in the center of interest in biology and medical sciences, and form a very active field of research. Mass spectrometry (MS), with its specificity and sensitivity, has the potential to identify and characterize molecular composition of these vesicles; but as yet there are only a limited, but fast-growing, number of publications that use MS workflows in this field. MS is the major tool to assess protein composition of extracellular vesicles: qualitative and quantitative proteomics approaches are both reviewed. Beside proteins, lipid and metabolite composition of vesicles might also be best assessed by MS techniques; however there are few applications as yet in this respect. The role of alternative analytical approaches, like gel-based proteomics and antibody-based immunoassays, are also mentioned. The objective of the review is to give an overview of this fast-growing field to help orient MS-based research on extracellular vesicles.


Chronic obstructive pulmonary disease in Scottish military veterans.
Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Serving military personnel have previously been shown to be more likely to smoke, and to smoke more heavily, than civilians, but there is no clear consensus as to whether in later life, as veterans, they experience a higher prevalence and mortality from COPD than do non-veterans. We examined the risk of COPD in Scottish veterans and assessed the impact of changes in military smoking. Retrospective 30-year cohort study of 56 205 veterans born 1945-1985, and 172 741 people with no record of military service, matched for age, sex and area of residence, using Cox proportional hazard models to examine the association between veteran status, birth cohort, length of service and risk of COPD resulting in hospitalisation or death. There were 1966 (3.52%) cases of COPD meeting the definition in veterans, compared with 5434 (3.19%) in non-veterans. The difference was statistically significant (p=0.001) in the unadjusted model although it became non-significant after adjusting for deprivation. The highest risk was seen in the oldest (1945-1949) birth cohort and in veterans with the shortest service (Early Service Leavers). The risk was significantly reduced in veterans born from 1960, and in those with over 12 years' service. Our findings are consistent with falling rates of military smoking since the 1960s, and with the reduction in smoking with longer service. The oldest veterans, and those with the shortest service, are least likely to have benefited from this, as reflected in their higher risk for COPD.


Organometallic photovoltaics: a new and versatile approach for harvesting solar energy using conjugated polymetallaynes.
Energy remains one of the world's great challenges. Growing concerns about limited fossil fuel resources and the accumulation of CO(2) in the atmosphere from burning those fuels have stimulated tremendous academic and industrial interest. Researchers are focusing both on developing inexpensive renewable energy resources and on improving the technologies for energy conversion. Solar energy has the capacity to meet increasing global energy needs. Harvesting energy directly from sunlight using photovoltaic technology significantly reduces atmospheric emissions, avoiding the detrimental effects of these gases on the environment. Currently inorganic semiconductors dominate the solar cell production market, but these materials require high technology production and expensive materials, making electricity produced in this manner too costly to compete with conventional sources of electricity. Researchers have successfully fabricated efficient organic-based polymer solar cells (PSCs) as a lower cost alternative. Recently, metalated conjugated polymers have shown exceptional promise as donor materials in bulk-heterojunction solar cells and are emerging as viable alternatives to the all-organic congeners currently in use. Among these metalated conjugated polymers, soluble platinum(II)-containing poly(arylene ethynylene)s of variable bandgaps (∼1.4-3.0 eV) represent attractive candidates for a cost-effective, lightweight solar-energy conversion platform. This Account highlights and discusses the recent advances of this research frontier in organometallic photovoltaics. The emerging use of low-bandgap soluble platinum-acetylide polymers in PSCs offers a new and versatile strategy to capture sunlight for efficient solar power generation. Properties of these polyplatinynes--including their chemical structures, absorption coefficients, bandgaps, charge mobilities, accessibility of triplet excitons, molecular weights, and blend film morphologies--critically influence the device performance. Our group has developed a novel strategy that allows for tuning of the optical absorption and charge transport properties as well as the PSC efficiency of these metallopolyynes. The absorbance of these materials can also be tuned to traverse the near-visible and near-infrared spectral regions. Because of the diversity of transition metals available and chemical versatility of the central spacer unit, we anticipate that this class of materials could soon lead to exciting applications in next-generation PSCs and other electronic or photonic devices. Further research in this emerging field could spur new developments in the production of renewable energy.


