Longitudinal determinants of walking, moderate, and vigorous physical activity in Australian adults.
To explore longitudinal (demographic, socioeconomic, health and psychological) determinants of walking, moderate and vigorous physical activity. The sample included 11,133 adult participants (5913 women; 5220 men) taken from the Household, Income and Labour Dynamics in Australia (HILDA) project. Demographic, socioeconomic, health and psychological data were collected in 2010 and estimates of walking, moderate and vigorous physical activity were collected in 2014. Participant age, sex, occupational status, working hours, and neighbourhood remoteness were most strongly related to total physical activity. Psychological traits (personality and distress sensitivity) were unrelated to subsequent physical activity, and health-related behaviours (diet variables and smoking frequency) were moderately related. Participant demographics (age and sex) were most important for vigorous intensity physical activity, and socioeconomic factors (e.g., neighbourhood remoteness, total income, occupational status, weekly hours worked) were most important for moderate intensity physical activity. This investigation shows that demographic, socioeconomic, and health-related variables are important determinants of adult physical activity levels, and that demographic and socioeconomic factors might become more or less important for different intensities of physical activity.


Biofilm formation is a risk factor for mortality in patients with Candida albicans bloodstream infection-Scotland, 2012-2013.
Bloodstream infections caused by Candida species remain a significant cause of morbidity and mortality in hospitalized patients. Biofilm formation by Candida species is an important virulence factor for disease pathogenesis. A prospective analysis of patients with Candida bloodstream infection (n = 217) in Scotland (2012-2013) was performed to assess the risk factors associated with patient mortality, in particular the impact of biofilm formation. Candida bloodstream isolates (n = 280) and clinical records for 157 patients were collected through 11 different health boards across Scotland. Biofilm formation by clinical isolates was assessed in vitro with standard biomass assays. The role of biofilm phenotype on treatment efficacy was also evaluated in vitro by treating preformed biofilms with fixed concentrations of different classes of antifungal. Available mortality data for 134 patients showed that the 30-day candidaemia case mortality rate was 41%, with predisposing factors including patient age and catheter removal. Multivariate Cox regression survival analysis for 42 patients showed a significantly higher mortality rate for Candida albicans infection than for Candida glabrata infection. Biofilm-forming ability was significantly associated with C. albicans mortality (34 patients). Finally, in vitro antifungal sensitivity testing showed that low biofilm formers and high biofilm formers were differentially affected by azoles and echinocandins, but not by polyenes. This study provides further evidence that the biofilm phenotype represents a significant clinical entity, and that isolates with this phenotype differentially respond to antifungal therapy in vitro. Collectively, these findings show that greater clinical understanding is required with respect to Candida biofilm infections, and the implications of isolate heterogeneity.


Mechanics and energetics in tool manufacture and use: a synthetic approach.
Tool manufacture and use are observed not only in humans but also in other animals such as mammals, birds and insects. Manufactured tools are used for biomechanical functions such as effective control of fluids and small solid objects and extension of reaching. These tools are passive and used with gravity and the animal users' own energy. From the perspective of evolutionary biology, manufactured tools are extended phenotypes of the genes of the animal and exhibit phenotypic plasticity. This incurs energetic cost of manufacture as compared to the case with a fixed tool. This paper studies mechanics and energetics aspects of tool manufacture and use in non-human beings. Firstly, it investigates possible mechanical mechanisms of the use of passive manufactured tools. Secondly, it formulates the energetic cost of manufacture and analyses when phenotypic plasticity benefits an animal tool maker and user. We take a synthetic approach and use a controlled physical model, i.e. a robot arm. The robot is capable of additively manufacturing scoop and gripper structures from thermoplastic adhesives to pick and place fluid and solid objects, mimicking primates and birds manufacturing tools for a similar function. We evaluate the effectiveness of tool use in pick-and-place and explain the mechanism for gripper tools picking up solid objects with a solid-mechanics model. We propose a way to formulate the energetic cost of tool manufacture that includes modes of addition and reshaping, and use it to analyse the case of scoop tools. Experiment results show that with a single motor trajectory, the robot was able to effectively pick and place water, rice grains, a pebble and a plastic box with a scoop tool or gripper tools that were manufactured by itself. They also show that by changing the dimension of scoop tools, the energetic cost of tool manufacture and use could be reduced. The work should also be interesting for engineers to design adaptive machines.


Ornithine decarboxylase and polyamines in colorectal neoplasia and mucosa.
Ornithine decarboxylase (ODC) and polyamines are intimately involved in normal cellular proliferation and are likely to play a role in carcinogenesis. ODC activity and polyamine content were measured in tissue samples obtained during colonoscopy from 48 benign neoplastic polyps (20 tubular adenomas; 28 villous adenomas), 18 cancers (including 5 malignant polyps), and adjacent mucosa. ODC activity in polyp and cancer tissue specimens was higher than in adjacent mucosa in 75 and 83% of pairs, respectively. Similarly, putrescine, spermidine, and spermine contents were higher in the majority of polyps and cancers compared to adjacent mucosa. ODC activity and polyamine content in colonic mucosa from 10 patients without a history of colorectal neoplasia were not different from adjacent mucosal values in the patients with neoplasia. In conclusion, ODC and polyamines are elevated in the majority of colorectal neoplasms, but amounts in normal mucosa do not differentiate between patients with cancer, benign neoplastic polyps, and normal subjects.


Venous architecture of the glabellar to the forehead region.
The precise venous anatomy of the glabellar to the forehead region remains unknown. This study aimed to detail the venous architecture of the glabellar region to the forehead in conjunction with that of the supratrochlear artery to reduce the risk of venous congestion of flaps in this area. Fifteen fresh human cadavers were examined here. In five specimens, contrast medium was injected only into the venous system; in 10 specimens, two different types of contrast media were injected into the arterial and venous systems, respectively. A total of 30 hemifacial specimens were radiographed stereoscopically and observed microscopically. In all the cadavers, a distinct vein (termed as the "transverse nasal root vein") connected the bilateral angular veins. One or two large ascending veins branched from the transverse nasal root or angular vein, coursing toward the forehead skin. Numerous small veins branched out from the large ascending vein(s), forming a subdermal polygonal venous network. Small ascending veins arose from this network and coursed toward the dermis, draining venous flow from the dermis. Three different-sized valves prevented the reflux of blood in the venous pathway. The large ascending vein(s) and supratrochlear artery ran parallel only in the medial canthal area. Tiny venous vasa vasorum surrounded the adventitia of the supratrochlear artery and anastomosed with the polygonal venous network, while a few small veins from the vasa vasorum ascended toward the dermis. Understanding the venous architecture of this region is expected to facilitate the safe elevation of various flaps in the area.


Ancestral inference and the study of codon bias evolution: implications for molecular evolutionary analyses of the Drosophila melanogaster subgroup.
Reliable inference of ancestral sequences can be critical to identifying both patterns and causes of molecular evolution. Robustness of ancestral inference is often assumed among closely related species, but tests of this assumption have been limited. Here, we examine the performance of inference methods for data simulated under scenarios of codon bias evolution within the Drosophila melanogaster subgroup. Genome sequence data for multiple, closely related species within this subgroup make it an important system for studying molecular evolutionary genetics. The effects of asymmetric and lineage-specific substitution rates (i.e., varying levels of codon usage bias and departures from equilibrium) on the reliability of ancestral codon usage was investigated. Maximum parsimony inference, which has been widely employed in analyses of Drosophila codon bias evolution, was compared to an approach that attempts to account for uncertainty in ancestral inference by weighting ancestral reconstructions by their posterior probabilities. The latter approach employs maximum likelihood estimation of rate and base composition parameters. For equilibrium and most non-equilibrium scenarios that were investigated, the probabilistic method appears to generate reliable ancestral codon bias inferences for molecular evolutionary studies within the D. melanogaster subgroup. These reconstructions are more reliable than parsimony inference, especially when codon usage is strongly skewed. However, inference biases are considerable for both methods under particular departures from stationarity (i.e., when adaptive evolution is prevalent). Reliability of inference can be sensitive to branch lengths, asymmetry in substitution rates, and the locations and nature of lineage-specific processes within a gene tree. Inference reliability, even among closely related species, can be strongly affected by (potentially unknown) patterns of molecular evolution in lineages ancestral to those of interest.


Selection, recombination, and G----A hypermutation of human immunodeficiency virus type 1 genomes.
Human immunodeficiency virus type 1 (HIV-1) isolates are genetically so heterogeneous that they must be described in terms of populations of related but distinct genomes called quasispecies. A recent study of the influence of ex vivo culturing on HIV-1 quasispecies demonstrated that usually low-abundance genomes outgrew the more prominent forms. Here it is shown that multiple passages of an HIV-1 isolate on peripheral blood mononuclear cells resulted in the outgrowth of very minor forms. A single passage of equal proportions of supernatants to either of the established lymphocyte and monocyte cell lines Molt-3 and U937-2, respectively, resulted in the isolation of different sets of minor forms. Recombination between component sequences was observed. Extensive and monotonous base substitutions of G----A (G----A hypermutation) were evident in many sequences. A strong preference for the transition within the GpA dinucleotide was observed. Dislocation mutagenesis, in this case, a -1 slippage or dislocation of the primer with respect to the template, during DNA synthesis by the HIV-1 reverse transcriptase would explain this bias. When the consequences of polymerase errors, recombination, hypermutation, and instability are added to the genetic description of HIV-1, the real complexity of this virus starts to become apparent.