Myd88 deficiency influences murine tracheal epithelial metaplasia and submucosal gland abundance.
Tracheal epithelial remodelling, excess mucus production, and submucosal gland hyperplasia are features of numerous lung diseases, yet their origins remain poorly understood. Previous studies have suggested that NF-κB signalling may regulate airway epithelial homeostasis. The purpose of this study was to determine whether deletion of the NF-κB signalling pathway protein myeloid differentiation factor 88 (Myd88) influenced tracheal epithelial cell phenotype. We compared wild-type and Myd88-deficient or pharmacologically inhibited adult mouse tracheas and determined that in vivo Myd88 deletion resulted in increased submucosal gland number, secretory cell metaplasia, and excess mucus cell abundance. We also found that Myd88 was required for normal resolution after acute tracheal epithelial injury. Microarray analysis revealed that uninjured Myd88-deficient tracheas contained 103 transcripts that were differentially expressed relative to wild-type and all injured whole tracheal samples. These clustered into several ontologies and networks that are known to functionally influence epithelial cell phenotype. Comparing these transcripts to those expressed in airway progenitor cells revealed only five common genes, suggesting that Myd88 influences tracheal epithelial homeostasis through an extrinsic mechanism. Overall, this study represents the first identification of Myd88 as a regulator of adult tracheal epithelial cell phenotype.


Is vulvovaginal atrophy due to a lack of both estrogens and androgens?
The aim of this study was to review the preclinical data showing the role of both estrogens and androgens in the physiology of the vagina, and, most likely, in vulvovaginal atrophy of menopause. Mass spectrometry-based assays (validated according to the FDA guidelines) for the measurement of sex steroids, their precursors, and metabolites were used. In addition to fixation of the vagina for morphological examination, histomorphometry, immunocytochemistry, immunofluorescence, and quantitative reverse transcription polymerase chain reaction were performed. The vaginal epithelium of the animals receiving dehydroepiandrosterone (DHEA) was made of large multilayered columnar mucous cells showing distended cytoplasmic vacuoles representative of an androgenic effect. DHEA also stimulates collagen fiber compactness of the lamina propria (second layer)-an effect essentially due to an androgenic effect, whereas stimulation by DHEA of the muscularis in the third vaginal layer is approximately 70% due to the androgenic conversion of DHEA. Stimulation of the surface area of the nerve endings, on the contrary, is exclusively androgenic. Vaginal weight stimulation by DHEA is about 50% androgenic and 50% estrogenic. Practically all studies on the influence of steroid hormones in the vagina have focused on luminal epithelial cells. Since all estrogens and androgens in postmenopausal women are made intracellularly and derive from the conversion of circulating DHEA, it is of interest to observe from these preclinical data that DHEA exerts both estrogenic and androgenic activity in the three layers of the vagina, the stimulatory effect on nerve density being 100% androgenic. Taking vaginal weight as a global parameter, the stimulatory effect of DHEA in the rat vagina is about equally estrogenic and androgenic, thus illustrating the importance of androgens in vaginal morphology and function, and the likely importance of androgens in vulvovaginal atrophy of menopause.


Effects of the aminoglycoside antibiotics, streptomycin and neomycin, on neuromuscular transmission. II. Postsynaptic considerations.
The postsynaptic effects of two aminoglycoside antibiotics, streptomycin and neomycin, were studied on miniature end-plate currents (mepcs) and acetylcholine-induced end-plate current fluctuations in voltage-clamped costocutaneous muscles of the garter snake (species Thamnophis). Neomycin decreased the amplitude of mepcs and accelerated the time constants of mepc decay in a concentration-dependent manner without altering the single exponential nature of mepc decay. Neomycin also produced a voltage- and concentration-dependent nonlinearity in the current/voltage relationship. The relationship between the time constants of mepc decay and membrane potential was progressively reduced with increasing concentrations of neomycin. A concentration-dependent reduction in single channel conductance and channel lifetime was also obtained with neomycin. In contrast, streptomycin, in concentrations up to 5 X 10(-5) M, did not significantly alter either mepc amplitude, the time constant of mepc decay, the relationship between the mepc decay time constant and membrane potential or the lifetime and conductance of single end-plate channels. In very high concentrations (greater than 1 mM) streptomycin decreased mepc amplitude and prolonged mepc decay at hyperpolarized membrane potentials. The results suggest that neomycin interacts with the ionic channels of the acetylcholine receptor in their open configuration, whereas streptomycin acts primarily by blocking the receptor. The significant differences in the molecular actions of these two antibiotics may provide an explanation for the observed differences in the character and reversal of the neuromuscular block produced by these antibiotics.