Catheter-related bacteremia in hemodialysis patients: the role of the central venous catheter in prevention and therapy.
Infections are a leading cause of morbidity and mortality in patients with end-stage renal disease. Infections in hemodialysis patients are strongly associated with the use of an indwelling central venous catheter. S. aureus, coagulase-negative staphylococci and Gram-negative rods account for the majority of these infections. The outcome of catheter-related bacteremia depends on appropriate antibiotic therapy and management of the hemodialysis catheter. Most studies note that there is no difference in outcome if the catheter is changed over a guidewire in addition to antibiotic therapy or if the catheter is completely removed and reinserted at a later date. However, bacteremia with certain organisms, particularly S. aureus, is associated with complications. Thus, the data suggests that the catheter needs to be promptly removed in patients developing S. aureus bacteremia.Bacterial biofilm likely has a critical role in the pathogenesis of these infections. Numerous in vitro and in vivo studies have demonstrated both a reduction in infection rate with the use of antibiotic catheter locks as well as a reduction in the production of or eradication of bacterial biofilm. Future studies ought to target, firstly, a reduction in the reliance on central venous catheters; and secondly, the formulation of practical strategies to reduce patient risk for developing catheter-related bacteremia.


Effects of Exercise on Type 2 Diabetes Mellitus-Related Cognitive Impairment and Dementia.
Cognitive impairment and dementia are common contributors to institutionalization and loss of quality of life in older people. Both type 2 diabetes mellitus (T2DM) and physical inactivity are prevalent and important modifiable risk factors for developing dementia. Physical activity is recommended in the management of T2DM, and there is growing evidence that exercise, a subgroup of physical activity, is also beneficial for maintaining and improving brain structure and function. This paper reviews the evidence for a benefit of exercise on T2DM related cognitive impairment and dementia. In addition, the type (e.g., aerobic, resistance), intensity, duration, and frequency of exercise are discussed. This review shows that although exercise has known benefits on the mechanisms linking T2DM to dementia, there are very few randomized controlled trials examining whether this is the case. It is concluded that the uptake of exercise for the brain has great potential to improve quality of life and provide significant cost savings, but further research is warranted to clarify the effects of exercise on T2DM and those on dementia.


Relations of Shared and Unique Components of Personality and Psychosocial Functioning to Depressive Symptoms.
Consistent with theories of depression, several personality (e.g., high neuroticism, low extraversion) and psychosocial (e.g., interpersonal problems, cognitive content) variables predict depressive symptoms substantively. In this extended replication, we clarified whether 13 theoretically relevant personality and psychosocial variables were unique versus overlapping predictors of symptoms among 351 adult outpatients with recurrent major depressive disorder who received acute-phase cognitive therapy (CT). Using factor analysis and regression methods, we partitioned the measures' variance into general components common across the two types of measures (psychosocial and personality), within-type components shared only with other measures of the same type, and scale-specific components. From early to late in CT, and from late in CT through 8 months after response, the general components were the strongest (median r = .23)-and scale-specific components the weakest (median r = .01)-forward predictors of symptoms. We discuss implications for measurement and treatment of depression.


Relevance of an academic GMP Pan-European vector infra-structure (PEVI).
In the past 5 years, European investigators have played a major role in the development of clinical gene therapy. The provision of substantial funds by some individual member states to construct GMP facilities makes it an opportune time to network available gene therapy GMP facilities at an EU level. The integrated coordination of GMP production facilities and human skills for advanced gene and genetically-modified (GM) cell therapy, can dramatically enhance academic-led "First-in-man" gene therapy trials. Once proof of efficacy is gathered, technology can be transferred to the private sector which will take over further development taking advantage of knowledge and know-how. Complex technical challenges require existing production facilities to adapt to emerging technologies in a coordinated manner. These include a mandatory requirement for the highest quality of production translating gene-transfer technologies with pharmaceutical-grade GMP processes to the clinic. A consensus has emerged on the directions and priorities to adopt, applying to advanced technologies with improved efficacy and safety profiles, in particular AAV, lentivirus-based and oncolytic vectors. Translating cutting-edge research into "First-in-man" trials require that pre-normative research is conducted which aims to develop standard assays, processes and candidate reference materials. This research will help harmonise practices and quality in the production of GMP vector lots and GM-cells. In gathering critical expertise in Europe and establish conditions for interoperability, the PEVI infrastructure will contribute to the demands of the advanced therapy medicinal products* regulation and to both health and quality of life of EU-citizens.


Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta are protected against diet-induced obesity.
The CCAAT/enhancer-binding protein beta (C/EBPbeta) is required for adipocyte differentiation and maturation. We have studied the role of the transcription factor, C/EBPbeta, in the development of diet-induced obesity. Mice with a deletion in the gene for C/EBPbeta (C/EBPbeta(-/-)) and wild-type mice were fed a high-fat diet (60% fat) for 12 weeks. The C/EBPbeta(-/-) mice lost body fat, whereas the wild-type mice increased their total body fat on a high-fat diet. The C/EBPbeta(-/-) mice had lower levels of blood triglycerides, free fatty acids, cholesterol, and hepatic triglyceride accumulation compared with the wild-type mice, thus protecting them from diet-induced obesity and fatty liver on a high-fat diet. Deletion of C/EBPbeta gene resulted in greatly reducing hepatic lipogenic genes, acetyl CoA carboxylase, and fatty acid synthase and increasing the expression of beta-oxidation genes in the brown adipose tissue. CO(2) production was significantly higher in the C/EBPbeta(-/-) mice as was the level of uncoupling protein (UCP)-1 and UCP-3 in the muscle. In conclusion, the transcription factor C/EBPbeta is an important regulator in controlling lipid metabolism and in the development of diet-induced obesity.


Telomeres, age and reproduction in a long-lived reptile.
A major interest has recently emerged in understanding how telomere shortening, mechanism triggering cell senescence, is linked to organism ageing and life history traits in wild species. However, the links between telomere length and key history traits such as reproductive performances have received little attention and remain unclear to date. The leatherback turtle Dermochelys coriacea is a long-lived species showing rapid growth at early stages of life, one of the highest reproductive outputs observed in vertebrates and a dichotomised reproductive pattern related to migrations lasting 2 or 3 years, supposedly associated with different environmental conditions. Here we tested the prediction of blood telomere shortening with age in this species and investigated the relationship between blood telomere length and reproductive performances in leatherback turtles nesting in French Guiana. We found that blood telomere length did not differ between hatchlings and adults. The absence of blood telomere shortening with age may be related to an early high telomerase activity. This telomere-restoring enzyme was formerly suggested to be involved in preventing early telomere attrition in early fast-growing and long-lived species, including squamate reptiles. We found that within one nesting cycle, adult females having performed shorter migrations prior to the considered nesting season had shorter blood telomeres and lower reproductive output. We propose that shorter blood telomeres may result from higher oxidative stress in individuals breeding more frequently (i.e., higher costs of reproduction) and/or restoring more quickly their body reserves in cooler feeding areas during preceding migration (i.e., higher foraging costs). This first study on telomeres in the giant leatherback turtle suggests that blood telomere length predicts not only survival chances, but also reproductive performances. Telomeres may therefore be a promising new tool to evaluate individual reproductive quality which could be useful in such species of conservation concern.


Excited-state hydrogen atom abstraction initiates the photochemistry of β-2'-deoxycytidine.
Understanding the effects of ultraviolet radiation on nucleotides in solution is an important step towards a comprehensive description of the photochemistry of nucleic acids and their constituents. Apart from having implications for mutagenesis and DNA photoprotection mechanisms, the photochemistry of cytidines is a central element in UV-assisted syntheses of pyrimidine nucleotides under prebiotically plausible conditions. In this contribution, we present UV-irradiation experiments of β-2'-deoxycytidine in aqueous solution involving H-D exchange followed by NMR spectroscopic analysis of the photoproducts. We further elucidate the outcome of these experiments by means of high-level quantum chemical calculations. In particular, we show that prolonged UV-irradiation of cytidine may lead to H-C1' hydrogen atom abstraction by the carbonyl oxygen atom of cytosine. This process may enable photoanomerisation and nucleobase loss, two previously unexplained photoreactions observed in pyrimidine nucleotides.


Performance of Qure.ai automatic classifiers against a large annotated database of patients with diverse forms of tuberculosis.
Availability of trained radiologists for fast processing of CXRs in regions burdened with tuberculosis always has been a challenge, affecting both timely diagnosis and patient monitoring. The paucity of annotated images of lungs of TB patients hampers attempts to apply data-oriented algorithms for research and clinical practices. The TB Portals Program database (TBPP, https://TBPortals.niaid.nih.gov) is a global collaboration curating a large collection of the most dangerous, hard-to-cure drug-resistant tuberculosis (DR-TB) patient cases. TBPP, with 1,179 (83%) DR-TB patient cases, is a unique collection that is well positioned as a testing ground for deep learning classifiers. As of January 2019, the TBPP database contains 1,538 CXRs, of which 346 (22.5%) are annotated by a radiologist and 104 (6.7%) by a pulmonologist-leaving 1,088 (70.7%) CXRs without annotations. The Qure.ai qXR artificial intelligence automated CXR interpretation tool, was blind-tested on the 346 radiologist-annotated CXRs from the TBPP database. Qure.ai qXR CXR predictions for cavity, nodule, pleural effusion, hilar lymphadenopathy was successfully matching human expert annotations. In addition, we tested the 12 Qure.ai classifiers to find whether they correlate with treatment success (information provided by treating physicians). Ten descriptors were found as significant: abnormal CXR (p = 0.0005), pleural effusion (p = 0.048), nodule (p = 0.0004), hilar lymphadenopathy (p = 0.0038), cavity (p = 0.0002), opacity (p = 0.0006), atelectasis (p = 0.0074), consolidation (p = 0.0004), indicator of TB disease (p = < .0001), and fibrosis (p = < .0001). We conclude that applying fully automated Qure.ai CXR analysis tool is useful for fast, accurate, uniform, large-scale CXR annotation assistance, as it performed well even for DR-TB cases that were not used for initial training. Testing artificial intelligence algorithms (encapsulating both machine learning and deep learning classifiers) on diverse data collections, such as TBPP, is critically important toward progressing to clinically adopted automatic assistants for medical data analysis.


Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia.
The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3+/-1.9% in 1997-2001 to 77.4+/-1.7% in 2002-2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997-2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.


Protein Corona-Induced Modification of Silver Nanoparticle Aggregation in Simulated Gastric Fluid.
Due to their widespread incorporation into a range of biomedical and consumer products, the ingestion of silver nanoparticles (AgNPs) is of considerable concern to human health. However, the extent to which AgNPs will be modified within the gastric compartment of the gastrointestinal tract is still poorly understood. Studies have yet to fully evaluate the extent of physicochemical changes to AgNPs in the presence of biological macromolecules, such as pepsin, the most abundant protein in the stomach, or the influence of AgNPs on protein structure and activity. Herein, AgNPs of two different sizes and surface coatings (20 and 110 nm, citrate or polyvinylpyrrolidone) were added to simulated gastric fluid (SGF) with or without porcine pepsin at three pHs (2.0, 3.5, and 5.0), representing a range of values between preprandial (fasted) and postprandial (fed) conditions. Rapid increases in diameter were observed for all AgNPs, with a greater increase in diameter in the presence of pepsin, indicating that pepsin facilitated AgNPs aggregation. AgNPs interaction with pepsin only minimally reduced the protein's proteolytic functioning capability, with the greatest inhibitory effect caused by smaller (20 nm) particles of both coatings. No changes in pepsin secondary structural elements were observed for the different AgNPs, even at high particle concentrations. This research highlights the size-dependent kinetics of nanoparticle aggregation or dissolution from interaction with biological elements such as proteins in the gastrointestinal tract. Further, these results demonstrate that, in addition to mass, knowing the chemical form and aggregation state of nanoparticles is critical when evaluating toxicological effects from nanoparticle exposure in the body.


Reversing bacterial resistance to antibiotics by phage-mediated delivery of dominant sensitive genes.
Pathogen resistance to antibiotics is a rapidly growing problem, leading to an urgent need for novel antimicrobial agents. Unfortunately, development of new antibiotics faces numerous obstacles, and a method that resensitizes pathogens to approved antibiotics therefore holds key advantages. We present a proof of principle for a system that restores antibiotic efficiency by reversing pathogen resistance. This system uses temperate phages to introduce, by lysogenization, the genes rpsL and gyrA conferring sensitivity in a dominant fashion to two antibiotics, streptomycin and nalidixic acid, respectively. Unique selective pressure is generated to enrich for bacteria that harbor the phages carrying the sensitizing constructs. This selection pressure is based on a toxic compound, tellurite, and therefore does not forfeit any antibiotic for the sensitization procedure. We further demonstrate a possible way of reducing undesirable recombination events by synthesizing dominant sensitive genes with major barriers to homologous recombination. Such synthesis does not significantly reduce the gene's sensitization ability. Unlike conventional bacteriophage therapy, the system does not rely on the phage's ability to kill pathogens in the infected host, but instead, on its ability to deliver genetic constructs into the bacteria and thus render them sensitive to antibiotics prior to host infection. We believe that transfer of the sensitizing cassette by the constructed phage will significantly enrich for antibiotic-treatable pathogens on hospital surfaces. Broad usage of the proposed system, in contrast to antibiotics and phage therapy, will potentially change the nature of nosocomial infections toward being more susceptible to antibiotics rather than more resistant.


The Role of Andorgens in the Erectile Response: A 1999 Perspective.
Evidence from several laboratories strongly supports a critical role for androgens in the maintenance of the mammalian erectile response. In animal studies, androgens appear to act at the end-organ level (i.e., corporal tissue and vasculature), as well as in the portions of the nervous system which mediate erection. Particularly in the rat model, androgens act centrally to support copulatory behavior and peripherally to maintain the production of nitric oxide and support the veno-occlusive mechanisms. Other studies suggest that alternative, non-NO-dependent, pathways may also be androgen sensitive. However, despite this expanding knowledge base about how androgens act in the erectile response in laboratory animals, the recent studies have not greatly clarified the role of androgens in human penile erection. There does not seem to be a strong cause and effect relation between blood androgen concentrations and erectile function; even in severely hypogonadal men, the erectile response is not always lost, and testosterone treatment of hypogonadal men with erectile dysfunction does not necessarily restore lost erectile function. In addition, different types of erection (nocturnal, in response to visual sexual stimulation, in response to sexual partner) may require different degrees of androgenic support.


Heterodimeric transforming growth factor beta. Biological properties and interaction with three types of cell surface receptors.
Type beta transforming growth factors (TGF) are disulfide-linked homo- and heterodimers of two related polypeptide chains, beta 1 and beta 2. The homodimers TGF-beta 1 and TGF-beta 2 are widely distributed, but the heterodimer TGF-beta 1.2 has been found only in porcine platelets (Cheifetz, S., Weatherbee, J.A., Tsang, M.L.-S., Anderson, J.K., Mole, J.E., Lucas, R., and Massagué, J. (1987) Cell 48, 409-415). Here we characterize the receptor binding and biological properties of TGF-beta 1.2 and compare them with those of TGF-beta 1 and TGF-beta 2. Three types of cell surface receptors previously identified by affinity labeling with 125I-TGF-beta 1 are available for binding to TGF-beta 1.2. These three types of receptors are detected as 65-kDa (type I), 85-95-kDa (type II), and 250-350-kDa (type III) affinity-labeled receptor complexes on electrophoresis gels. They co-exist in many cell types, have high affinity for TGF-beta 1, and varying degrees of affinity for TGF-beta 2. Of the 11 cell lines screened in the present study none showed evidence for additional receptor types that would bind TGF-beta 2 but not TGF-beta 1. In receptor competition studies, TGF-beta 1, TGF-beta 1.2, and TGF-beta 2 competed for binding to type I and type II receptors with a relative order of potencies of 16:5:1 and 12:3:1, respectively, whereas all three forms of TGF-beta were equipotent as ligands for the type III receptors. The three forms of TGF-beta were equally potent at stimulating the biosynthesis of extracellular sulfated proteoglycan in BRL-3A rat liver epithelial cells, a response that presumably involves the type III receptor present in these cells. In contrast, the ability of the three ligands to inhibit the growth of B6SUt-A multipotential hematopoietic progenitor cells which display only type I receptors decreased in the order TGF-beta 1, TGF-beta 1.2, and TGF-beta 2 with a relative potency of 100:30:1. The results indicate that the presence of one beta 1 chain in TGF-beta 1.2 increases (with respect to TGF-beta 2) the biological potency and binding affinity toward receptor types I and II, but the presence of a second beta 1 chain in the dimer is required for full potency.


Proliferation characteristics and polyploidization of cultured myofibroblasts from a patient with fibroblastic rheumatism.
Fibroblast-like cells were obtained from a nodule of a patient with fibroblastic rheumatism, and grown in culture for different times (from passage 3 to 21). These cells as well as the fibroblasts taken from an unaffected skin area (controls) of the same patient, have been investigated by fluorescence microscopy, cytochemical methods and cytometry, to evaluate their cytodifferentiation features and cytokinetic characteristics. In addition, in low-passage cultures, the secretion of collagen and of non-collagenic proteins was evaluated using electrophoretic techniques. The immunolabeling with antibodies against sm-specific a-actin (which was taken as a marker of myofibroblasts) showed that, already in low-passage cultures, the percentage of myofibroblasts was higher in the nodule-derived cell populations, and progressively increased with increasing passages. This suggests that myofibroblasts have higher proliferation potential than control fibroblasts. Myofibroblasts were also found to undergo polyploidization and hypertrophy, especially in high-passage cultures. Based on these results, it may be hypothesized that in fibroblastic rheumatism the development of the typical nodules could depend on the intrinsic capability of myofibroblats of proliferating faster than normal fibroblasts and of becoming polyploid and hypertrophic. Nodule-derived cells in culture synthesized slightly less collagen and non-collagen proteins than did the control fibroblasts; this suggests that the increased fibrosis observed in nodules in situ could be likely dependent on a reduced degradation of the extracellular matrix components.


Increased Serum C-reactive Protein and Corpus Callosum Alterations in Older Adults.
Chronic systemic low-grade inflammation is associated with aging, but little is known on whether age-related inflammation affects brain structure, particularly white matter. The current study tested the hypothesis that in older adults without dementia, higher serum levels of high-sensitivity C-reactive protein (hs-CRP) are associated with reduced corpus callosum (CC) areas. French community-dwelling subjects (ESPRIT study) aged 65 and older (N=101) underwent hs-CRP testing and structural magnetic resonance imaging (MRI). Multiple linear regression models were carried out. In the unadjusted model, higher hs-CRP level was significantly associated with smaller anterior, mid, and total midsagittal CC areas, but not with the posterior CC area. These associations were independent of demographic characteristics and intracranial volume. After adjustment for body mass index, diabetes, inflammation-related chronic pathologies and white matter lesions (WML), only the associations between hs-CRP level and smaller anterior and total midsagittal CC areas were still significant, although weaker. These findings suggest that low-grade inflammation is associated with CC structural integrity alterations in older adults independently of physical or neuropsychiatric pathologies.


miARma-Seq: a comprehensive tool for miRNA, mRNA and circRNA analysis.
Large-scale RNAseq has substantially changed the transcriptomics field, as it enables an unprecedented amount of high resolution data to be acquired. However, the analysis of these data still poses a challenge to the research community. Many tools have been developed to overcome this problem, and to facilitate the study of miRNA expression profiles and those of their target genes. While a few of these enable both kinds of analysis to be performed, they also present certain limitations in terms of their requirements and/or the restrictions on data uploading. To avoid these restraints, we have developed a suite that offers the identification of miRNA, mRNA and circRNAs that can be applied to any sequenced organism. Additionally, it enables differential expression, miRNA-mRNA target prediction and/or functional analysis. The miARma-Seq pipeline is presented as a stand-alone tool that is both easy to install and flexible in terms of its use, and that brings together well-established software in a single bundle. Our suite can analyze a large number of samples due to its multithread design. By testing miARma-Seq in validated datasets, we demonstrate here the benefits that can be gained from this tool by making it readily accessible to the research community.