Domiciliary use of transcutaneous electrical stimulation for patients with obstructive sleep apnoea: a conceptual framework for the TESLA home programme.
Obstructive sleep apnoea (OSA) is a global health problem of increasing prevalence. Effective treatments are available with continuous positive airway pressure (CPAP) therapy and mandibular advancement devices (MAD). However, there is limited long-term adherence to therapy, as CPAP and MAD require permanent usage to avoid recurrence of the symptoms and adverse ill health. Alternative treatments would aid in the treatment cascade to manage OSA effectively whenever standard therapy has been trialled and failed. Hypoglossal nerve stimulation (HNS), an invasive approach to stimulate the pharyngeal dilator muscles of the upper airway during sleep, has been approved for the treatment of OSA by several healthcare systems in recent years. In parallel to the development of HNS, a non-invasive approach has been developed to deliver electrical stimulation. Transcutaneous electrical stimulation in obstructive sleep apnoea (TESLA) uses non-invasive electrical stimulation to increase neuromuscular tone of the upper airway dilator muscles of patients with OSA during sleep. Data from previous feasibility studies and randomised controlled trials have helped to identify a subgroup of patients who are "responders" to this treatment. However, further investigations are required to assess usability, functionality and task accomplishment of this novel treatment. Consideration of these factors in the study design of future clinical trials will strengthen research methodology and protocols, improve patient related outcome measures and assessments, to optimise this emerging therapeutical option. In this review, we will introduce a conceptual framework for the TESLA home programme highlighting qualitative aspects and outcomes.


The social and psychological impact of endometriosis on women's lives: a critical narrative review.
BACKGROUND Endometriosis is a chronic condition affecting between 2 and 17% of women of reproductive age. Common symptoms are chronic pelvic pain, fatigue, congestive dysmenorrhoea, heavy menstrual bleeding and deep dyspareunia. Studies have demonstrated the considerable negative impact of this condition on women's quality of life (QoL), especially in the domains of pain and psychosocial functioning. The impact of endometriosis is likely to be exacerbated by the absence of an obvious cause and the likelihood of chronic, recurring symptoms. The aims of this paper are to review the current body of knowledge on the social and psychological impact of endometriosis on women's lives; to provide insights into women's experience of endometriosis; to provide a critical commentary on the current state of knowledge and to make recommendations for future psycho-social research. METHODS The review draws on a method of critical narrative synthesis to discuss a heterogeneous range of both quantitative and qualitative studies from several disciplines. This included a systematic search, a structured process for selecting and collecting data and a systematic thematic analysis of results. RESULTS A total of 42 papers were included in the review; 23 used quantitative methods, 16 used qualitative methods and 3 were mixed methods studies. The majority of papers came from just four countries: UK (10), Australia (8), Brazil (6) and the USA (5). Key categories of impact identified in the thematic analysis were diagnostic delay and uncertainty; 'QoL' and everyday activities; intimate relationships; planning for and having children; education and work; mental health and emotional wellbeing and medical management and self-management. CONCLUSIONS Endometriosis has a significant social and psychological impact on the lives of women across several domains. Many studies have methodological limitations and there are significant gaps in the literature especially in relation to a consideration of the impact on partners and children. We recommend additional prospective and longitudinal research utilizing mixed methods approaches and endometriosis-specific instruments to explore the impact of endometriosis in more diverse populations and settings. Furthermore, there is an urgent need to develop and evaluate interventions for supporting women and partners living with this chronic and often debilitating condition.