Importance of Soil Temperature for the Growth of Temperate Crops under a Tropical Climate and Functional Role of Soil Microbial Diversity.
A soil cooling system that prepares soil for temperate soil temperatures for the growth of temperate crops under a tropical climate is described herein. Temperate agriculture has been threatened by the negative impact of temperature increases caused by climate change. Soil temperature closely correlates with the growth of temperate crops, and affects plant processes and soil microbial diversity. The present study focuses on the effects of soil temperatures on lettuce growth and soil microbial diversity that maintains the growth of lettuce at low soil temperatures. A model temperate crop, loose leaf lettuce, was grown on eutrophic soil under soil cooling and a number of parameters, such as fresh weight, height, the number of leaves, and root length, were evaluated upon harvest. Under soil cooling, significant differences were observed in the average fresh weight (P<0.05) and positive development of the roots, shoots, and leaves of lettuce. Janthinobacterium (8.142%), Rhodoplanes (1.991%), Arthrospira (1.138%), Flavobacterium (0.857%), Sphingomonas (0.790%), Mycoplana (0.726%), and Pseudomonas (0.688%) were the dominant bacterial genera present in cooled soil. Key soil fungal communities, including Pseudaleuria (18.307%), Phoma (9.968%), Eocronartium (3.527%), Trichosporon (1.791%), and Pyrenochaeta (0.171%), were also recovered from cooled soil. The present results demonstrate that the growth of temperate crops is dependent on soil temperature, which subsequently affects the abundance and diversity of soil microbial communities that maintain the growth of temperate crops at low soil temperatures.


A systematic proactive risk assessment of hazards in surgical wards: a quantitative study.
To identify and prioritize hazards in surgical wards and recommend interventions. Retrospective and prospective studies report the frequency and severity of surgical adverse events, but not in sufficient detail to allow interventions to be recommended in surgical wards. Seventy hours of observations were used to record all activities occurring in surgical wards, and from these activities health care processes were derived. Fifty-nine patients and staff quantified the hazard associated with each health care process through a risk assessment survey. Modified health care failure mode and effects analysis was applied to the most hazardous of these processes to quantify the hazard of their associated failures. Cause analysis was applied to the most hazardous failures within analyzed processes. Interventions addressing the prioritized failures were recommended. Surgical ward observations identified 81 activities. The risk assessment survey was used to quantify the hazard associated with 10 health care processes derived from these activities. The 5 most hazardous processes were prioritized for modified health care failure mode and effects analysis including hand hygiene, isolation of infection, vital signs, medication delivery, and hand off. Of 190 failures within these processes, 50 (26%) were considered hazardous and did not have effective control measures in place. The causes of these failures allowed interventions to be recommended. Proactive risk assessments were used to systematically identify and prioritize hazards in surgical wards and allowed interventions to be recommended. These are practical tools that can determine where patient safety efforts should be targeted in clinical health care environments.


The importance of being genomic: Non-coding and coding sequences suggest different models of toxin multi-gene family evolution.
Studies of multi-gene protein families, including many toxins, are crucial for understanding the role of gene duplication in generating protein diversity in general. However, many evolutionary analyses of gene families are based on coding sequences, and do not take into account many potentially confounding evolutionary factors, such as recombination and convergence due to selection. We illustrate this using snake venom gene sequences from the Phospholipase A2 (PLA2) subfamily. Novel gene sequences from 20 species of understudied Asian pitvipers were analyzed alongside available genomic PLA2 sequences from another four crotaline and several viperine species. In contrast to previous analyses of this toxin family based on cDNA sequences, we find that duplication events are concentrated at the tips of the tree, suggesting that major functions such as presynaptic neurotoxicity have evolved convergently multiple times in pitvipers. We provide evidence that this discrepancy is due to differing evolutionary patterns between introns and exons. The effects of several well-known sources of bias on the phylogeny were small, compared to the effect of analyses based on different partitions of the gene (whole gene sequence, non-coding regions, cDNA sequence). Switches of function were found to be largely associated with strong selection, and with duplication events. Use of coding sequences for phylogeny estimation potentially produces incorrect inferences about the action of selection on individual lineages and sites. Our results have major implications for phylogenomic methods of functional inference as well as for our understanding of the evolution of multigene families.


The effect of bulgecin A on peptidoglycan metabolism and physiology of Helicobacter pylori.
Helicobacter pylori, a human-specific bacterial pathogen responsible for severe gastric diseases, constitutes a major public health issue. In the last decade, rates of H. pylori resistance to antibiotics were increasing drastically, requiring alternative therapeutic strategies to deal with eradication failures. Therefore, we evaluated the potential of bulgecin A, a glycosidic inhibitor of the lytic transglycosylase (LTG) Slt70 of Escherichia coli, as a new therapeutic approach against the H. pylori infection. In this study, we show that bulgecin A is able to specifically inactivate the H. pylori LTG Slt, but not its ortholog MltD. Moreover, bulgecin A synergized with amoxicillin, an inhibitor of penicillin binding proteins, inducing strong morphological alterations, cellular damages, and cell death. Similarly, the simultaneous inactivation of the peptidoglycan (PG) peptidase HdpA and Slt led to inhibition of H. pylori growth, highlighting the strong potential of targeting the PG biosynthetic pathway at different biochemical steps to enhance our therapeutic approaches against bacteria. Hence, we propose that bulgecin A constitutes an attractive compound for the development of new therapeutic strategies against H. pylori combined with other inhibitors of PG biosynthetic enzymes.


Alternative bearings in total knee arthroplasty: risk of early revision compared to traditional bearings: an analysis of 62,177 primary cases.
There is no substantial clinical evidence for the superiority of alternative bearings in total knee arthroplasty (TKA). We compared the short-term revision risk in alternative surface bearing knees (oxidized zirconium (OZ) femoral implants or highly crosslinked polyethylene (HXLPE) inserts) with that for traditional bearings (cobalt-chromium (CoCR) on conventional polyethelene (CPE)). The risk of revision with commercially available HXLPE inserts was also evaluated. All 62,177 primary TKA cases registered in a Total Joint Replacement Registry between April 2001 and December 2010 were retrospectively analyzed. The endpoints for the analysis were all-cause revisions, septic revisions, or aseptic revisions. Bearing surfaces were categorized as OZ-CPE, CoCr-HXLPE, or CoCr-CPE. HXLPE inserts were stratified according to brand name. Confounding was addressed using propensity score weights. Marginal Cox-regression models adjusting for surgeon clustering were used. The proportion of females was 62%. Average age was 68 (SD 9.3) years, and median follow-up time was 2.8 (IQR 1.2-4.9) years. After adjustments, the risks of all-cause, aseptic, and septic revision with CoCr-HXLPE and OZ-CPE bearings were not statistically significantly higher than with traditional CoCr-CPE bearings. No specific brand of HXLPE insert was associated with a higher risk of all-cause, aseptic, or septic revision compared to CoCr-CPE. At least in the short term, none of the alternative knee bearings evaluated (CoCr-HXLPE or OZ-CPE) had a greater risk of all-cause, aseptic, and septic revision than traditional CoCr-CPE bearings.


Unusual haplotype structure at the proximal breakpoint of In(2L)t in a natural population of Drosophila melanogaster.
The existence of temporally stable frequency clines for In(2L)t in natural populations of Drosophila melanogaster suggests a role for selection in the maintenance of this polymorphism. We have collected nucleotide polymorphism data from the proximal breakpoint junction regions of In(2L)t to infer its evolutionary history. The finding of a novel LINE-like element near the In(2L)t breakpoint junction in sampled inverted chromosomes supports a transposable element-mediated origin for this inversion. An analysis of nucleotide variation in a Costa Rican population sample of standard and inverted chromosomes indicates a unique and relatively recent origin for In(2L)t. Additional In(2L)t alleles from three geographically diverse populations reveal no detectable geographic differentiation. Low levels of In(2L)t nucleotide polymorphism suggest a recent increase in the inversion's frequency in tropical populations. An unusual feature of our sample of standard alleles is a marked heterogeneity in levels of linkage disequilibrium among polymorphic sites across the breakpoint region. We introduce a test of neutral equilibrium haplotype structure that corrects both for multiple tests and for an arbitrarily chosen window size. It reveals that an approximately 1.4-kb region immediately spanning the breakpoint has fewer haplotypes than expected under the neutral model, given the expected level of recombination in this genomic region. Certain features of our data suggest that the unusual pattern in standard chromosomes is the product of selection rather than demography.


The critical role of community-based micro-grants for disability aids and equipment: results from a needs analysis.
To investigate the role of philanthropic micro-grants (maximum of $10,000) in the provision of aids and equipment for adults (aged 18-65 years of age) with complex disabilities and examine key trends in aids and equipment requests. This study examined, through quantitative and qualitative analysis, aids and equipment requests (n = 371 individual applications as represented by 136 service organisations in three Australian states) received by a not-for-profit (NFP) organisation across five consecutive years of an innovative micro-grants scheme. Findings highlight that living situation (living with family or living independently) significantly influences the nature of requests for respite, aids, equipment and home modifications. Specifically, people with complex disabilities living with their families require greater combined service provision (higher equipment need, respite support, home modifications) than those living independently (equipment need only). Type of disability did not influence request type. Qualitative data further indicated the "last resort" nature of respite requests, particularly for younger applicants (under 45 years of age) indicating critical unmet needs in the community. Results demonstrate the vital role of NFP organisations and philanthropic funds in supporting daily lifestyle aids and equipment (including respite) that might otherwise not be funded for people with complex disabilities. Although preliminary in its scope and prior to implementation of a National Disability Insurance Scheme (NDIS) in Australia, findings suggest both opportunity and risk to the uptake of community-based micro-grant funding: opportunity for users through the provision of essential aids and lifestyle supports, and risk through over-subscription and devolving of responsibility for critical support resources from public sector. The aids and equipment needs of adults under the age of 65 appear to have been underestimated, poorly defined and under-serviced. Service users need more assistance for their carers (i.e. equipment to facilitate safe lifting, urgent breaks from care routines) as well as aids, equipment and modifications to help them to live a more normal life (e.g. going to the beach). Living situation (i.e. independently or with family) significantly influences the nature and extent of aids and equipment requested. Supporting adults up to the age of 65 to live more independently would positively influence carers and family, while at the same time providing opportunities for more targeted personal care supports. Philanthropic and not-for-profit schemes are helping to address these needs through micro-grant schemes for purchases under $10 000, but sustainability is questioned. The introduction of Australia's National Disability Insurance Scheme (NDIS) presents an opportunity to consider the lifestyle needs of service users and carers, and determine who is best placed to address them.


Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype.
In many rodent brain regions, alcohol increases vesicular release of GABA, resulting in an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and the magnitude of tonic GABAA receptor (GABAAR) currents. A neglected issue in translating the rodent literature to humans is the possibility that phylogenetic differences alter the actions of alcohol. To address this issue we made voltage-clamp recordings from granule cells (GCs) in cerebellar slices from the non-human primate (NHP), Macaca fascicularis. We found that similar to Sprague Dawley rats (SDRs), NHP GCs exhibit a tonic conductance generated by α6δ subunit containing GABAARs, as evidenced by its blockade by the broad spectrum GABAAR antagonist, GABAzine (10 μM), inhibition by α6 selective antagonist, furosemide (100 μM), and enhancement by THDOC (10-20 nM) and THIP (500 nM). In contrast to SDR GCs, in most NHP GCs (~60%), application of EtOH (25-105 mM) did not increase sIPSC frequency or the tonic GABAAR current. In a minority of cells (~40%), EtOH did increase sIPSC frequency and the tonic current. The relative lack of response to EtOH was associated with reduced expression of neuronal nitric oxide synthase (nNOS), which we recently reported mediates EtOH-induced enhancement of vesicular GABA release in rats. The EtOH-induced increase in tonic GABAAR current was significantly smaller in NHPs than in SDRs, presumably due to less GABA release, because there were no obvious differences in the density of GABAARs or GABA transporters between SDR and NHP GCs. Thus, EtOH does not directly modulate α6δ subunit GABAARs in NHPs. Instead, EtOH enhanced GABAergic transmission is mediated by enhanced GABA release. Further, SDR GC responses to alcohol are only representative of a subpopulation of NHP GCs. This suggests that the impact of EtOH on NHP cerebellar physiology will be reduced compared to SDRs, and will likely have different computational and behavioral consequences.


When to consider thyroid dysfunction in the neurology clinic.
There are many neurological manifestations of thyroid disease, and thyroid function has taken its place in the "routine bloods" of neurology practice. However, although conditions such as carpal tunnel syndrome prompt thyroid testing despite any clear evidence for this approach, other symptoms of potential significance in terms of thyroid disease may be overlooked in the busy general neurology clinic, or abnormal thyroid tests may be assumed to be incidental. Psychiatric disorders, loss of consciousness, movement disorders and weakness may all be manifestations of primary thyroid disease. This is a symptom-based review where we will consider the evidence (or lack of it) for the association of various neurological problems with thyroid dysfunction, and also the pitfalls in interpretation of the biochemical tests.


The effectiveness of exercise as treatment for vasomotor menopausal symptoms: randomised controlled trial.
To investigate the effectiveness of exercise as treatment for vasomotor menopausal symptoms. Three-group randomised controlled trial, two exercise interventions and a control group. Primary Care, West Midlands UK. Perimenopausal and postmenopausal women experiencing at least five hot flushes/night sweats per day and not taken MHT in previous 3 months were recruited from 23 general practices. Participants in both exercise interventions groups were offered two face-to-face consultations with a physical activity facilitator to support engagement in regular exercise. In addition, one exercise group received a menopause-specific information DVD and written materials to encourage regular exercise and the other exercise group was offered the opportunity to attend exercise social support groups in their communities. Interventions lasted 6 months. The primary outcome was frequency of hot flushes/night sweats at 6-month up. Two hundred and sixty-one women were randomised (n = 87 per group). Neither of the exercise intervention groups reported significantly less frequent hot flushes/night sweats per week than controls (exercise-DVD versus control: -8.9, 95% CI -20.0 to 2.2; exercise-social support versus control: -5.2, 95% CI -16.7 to 6.3). This trial indicates that exercise is not an effective treatment for hot flushes/night sweats. Contrary to current clinical guidance, women should not be advised that exercise will relieve their vasomotor menopausal symptoms.


Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic Control of C(sp2)-H Oxidative Addition Results in ortho-to-Fluorine Selectivity.
The mechanism of C(sp2)-H borylation of fluorinated arenes with B2Pin2 (Pin = pinacolato) catalyzed by bis(phosphino)pyridine (iPrPNP) cobalt complexes was studied to understand the origins of the uniquely high ortho-to-fluorine regioselectivity observed in these reactions. Variable time normalization analysis (VTNA) of reaction time courses and deuterium kinetic isotope effect measurements established a kinetic regime wherein C(sp2)-H oxidative addition is fast and reversible. Monitoring the reaction by in situ NMR spectroscopy revealed the intermediacy of a cobalt(I)-aryl complex that was generated with the same high ortho-to-fluorine regioselectivity associated with the overall catalytic transformation. Deuterium labeling experiments and stoichiometric studies established C(sp2)-H oxidative addition of the fluorinated arene as the selectivity-determining step of the reaction. This step favors the formation of ortho-fluoroaryl cobalt intermediates due to the ortho fluorine effect, a phenomenon whereby ortho fluorine substituents stabilize transition metal-carbon bonds. Computational studies provided evidence that the cobalt-carbon bonds of the relevant intermediates in (iPrPNP)Co-catalyzed borylation are strengthened with increasing ortho fluorine substitution. The atypical kinetic regime involving fast and reversible C(sp2)-H oxidative addition in combination with the thermodynamic preference for forming cobalt-aryl bonds adjacent to fluorinated sites are the origin of the high regioselectivity in the catalytic borylation reaction.


Outbreaks of food poisoning in adults due to Escherichia coli O111 and campylobacter associated with coach trips to northern France.
Thirty-seven out of 48 people on a coach excursion to northern France developed gastrointestinal symptoms within 4 days of the trip. Twenty-six had stool samples positive for Escherichia coli O111, 8 were also positive for Campylobacter species, and 1 was positive for campylobacter alone. Strains of E. coli were positive for the effacing and attaching protein (eaeA) gene, but negative for other E. coli virulence genes, and therefore belonged to the enteropathogenic E. coli (EPEC) group. Twenty-two out of 37 people in a second party which followed the same itinerary 2 weeks later also became ill. One had a stool sample positive for E. coli O111. Analytical epidemiology suggested that the source of infections was a restaurant in northern France at which both parties had eaten.


Chronic carvedilol reduces mortality and renal damage in hypertensive stroke-prone rats.
The effects of carvedilol, a novel vasodilating beta-blocker and antioxidant, and propranolol on survival, neurobehavioral deficits, cardiovascular parameters, plasma renin, plasma aldosterone levels and renal pathology were determined in stroke-prone spontaneously hypertensive rats. Stroke-prone spontaneously hypertensive rats were allowed access to 1% NaCl as the drinking solution and a high fat diet supplemented with carvedilol (1200 or 2400 ppm) or propranolol (2400 ppm). The control group consisted of stroke-prone spontaneously hypertensive rats placed on the same diet with no drug supplement. Animals fed propranolol had a blood level of 864 +/- 68 ng/ml, whereas carvedilol-fed animals had blood levels of 24 +/- 4 ng/ml at 1200 ppm and 471 +/- 145 ng/ml at 2400 ppm. Carvedilol and propranolol treatment resulted in significant beta adrenoceptor blockade. Both compounds reduced heart rate, but had no significant effects on systolic arterial blood pressure. Carvedilol- and propranolol-treated animals also exhibited significant, prolonged protection from neurobehavioral deficits and mortality (P < .01). Elevated plasma renin activity and aldosterone levels seen in untreated controls were significantly decreased by propranolol (P < .05), and to a considerably greater extent by the same dose of carvedilol (P < .01). Carvedilol decreased renal histopathological damage and cardiac hypertrophy to a greater extent (P < .01) than propranolol (at equal doses). Both carvedilol (P < .01)- and propranolol (P < .01)-treated animals had considerably reduced renal damage at 18 weeks of treatment. Carvedilol reduced renal damage more than propranolol (P < .05). In addition, the lower (1200 ppm) dose of carvedilol, which decreased neurobehavioral deficits and mortality, had no significant effects on organ mass or renal function, but significantly (P < .01) reduced renal damage. These data indicate that both beta adrenoceptor blockers, especially carvedilol to a considerably greater degree, convey significant protection in a genetic model of severe hypertension that results in renal and cardiovascular organ pathology, neurobehavioral deficits and premature death.