The soybean 94-kilodalton vegetative storage protein is a lipoxygenase that is localized in paraveinal mesophyll cell vacuoles.
Soybean leaves contain three proteins (the vegetative storage proteins or VSPs) that respond to nitrogen status and are believed to be involved in the temporary storage of nitrogen. One of these proteins, with a molecular mass of 94 kD and termed vsp94, was microsequenced. Partial amino acid sequence indicated that vsp94 was highly homologous to the lipoxygenase protein family. Further evidence that vsp94 is a lipoxygenase was obtained by demonstrating that vsp94 cross-reacted with a lipoxygenase antibody. Also, a lipoxygenase cDNA coding region was able to detect changes in an mRNA that closely parallel changes in vsp94 protein levels resulting from alteration of nitrogen sinks. Extensive immunocytochemical data indicate that this vsp94/lipoxygenase is primarily expressed in the paraveinal mesophyll cells and is subcellularly localized in the vacuole. These observations are significant in that they suggest that plant lipoxygenases may be bifunctional proteins able to function enzymatically in the hydroperoxidation of lipids and also to serve a role in the temporary storage of nitrogen during vegetative growth.


Temporal properties of attention sharing consequent to disturbed balance.
The time course and extent of attentional shifts associated with compensatory balancing reactions were explored using a novel dual-task paradigm. Seated subjects performed a continuous visuomotor tracking task with the hand while the feet simultaneously balanced an inverted pendulum. The pendulum was randomly perturbed, evoking compensatory balance reactions. Changes in tracking performance were held to reflect attentional shifts. Discrete deviation in visuomotor tracking, typically a pause in tracking, began on average 235 ms after the onset of the balance reaction (TA EMG; average latency 90 ms). Such pauses lasted on average 600 ms, although additional errors in tracking lasted up to 9 s following the perturbation. The findings reveal evidence of dynamic shifts in attention associated with distinct phases of compensatory balance control. The initial phase appears to be triggered automatically, whereas later phases involve varying degrees of attentional resources.


An IoT-Enabled Stroke Rehabilitation System Based on Smart Wearable Armband and Machine Learning.
Surface electromyography signal plays an important role in hand function recovery training. In this paper, an IoT-enabled stroke rehabilitation system was introduced which was based on a smart wearable armband (SWA), machine learning (ML) algorithms, and a 3-D printed dexterous robot hand. User comfort is one of the key issues which should be addressed for wearable devices. The SWA was developed by integrating a low-power and tiny-sized IoT sensing device with textile electrodes, which can measure, pre-process, and wirelessly transmit bio-potential signals. By evenly distributing surface electrodes over user's forearm, drawbacks of classification accuracy poor performance can be mitigated. A new method was put forward to find the optimal feature set. ML algorithms were leveraged to analyze and discriminate features of different hand movements, and their performances were appraised by classification complexity estimating algorithms and principal components analysis. According to the verification results, all nine gestures can be successfully identified with an average accuracy up to 96.20%. In addition, a 3-D printed five-finger robot hand was implemented for hand rehabilitation training purpose. Correspondingly, user's hand movement intentions were extracted and converted into a series of commands which were used to drive motors assembled inside the dexterous robot hand. As a result, the dexterous robot hand can mimic the user's gesture in a real-time manner, which shows the proposed system can be used as a training tool to facilitate rehabilitation process for the patients after stroke.


A pair of tabersonine 16-hydroxylases initiates the synthesis of vindoline in an organ-dependent manner in Catharanthus roseus.
Hydroxylation of tabersonine at the C-16 position, catalyzed by tabersonine 16-hydroxylase (T16H), initiates the synthesis of vindoline that constitutes the main alkaloid accumulated in leaves of Catharanthus roseus. Over the last decade, this reaction has been associated with CYP71D12 cloned from undifferentiated C. roseus cells. In this study, we isolated a second cytochrome P450 (CYP71D351) displaying T16H activity. Biochemical characterization demonstrated that CYP71D12 and CYP71D351 both exhibit high affinity for tabersonine and narrow substrate specificity, making of T16H, to our knowledge, the first alkaloid biosynthetic enzyme displaying two isoforms encoded by distinct genes characterized to date in C. roseus. However, both genes dramatically diverge in transcript distribution in planta. While CYP71D12 (T16H1) expression is restricted to flowers and undifferentiated cells, the CYP71D351 (T16H2) expression profile is similar to the other vindoline biosynthetic genes reaching a maximum in young leaves. Moreover, transcript localization by carborundum abrasion and RNA in situ hybridization demonstrated that CYP71D351 messenger RNAs are specifically located to leaf epidermis, which also hosts the next step of vindoline biosynthesis. Comparison of high- and low-vindoline-accumulating C. roseus cultivars also highlights the direct correlation between CYP71D351 transcript and vindoline levels. In addition, CYP71D351 down-regulation mediated by virus-induced gene silencing reduces vindoline accumulation in leaves and redirects the biosynthetic flux toward the production of unmodified alkaloids at the C-16 position. All these data demonstrate that tabersonine 16-hydroxylation is orchestrated in an organ-dependent manner by two genes including CYP71D351, which encodes the specific T16H isoform acting in the foliar vindoline biosynthesis.