Health behaviors and infant health outcomes in homeless pregnant women in the United States.
To describe selected demographics; maternal health behaviors before, during, and after pregnancy; and infant health outcomes among homeless women in the United States. Analyses are based on Pregnancy Risk Assessment Monitoring System data from 31 participating states from 2000 to 2007 that were linked to birth certificate data, which contain demographic and medical information collected through the state's vital records system. Responses were then weighted to be representative of all women who gave birth in each state during that year. Assessment of these data takes into account the complex sampling designs employed by the states. Four percent of women reported homelessness within 12 months before pregnancy, with the highest percentage in Illinois, followed by Oregon and Washington. Homeless women were younger, unmarried, uninsured, less educated, less likely to initiate and sustain breastfeeding, and had less prenatal care and well-visits. They were also more likely to be black, Hispanic, smoke cigarettes, be underweight or have class III obesity, and not take preconception multivitamins. Infants had lower birth weights, a longer hospital stay, and were more likely to receive neonatal intensive care. In this study we provide additional insight into homelessness in the perinatal period and provide information on ways to direct interventions aimed at improving the health of homeless mothers and infants. Additional research is needed to determine factors that influence pregnancy weight gain and infant feeding practices among homeless women and how this affects infant health.


Estrogen alone in postmenopausal women and breast cancer detection by means of mammography and breast biopsy.
As the influence of estrogen alone on breast cancer detection is not established, we examined this issue in the Women's Health Initiative trial, which randomly assigned 10,739 postmenopausal women with prior hysterectomy to conjugated equine estrogen (CEE; 0.625 mg/d) or placebo. Screening mammography and breast exams were performed at baseline and annually. Breast biopsies were based on clinical findings. Effects of CEE alone on breast cancer detection were determined by using receiver operating characteristic (ROC) analyses of mammogram performance. After a 7.1-year mean follow-up, fewer invasive breast cancers were diagnosed in the CEE than in the placebo group, but the difference was not statistically significant. Use of CEE alone increased mammograms with short-interval follow-up recommendations (cumulative, 39.2% v 29.6.3%; P < .001) but not abnormal mammograms (ie, those suggestive of or highly suggestive of malignancy; cumulative, 7.3% v 7.0%; P = .41). Breast biopsies were more frequent in the CEE group (cumulative, 12.5% v 10.7%; P = .004) and less commonly diagnosed as cancer (8.9% v 15.8%, respectively, with positive biopsies; P = .04). Mammographic breast cancer detection in the CEE group was significantly compromised only in the early years of use. CEE alone use for 5 years results in approximately one in 11 and one in 50 women having otherwise avoidable mammograms with short-interval follow-up recommendations or breast biopsies, respectively. Although the breast biopsies on CEE were less commonly diagnosed as cancer, breast cancer detection was not substantially compromised. These findings differ from estrogen-plus-progestin use, for which significantly increased abnormal mammograms and a compromise in breast cancer detection are seen.


Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability.
DNA damage response mechanisms encompass pathways of DNA repair, cell cycle checkpoint arrest and apoptosis. Together, these mechanisms function to maintain genomic stability in the face of exogenous and endogenous DNA damage. ATM is activated in response to double strand breaks and initiates cell cycle checkpoint arrest. Recent studies in human fibroblasts have shown that ATM also regulates a mechanism of end-processing that is required for a component of double strand break repair. Human fibroblasts rarely undergo apoptosis after ionising radiation and, therefore, apoptosis is not considered in our review. The dual function of ATM raises the question as to how the two processes, DNA repair and checkpoint arrest, interplay to maintain genomic stability. In this review, we consider the impact of ATM's repair and checkpoint functions to the maintenance of genomic stability following irradiation in G2. We discuss evidence that ATM's repair function plays little role in the maintenance of genomic stability following exposure to ionising radiation. ATM's checkpoint function has a bigger impact on genomic stability but strikingly the two damage response pathways co-operate in a more than additive manner. In contrast, ATM's repair function is important for survival post irradiation.


MOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway.
The Hippo tumor suppressor pathway regulates organ size and tissue homoeostasis in response to diverse signaling inputs. The core of the pathway consists of a short kinase cascade: MST1 and MST2 phosphorylate and activate LATS1 and LATS2, which in turn phosphorylate and inactivate key transcriptional coactivators, YAP1 and TAZ (gene WWTR1). The MOB1 adapter protein regulates both phosphorylation reactions firstly by concurrently binding to the upstream MST and downstream LATS kinases to enable the trans phosphorylation reaction, and secondly by allosterically activating the catalytic function of LATS1 and LATS2 to directly stimulate phosphorylation of YAP and TAZ. Studies of yeast Mob1 and human MOB1 revealed that the ability to recognize phosphopeptide sequences in their interactors, Nud1 and MST2 respectively, was critical to their roles in regulating the Mitotic Exit Network in yeast and the Hippo pathway in metazoans. However, the underlying rules of phosphopeptide recognition by human MOB1, the implications of binding specificity for Hippo pathway signaling, and the generality of phosphopeptide binding function to other human MOB family members remained elusive.Employing proteomics, peptide arrays and biochemical analyses, we systematically examine the phosphopeptide binding specificity of MOB1 and find it to be highly complementary to the substrate phosphorylation specificity of MST1 and MST2. We demonstrate that autophosphorylation of MST1 and MST2 on several threonine residues provides multiple MOB1 binding sites with varying binding affinities which in turn contribute to a redundancy of MST1-MOB1 protein interactions in cells. The crystal structures of MOB1A in complex with two favored phosphopeptide sites in MST1 allow for a full description of the MOB1A phosphopeptide-binding consensus. Lastly, we show that the phosphopeptide binding properties of MOB1A are conserved in all but one of the seven MOB family members in humans, thus providing a starting point for uncovering their elusive cellular functions.


A sensorimotor network for the bodily self.
Neuroscientists and philosophers, among others, have long questioned the contribution of bodily experience to the constitution of self-consciousness. Contemporary research answers this question by focusing on the notions of sense of agency and/or sense of ownership. Recently, however, it has been proposed that the bodily self might also be rooted in bodily motor experience, that is, in the experience of oneself as instantiating a bodily structure that enables a specific range of actions. In the current fMRI study, we tested this hypothesis by making participants undergo a hand laterality judgment task, which is known to be solved by simulating a motor rotation of one's own hand. The stimulus to be judged was either the participant's own hand or the hand of a stranger. We used this task to investigate whether mental rotation of pictures depicting one's own hands leads to a different activation of the sensorimotor areas as compared with the mental rotation of pictures depicting another's hand. We revealed a neural network for the general representation of the bodily self encompassing the SMA and pre-SMA, the anterior insula, and the occipital cortex, bilaterally. Crucially, the representation of one's own dominant hand turned out to be primarily confined to the left premotor cortex. Our data seem to support the existence of a sense of bodily self encased within the sensorimotor system. We propose that such a sensorimotor representation of the bodily self might help us to differentiate our own body from that of others.


Development of a measure of "acculturation" for ethnic Fijians: methodologic and conceptual considerations for application to eating disorders research.
Acculturation has been examined as a risk factor for eating disorders, but interpretation of findings has been limited by inconsistent operationalization of this construct across studies. The study aim was to develop and evaluate a population-specific measure of acculturation for ethnic Fijian adolescent schoolgirls, to use in future analyses related to eating disorders. Our findings suggest that acculturation is a multidimensional construct characterized by distinct, though related, dimensions of orientation to ethnic Fijian and/or western/global culture with respect to a range of behaviors and attitudes. In contrast to theoretical models positing uni-dimensional, orthogonal, or oblique relations between cultural identities in individuals undergoing acculturation, our study findings support a heterogeneous pattern among correlations of dimensions across contrasting cultural identities. We suggest multidimensional measures of acculturation are optimal--and socio-demographic proxies inadequate--for characterization of this complex process for health research.


Practical Recommendations Relevant to the Use of Resistance Training for COVID-19 Survivors.
The novel coronavirus disease (COVID-19) has emerged at the end of 2019 and caused a global pandemic. The disease predominantly affects the respiratory system; however, there is evidence that it is a multisystem disease that also impacts the cardiovascular system. Although the long-term consequences of COVID-19 are not well-known, evidence from similar diseases alerts for the possibility of long-term impaired physical function and reduced quality of life, especially in those requiring critical care. Therefore, rehabilitation strategies are needed to improve outcomes in COVID-19 survivors. Among the possible strategies, resistance training (RT) might be particularly interesting, since it has been shown to increase functional capacity both in acute and chronic respiratory conditions and in cardiac patients. The present article aims to propose evidence-based and practical suggestions for RT prescription for people who have been diagnosed with COVID-19 with a special focus on immune, respiratory, and cardiovascular systems. Based on the current literature, we present RT as a possible safe and feasible activity that can be time-efficient and easy to be implemented in different settings.


Repression of tyrosine hydroxylase is responsible for the sex-linked chocolate mutation of the silkworm, Bombyx mori.
Pigmentation patterning has long interested biologists, integrating topics in ecology, development, genetics, and physiology. Wild-type neonatal larvae of the silkworm, Bombyx mori, are completely black. By contrast, the epidermis and head of larvae of the homozygous recessive sex-linked chocolate (sch) mutant are reddish brown. When incubated at 30 degrees C, mutants with the sch allele fail to hatch; moreover, homozygous mutants carrying the allele sch lethal (sch(l)) do not hatch even at room temperature (25 degrees C). By positional cloning, we narrowed a region containing sch to 239,622 bp on chromosome 1 using 4,501 backcross (BC1) individuals. Based on expression analyses, the best sch candidate gene was shown to be tyrosine hydroxylase (BmTh). BmTh coding sequences were identical among sch, sch(l), and wild-type. However, in sch the approximately 70-kb sequence was replaced with approximately 4.6 kb of a Tc1-mariner type transposon located approximately 6 kb upstream of BmTh, and in sch(l), a large fragment of an L1Bm retrotransposon was inserted just in front of the transcription start site of BmTh. In both cases, we observed a drastic reduction of BmTh expression. Use of RNAi with BmTh prevented pigmentation and hatching, and feeding of a tyrosine hydroxylase inhibitor also suppressed larval pigmentation in the wild-type strain, pnd(+) and in a pS (black-striped) heterozygote. Feeding L-dopa to sch neonate larvae rescued the mutant phenotype from chocolate to black. Our results indicate the BmTh gene is responsible for the sch mutation, which plays an important role in melanin synthesis producing neonatal larval color.


Relationship between phospholipid transfer protein activity and HDL level and size among inbred mouse strains.
Because of the paucity of data on phospholipid transfer protein (PLTP) activity and lipoprotein phospholipid in mouse strains, plasma PLTP activity (PLTA), plasma phospholipid and cholesterol, HDL phospholipid and cholesterol, and HDL size distribution were determined in 15 inbred mouse strains. The 15 inbred mouse strains differed in their relatedness to one another and consisted of six largely unrelated groups: Castaneus, Swiss, C57BL, AKR, DBA, and NZB. Lipid and PLTA analyses were performed on plasma pools from male and female mice that had fasted for 4 h prior to blood draw. Among the representative unrelated strains fed the chow diet, there was a highly significant relationship between PLTA and plasma phospholipid (r(s) = 0.727, P < 0.01), HDL phospholipid (r(s) = 0.762, P < 0.01), HDL cholesterol (r(s) = 0.699, P < 0.02), percentage of large HDL particles (r(s) = 0.699, P < 0.02), and HDL peak size (r(s) = 0.776, P < 0.01). Similar results were obtained among these strains fed a high fat, high cholesterol diet. PLTA increased in all strains fed the high fat diet (chix = 94%, range 6 to 221%). Strain SM having relatively low PLTA and HDL was crossed with strain NZB having high PLTA and HDL. The F1 progeny from this cross were backcrossed to strain SM and 41 male backcross progeny collected. Among these individual backcrossed animals, PLTA was highly correlated with plasma phospholipid (r(s) = 0.508, P = 0.001), HDL phospholipid (r(s) = 0.566, P < 0.001), HDL cholesterol (r(s) = 0.532, P < 0.001), and percentage of large HDL particles (r(s) = 0.446, P = 0.020). Therefore, we conclude that PLTP is a determinant of HDL level and size in mice.-Albers, J. J., W. Pitman, G. Wolfbauer, M. C. Cheung, H. Kennedy, A-Y. Tu, S. M. Marcovina, and B. Paigen. Relationship between phospholipid transfer protein activity and HDL level and size among inbred mouse strains.


Kazakhstan's CO2 emissions in the post-Kyoto Protocol era: Production- and consumption-based analysis.
The first commitment period of the Kyoto Protocol came to an end in 2012 and more developing countries began to participate in the new phase of world carbon emission reduction. Kazakhstan is an important energy export country and a pivot of the "Belt and Road Initiative" (BRI). Despite its emissions are relatively small compared with huge emitters such as China and the US, Kazakhstan also faces great pressure in terms of CO2 emission reduction and green development. Accurately accounting CO2 emissions in Kazakhstan from both production and consumption perspectives is the first step for further emissions control actions. This paper constructs production-based CO2 emission inventories for Kazakhstan from 2012 to 2016, and then further analyses the demand-driven emissions within the domestic market and international trade (exports and imports) using environmentally extended input-output analysis. The production-based inventory includes 43 energy products and 30 sectors to provide detailed data for CO2 emissions in Kazakhstan. The consumption-based accounting results showed that certain sectors like construction drive more emissions and that the fuel consumption in different sectors varies. Furthermore, Russia and China are major consumers of Kazakhstan's energy and associated emissions, with the construction sector playing the most important role in it. The results suggested that both technology and policy actions should be taken into account to reduce CO2 emissions and that the BRI is also a good chance for Kazakhstan to develop a "Green Economy".


Neuronal Differentiation of a Human Induced Pluripotent Stem Cell Line (FS-1) Derived from Newborn Foreskin Fibroblasts.
Isolation of induced pluripotent stem cells (iPSCs) from fully differentiated somatic cells has revolutionized existing concepts of cell differentiation and stem cells. Importantly, iPSCs generated from somatic cells of patients can be used to model different types of human diseases. They may also serve as autologous cell sources that can be used in transplantation therapy. In this study, we investigated the neuronal properties of an iPSC line that is derived from human neonatal foreskin fibroblasts (FS-1). We initially examined the morphology and marker expression of FS-1 cells at undifferentiated stage. We then spontaneously differentiated FS-1 cells in suspension culture and examined the expression of markers representing three germ layers. We finally differentiated FS-1 cells into neuronal lineages by co-culturing them with PA6 stromal cells, and found that, under the conditions we used, they have a tendency to differentiate into more forebrain-type neurons, suggesting that FS-1 iPSC-derived neural cells will be useful to be used in cell therapy of stroke or Huntington's disease, among others. Taken together, FS-1 cells derived from human neonatal fibroblasts exhibit very similar properties with human ES cells, and can provide useful sources for cell therapy and various other applications.


A curated benchmark of enhancer-gene interactions for evaluating enhancer-target gene prediction methods.
Many genome-wide collections of candidate cis-regulatory elements (cCREs) have been defined using genomic and epigenomic data, but it remains a major challenge to connect these elements to their target genes. To facilitate the development of computational methods for predicting target genes, we develop a Benchmark of candidate Enhancer-Gene Interactions (BENGI) by integrating the recently developed Registry of cCREs with experimentally derived genomic interactions. We use BENGI to test several published computational methods for linking enhancers with genes, including signal correlation and the TargetFinder and PEP supervised learning methods. We find that while TargetFinder is the best-performing method, it is only modestly better than a baseline distance method for most benchmark datasets when trained and tested with the same cell type and that TargetFinder often does not outperform the distance method when applied across cell types. Our results suggest that current computational methods need to be improved and that BENGI presents a useful framework for method development and testing.


Epinephrine enables Pavlovian fear conditioning under anesthesia.
Rats under Pavlovian defensive conditioning (noise paired with shock) while under general anesthesia. Peripheral administration of epinephrine (0.01 to 1.0 milligram per kilogram of body weight) during training resulted in the acquisition of conditioned fear, as shown 10 days later by conditioned suppression of water drinking. Analysis of heart rate and measurement of reflexes during training indicated that epinephrine did not lighten the state of anesthesia. These results indicate that epinephrine enables the learning of conditioned fear in the anesthetized brain.


Increase in milk yield following eprinomectin treatment at calving in pastured dairy cattle.
Gastrointestinal nematodes rarely cause signs of clinical disease in adult cattle. However, they have been shown to exert a negative impact on production in lactating animals, as seen by improved production following elimination of the worms using anthelmintics. A double blind, randomized clinical trial was performed in 28 dairy herds in Canada. The objective of the study was to evaluate the effect of treatment with eprinomectin pour-on solution (IVOMEC EPRINEX) at calving on production, in cattle that have had some exposure to pasture. Cows were randomly allocated to treatment or placebo in blocks of 10, based on calving date, and treated with eprinomectin or placebo on the day of calving. Information on milk production was obtained from all animals, as well as recorded cases of selected diseases. Milk production results from the Canadian dairy herd management system database were analysed using a mixed model with herd as a random effect and test within-cow as a repeated measurement. Test day milk yields from the first six tests after treatment were included in the model, representing a period of between 180 and 200 days in milk (dim). Treated cows produced an additional 0.94 kg of milk per day when compared to the controls over this period. The production effect was independent of calving season, age of the animal and geographical location. No effect of treatment was seen on milk composition, somatic cell count (scc) or on the selected health parameters that were recorded for all included animals. Monthly fecal egg counts (FEC) were performed for eight randomly selected animals in each herd. The observed FEC were low in this study, with a range from 0 to 419 trichostrongyle type eggs per 5g (ep5g) of feces in animals not yet treated with the anthelmintic. The average count was 9.8 and the median was 1.0. FECs dropped immediately after calving and stayed lower for at least 100 days in treated animals when compared to controls. In conclusion, gastrointestinal nematodes appear to have an effect on milk production in Canadian dairy cows that have had some degree of pasture exposure. Eliminating the present subclinical parasite burdens produced a consistent increase in milk production that can yield economic benefits for the dairy producer.


Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia.
Spinocerebellar ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other ataxia-causing proteins and the ataxia network. To begin to understand the biological relevance of these protein interactions within the ataxia network, we used OMIM to identify diseases associated with the expanded ataxia network. We then used Medicare patient records to determine if any of these diseases co-occur with hereditary ataxia. We found that patients with ataxia are at 3.03-fold greater risk of these diseases than Medicare patients overall. One of the diseases comorbid with ataxia is macular degeneration (MD). The ataxia network is significantly (P= 7.37 × 10(-5)) enriched for proteins that interact with known MD-causing proteins, forming a MD subnetwork. We found that at least two of the proteins in the MD subnetwork have altered expression in the retina of Ataxin-7(266Q/+) mice suggesting an in vivo functional relationship with ATXN7. Together these data reveal novel protein interactions and suggest potential pathways that can contribute to the pathophysiology of ataxia, MD, and diseases comorbid with ataxia.