Skipping vs. running as the bipedal gait of choice in hypogravity.
Hypogravity challenges bipedal locomotion in its common forms. However, as previously theoretically and empirically suggested, humans can rely on "skipping," a less common gait available as a functional analog (perhaps a vestigium) of quadrupedal gallop, to confidently move when gravity is much lower than on Earth. We set up a 17-m-tall cavaedium (skylight shaft) with a bungee rubber body-suspension system and a treadmill to investigate the metabolic cost and the biomechanics of low-gravity (Mars, Moon) locomotion. Although skipping is never more metabolically economical than running, the difference becomes marginal at lunar gravities, with both bouncing gaits approaching values of walking on Earth (cost ≈ 2 J · kg(-1)· m(-1)). Nonmetabolic factors may thus be allowed to dominate the choice of skipping on the Moon. On the basis of center of pressure measurements and body segments kinetics, we can speculate that these factors may include a further reduction of mechanical work to move the limbs when wearing space suits and a more effective motor control during the ground (regoliths)-boot interaction.


Microfluidic Generation of Particle-Stabilized Water-in-Water Emulsions.
Herein, we present a microfluidic platform that generates particle-stabilized water-in-water emulsions. The water-in-water system that we use is based on an aqueous two-phase system of polyethylene glycol (PEG) and dextran (DEX). DEX droplets are formed passively, in the continuous phase of PEG and carboxylated particle suspension at a flow-focusing junction inside a microfluidic device. As DEX droplets travel downstream inside the microchannel, carboxylated particles that are in the continuous phase partition to the interface of the DEX droplets due to their affinity to the interface of PEG and DEX. As the DEX droplets become covered with carboxylated particles, they become stabilized against coalescence. We study the coverage and stability of the emulsions, while tuning the concentration and the size of the carboxylated particles, downstream inside the reservoir of the microfluidic device. These particle-stabilized water-in-water emulsions showcase good particle adsorption under shear, while being flowed through narrow microchannels. The intrinsic biocompatibility advantages of particle-stabilized water-in-water emulsions make them a good alternative to traditional particle-stabilized water-in-oil emulsions. To illustrate a biotechnological application of this platform, we show a proof-of-principle of cell encapsulation using this system, which with further development may be used for immunoisolation of cells for transplantation purposes.


The cardiovascular phenotype of a mouse model of acromegaly.
Although, it is accepted that there is an excess of cardiovascular mortality in acromegaly, it is uncertain whether this is due to the direct effects of growth hormone-induced-cardiomyopathy or is a consequence of atherosclerosis secondary to the metabolic syndrome often observed in this condition. Direct comparison of a mouse model of acromegaly to a mouse model of Laron's syndrome allowed us to carry out detailed phenotyping and better understand the role GH plays in the circulatory system. Transgenic mice that overexpress the growth hormone gene (GH) developed gigantism, including insulin resistance and higher blood pressures commensurate with increased body mass. In these giant mice, the hearts were hypertrophied but haemodynamic studies suggested contractile function was normal. Segments of small arteries mounted in a pressure myograph showed vascular wall hypertrophy but a preserved lumen diameter. Vascular contractile function was normal. Mice in which the GH receptor gene was disrupted or 'knocked out' were dwarf and had low blood pressure, small hearts and blood vessels but a normally functioning circulation. Correlations of body mass with cardiovascular parameters suggested that blood pressure and structural characteristics develop in line with body size. In this transgenic mouse model of acromegaly, there is cardiac and vascular hypertrophy commensurate with GH excess but normal function. Our findings support the contention that the excess mortality in this condition may be due to the development of hypertrophic cardiomyopathy rather than increased rates of atherosclerotic coronary artery disease.