ACTION OF FORMALDEHYDE ON ENZYMES AND ON CERTAIN PBOTEIDS.
THE FOLLOWING GENERAL CONCLUSIONS MAY BE DRAWN FROM THE PRECEDING WORK: Fibrin is altered by formaldehyde and is then less easily digested by pepsin and by trypsin. Papaïn is apparently unable to digest fibrin even when this is exposed to very weak formaldehyde (1:1000) for a very short time. The casein of milk, on contact with formaldehyde, undergoes rapid alteration and is as a result not coagulated by rennet, or but very slowly. Such altered casein, like similar fibrin, is not readily digested by the proteolytic ferments. The longer the formaldehyde acts on casein and on fibrin the more marked is the result. Pepsin is not affected by a one per cent solution of formaldehyde, even when the mixture has stood for four weeks. Even a five per cent solution of formaldehyde acting for three weeks has no effect on pepsin. Contrary results obtained by others are due to an alteration of the fibrin by the formaldehyde. A putrid solution of pepsin in distilled water one month old digests fibrin as readily as a fresh solution. Rennet is not affected even by a four per cent solution of formaldehyde acting for several weeks. The absence of coagulation at times is due to the action of formaldehyde on the casein of the milk and not on the rennet ferment. Papaïn is very quickly altered by formaldehyde, even in very dilute solution. Moreover, it is unable to digest fibrin that has been exposed to the action of a very dilute solution of formaldehyde for a short time. Trypsin is altered by formaldehyde to such an extent that digestion of fibrin will not take place, or but very slowly. The extent to which trypsin is affected by formaldehyde depends largely upon the amount of organic matter present, as well as on the amount of ferment in the solution. Amylopsin is not destroyed by very dilute solutions of formaldehyde, but stronger solutions decrease the activity of the ferment, and if used in sufficient concentration will destroy it completely. Ptyalin, like the diastatic ferment of the pancreas, is not destroyed by dilute solutions of formaldehyde. If the latter is used in rather strong concentration and allowed to act for some time it will destroy the ferment. The action of formaldehyde is more rapid and more marked at a slightly elevated temperature than at ordinary room temperature. Malt diastase, unlike the diastatic ferments of the saliva and pancreatic solution, is not destroyed by formaldehyde when this is used in moderate amount and at ordinary temperature. Unlike pepsin, a solution of malt diastase readily undergoes decomposition on standing even for one or more days. This destruction is undoubtedly due to bacteria since it does not take place when formaldehyde is present. Consequently the favoring action which formaldehyde apparently exerts on diastase really consists in the inhibition of the growth of micro-organisms, and hence the diastase is protected against decomposition.


Clinical application for the preservation of phospho-proteins through in-situ tissue stabilization.
Protein biomarkers will play a pivotal role in the future of personalized medicine for both diagnosis and treatment decision-making. While the results of several pre-clinical and small-scale clinical studies have demonstrated the value of protein biomarkers, there have been significant challenges to translating these findings into routine clinical care. Challenges to the use of protein biomarkers include inter-sample variability introduced by differences in post-collection handling and ex vivo degradation of proteins and protein modifications. In this report, we re-create laboratory and clinical scenarios for sample collection and test the utility of a new tissue stabilization technique in preserving proteins and protein modifications. In the laboratory setting, tissue stabilization with the Denator Stabilizor T1 resulted in a significantly higher yield of phospho-protein when compared to standard snap freeze preservation. Furthermore, in a clinical scenario, tissue stabilization at collection resulted in a higher yield of total phospho-protein, total phospho-tyrosine, pErkT202/Y204 and pAktS473 when compared to standard methods. Tissue stabilization did not have a significant effect on other post-translational modifications such as acetylation and glycosylation, which are more stable ex-vivo. Tissue stabilization did decrease total RNA quantity and quality. Stabilization at the time of collection offers the potential to better preserve tissue protein and protein modification levels, as well as reduce the variability related to tissue processing delays that are often associated with clinical samples.


Laparoscopic mini-gastric bypass for failed vertical banded gastroplasty.
Bariatric surgery is the only method for sustained weight loss in morbid obesity. However, 10-25% of patients will require re-operation for unsatisfactory weight loss or weight regain after restrictive surgery. Re-operation is associated with higher morbidity and mortality. This study is to evaluate the s a fety and efficacy of laparoscopic mini-gastric bypass (LMGB) for failed vertical banded gastroplasty (VBG). From May 2001 to March 2003, 29 consecutive patients underwent LMGB for failed VBG. Average age was 39.7 years (range 22 to 56), and average BMI before re-operation was 41.7 kg/m(2) (range 35.0-70.8). 8 patients had previous open VBG, and 21 had laparoscopic VBG. The re-operation was for regain of weight in 16 patients, inadequate weight loss in 10 patients, and severe reflux esophagitis in 3 patients. Re-operation was performed after an average of 58.5 months (range 14 to 180). All the re-operations were completed laparoscopically. Average operative time was 171.4 minutes (range 130 to 290). There was 1 mortality, due to leakage (3.4%). 1 re-operation was necessary, for incarceration of small bowel in a trocar wound 10 days after the LMGB (3.4%). 1 anastomotic site bleeding and 1 wound infection occurred. Average BMI 12 months after the LMGB was 32.1 kg/m(2) (range 26.4 to 42.7). The quality of life study was significantly improved. The revision operation had much more technical difficulty for those with previous open VBG than laparoscopic VBG. LMGB is an effective and safe revision operation for patients with failed VBG. A large series and long-term follow up is needed for confirmation.


Management of Hypertension in Patients with Chronic Kidney Disease in Asia.
Hypertension is both a cause and consequence of chronic kidney disease (CKD). According to the Chinese national survey in 2007-2010, the prevalence of CKD was much higher in hypertensive patients (18.9%, n=16,691) than in the overall population sample (10.8%, n=47,204). CKD in hypertension confers risks to the kidneys as well as other organs. Probably because of high dietary salt intake, Asian hypertensive patients with CKD show high prevalence of non-dipping and reversed dipping blood pressure pattern, and may have even higher risks of cardiovascular disease. Therefore, out-of-office blood pressure evaluation and comprehensive cardiovascular evaluations are required. Most of current hypertension guidelines recommend intensive antihypertensive treatment in hypertensive patients with CKD. This is probably of particular relevance for cardiovascular prevention in Asia, because stroke, as a major complication of hypertension in Asia, is more closely related to blood pressure than coronary events. Intensive blood pressure control to 130/80 mmHg is often required to prevent CKD progression and cardiovascular complications. The inhibitors of the renin-angiotensin system (RAS) are recommended as the first line antihypertensive medications in patients with a glomerular filtration rate higher than 30 ml/min/1.73 m², which may more efficaciously prevent end-stage renal disease and cardiovascular events. Nonetheless, combination therapy of RAS inhibitors with other classes of antihypertensive drugs, such as calcium-channel blockers, diuretics, etc, is required to control blood pressure to the target.


A kinetic study of ozone decomposition on illuminated oxide surfaces.
The heterogeneous chemistry and photochemistry of ozone on oxide components of mineral dust aerosol, including α-Fe(2)O(3), TiO(2), and α-Al(2)O(3), at different relative humidities have been investigated using an environmental aerosol chamber. The rate and extent of ozone decomposition on these oxide surfaces are found to be a function of the nature of the surface as well as the presence of light and relative humidity. Under dark and dry conditions, only α-Fe(2)O(3) exhibits catalytic decomposition toward ozone, whereas the reactivity of TiO(2) and α-Al(2)O(3) is rapidly quenched upon ozone exposure. However, upon irradiation, TiO(2) is active toward O(3) decomposition and α-Al(2)O(3) remains inactive. In the presence of relative humidity, ozone decay on α-Fe(2)O(3) subject to irradiation or under dark conditions is found to decrease. In contrast, ozone decomposition is enhanced for irradiated TiO(2) as relative humidity initially increases but then begins to decrease at higher relative humidity levels. A kinetic model was used to obtain heterogeneous reaction rates for different homogeneous and heterogeneous reaction pathways taking place in the environmental aerosol chamber. The atmospheric implications of these results are discussed.


Reinforcement learning or active inference?
This paper questions the need for reinforcement learning or control theory when optimising behaviour. We show that it is fairly simple to teach an agent complicated and adaptive behaviours using a free-energy formulation of perception. In this formulation, agents adjust their internal states and sampling of the environment to minimize their free-energy. Such agents learn causal structure in the environment and sample it in an adaptive and self-supervised fashion. This results in behavioural policies that reproduce those optimised by reinforcement learning and dynamic programming. Critically, we do not need to invoke the notion of reward, value or utility. We illustrate these points by solving a benchmark problem in dynamic programming; namely the mountain-car problem, using active perception or inference under the free-energy principle. The ensuing proof-of-concept may be important because the free-energy formulation furnishes a unified account of both action and perception and may speak to a reappraisal of the role of dopamine in the brain.


The molecular biology of axon guidance.
Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.


Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation.
The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.


Non-EST based prediction of exon skipping and intron retention events using Pfam information.
Most of the known alternative splice events have been detected by the comparison of expressed sequence tags (ESTs) and cDNAs. However, not all splice events are represented in EST databases since ESTs have several biases. Therefore, non-EST based approaches are needed to extend our view of a transcriptome. Here, we describe a novel method for the ab initio prediction of alternative splice events that is solely based on the annotation of Pfam domains. Furthermore, we applied this approach in a genome-wide manner to all human RefSeq transcripts and predicted a total of 321 exon skipping and intron retention events. We show that this method is very reliable as 78% (250 of 321) of our predictions are confirmed by ESTs or cDNAs. Subsequent analyses of splice events within Pfam domains revealed a significant preference of alternative exon junctions to be located at the protein surface and to avoid secondary structure elements. Thus, splice events within Pfams are probable to alter the structure and function of a domain which makes them highly interesting for detailed biological investigation. As Pfam domains are annotated in many other species, our strategy to predict exon skipping and intron retention events might be important for species with a lower number of ESTs.