Molecular signatures of the primitive prostate stem cell niche reveal novel mesenchymal-epithelial signaling pathways.
Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system. We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2), lipid metabolism (e.g., Srebp1) and cell migration (e.g., Areb6 and Rreb1). Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche. We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may be common to mammalian niches in general. This study provides a comprehensive source for further studies of mesenchymal/epithelial interactions in the prostate stem cell niche. The elucidation of pathways in the normal primitive niche may provide greater insight into mechanisms subverted during abnormal proliferative and oncogenic processes. Understanding these events may result in the development of specific targeted therapies for prostatic diseases such as benign prostatic hypertrophy and carcinomas.


Molecular architecture and connectivity of the budding yeast Mtw1 kinetochore complex.
Kinetochores are large multiprotein complexes that connect centromeres to spindle microtubules in all eukaryotes. Among the biochemically distinct kinetochore complexes, the conserved four-protein Mtw1 complex is a central part of the kinetochore in all organisms. Here we present the biochemical reconstitution and characterization of the budding yeast Mtw1 complex. Direct visualization by electron microscopy revealed an elongated bilobed structure with a 25-nm-long axis. The complex can be assembled from two stable heterodimers consisting of Mtw1p-Nnf1p and Dsn1p-Nsl1p, and it interacts directly with the microtubule-binding Ndc80 kinetochore complex via the centromere-proximal Spc24/Spc25 head domain. In addition, we have reconstituted a partial Ctf19 complex and show that it directly associates with the Mtw1 complex in vitro. Ndc80 and Ctf19 complexes do not compete for binding to the Mtw1 complex, suggesting that Mtw1 can bridge the microtubule-binding components of the kinetochore to the inner centromere.


Understanding the problem of glass transition on the basis of elastic waves in a liquid.
We propose that the properties of a glass transition can be understood on the basis of elastic waves. Elastic waves originating from atomic jumps in a liquid propagate local expansion due to the anharmonicity of the interatomic potential. This creates dynamic compressive stress, which increases the activation barrier for other events in a liquid. The non-trivial point is that the range of propagation of high-frequency elastic waves, d(el), increases with liquid relaxation time τ. A self-consistent calculation shows that this increase gives the Vogel-Fulcher-Tammann (VFT) law. In the proposed theory, we discuss the origin of two dynamic crossovers in a liquid: (1) the crossover from exponential to non-exponential and from Arrhenius to VFT relaxation at high temperature and (2) the crossover from the VFT to a more Arrhenius-like relaxation at low temperature. The corresponding values of τ at the two crossovers are in quantitative parameter-free agreement with experiments. The origin of the second crossover allows us to reconcile the ongoing controversy surrounding the possible divergence of τ. The crossover to Arrhenius relaxation universally takes place when d(el) reaches system size, thus avoiding divergence and associated theoretical complications such as identifying the nature of the phase transition and the second phase itself. Finally, we discuss the effect of volume on τ and the origin of liquid fragility.


When to be skeptical of negative studies: pitfalls in evaluating occupational risks using population-based case-control studies.
This study investigated arsenic and lung cancer incidence in a community setting in the Montreal area. Job histories and sociodemographic factors were collected by interview from 857 lung cancer cases, 533 general population controls, and 1,360 controls with other cancers. Chemist-hygienists assessed each subject's life-time occupational exposure to 294 substances. Logistic regressions yielded arsenic/lung cancer odds ratios of 1.1 (95% confidence interval = 0.60, 1.7) based on cancer controls, and 0.82 (95% confidence interval = 0.41, 1.6) based on population controls. Risk did not rise with increasing level or probability of exposure. Worksite studies consistently show lung carcinogenicity from arsenic. Since confounding from other chemicals was well controlled, the most likely explanation is substantially lower exposures than in previous studies. The lack of association in this study demonstrates the need for caution in interpreting negative findings from population-based case-control studies, particularly when exposures are low or rare, as well as the difficulty in generating hypotheses from such studies.


Guava pomace: a new source of anti-inflammatory and analgesic bioactives.
Guava pomace is an example of the processing waste generated after the manufacturing process from the juice industry that could be a source of bioactives. Thus, the present investigation was carried out in order to evaluate the anti-inflammatory and antinociceptive potential and determinate the main phenolic compounds of a guava pomace extract (GPE). The anti-inflammatory activity was evaluated by carrageenan, dextran, serotonin, histamine-induced paw edema and neutrophils migration in the peritoneal cavity models. Acetic acid-induced abdominal writhing and formalin test were performed to investigate the antinociceptive effects. In addition, the content of total phenolic and of individual phenolic compounds was determined by GC/MS. GPE showed anti-inflammatory activity by carrageenan, dextran, serotonin, histamine-induced paw edema and neutrophils migration in the peritoneal cavity models (p < 0.05). GPE also demonstrated antinociceptive activity by acetic acid-induced abdominal writhing and formalin test (p < 0.05). The total phenolic value was 3.40 ± 0.09 mg GAE/g and epicatechin, quercetin, myricetin, isovanilic and gallic acids were identified by GC/MS analysis. The presence of bioactive phenolic compounds as well as important effects demonstrated in animal models suggest that guava pomace could be an interesting source of anti-inflammatory and analgesic substances.


Experimental infection of cattle with Mycobacterium tuberculosis isolates shows the attenuation of the human tubercle bacillus for cattle.
The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis. However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross pathology and histopathology in cattle compared to M. bovis. Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation of M. tuberculosis strains for cattle, and emphasizes the potential of the bovine model as a 'One Health' approach to inform human TB biomarker development and post-exposure vaccine development.


Phototropism: at the crossroads of light-signaling pathways.
Phototropism enables plants to orient growth towards the direction of light and thereby maximizes photosynthesis in low-light environments. In angiosperms, blue-light photoreceptors called phototropins are primarily involved in sensing the direction of light. Phytochromes and cryptochromes (sensing red/far-red and blue light, respectively) also modulate asymmetric hypocotyl growth, leading to phototropism. Interactions between different light-signaling pathways regulating phototropism occur in cryptogams and angiosperms. In this review, we focus on the molecular mechanisms underlying the co-action between photosensory systems in the regulation of hypocotyl phototropism in Arabidopsis thaliana. Recent studies have shown that phytochromes and cryptochromes enhance phototropism by controlling the expression of important regulators of phototropin signaling. In addition, phytochromes may also regulate growth towards light via direct interaction with the phototropins.


Prokaryotic DNA sequences in patients with chronic idiopathic prostatitis.
Half of all men experience symptoms of prostatitis at some time in their lives, but the etiology is unknown for more than 90% of patients. Optimal clinical and culture methods were used to select 135 men with chronic prostatitis refractory to multiple previous courses of antimicrobial therapy. The subjects had no evidence of structural or functional lower genitourinary tract abnormalities of bacteriuria or bacterial prostatitis by traditional clinical tests, or of urethritis or urethral pathogens by culture. Specific PCR assays detected Mycoplasma genitalium, Chlamydia trachomatis, or Trichomonas vaginalis in 10 patients (8%). Broad-spectrum PCR tests detected tetracycline resistance-encoding genes, tetM-tetO-tetS, in 25% of patients and 16S rRNA in 77% of subjects. The tetM-tetO-tetS-positive cases constituted a subset of the 16S rRNA-positive cases. Patients with 16S rRNA were more likely to have > or = 1,000 leukocytes per mm3 in their expressed prostatic secretion than men whose prostate biopsy specimens were negative for 16S rRNA (P < 0.001). Based on direct sequencing and repetitive cloning, multiple sources of 16S rRNA were observed in individual patients. Sequences of 29 cloned PCR products revealed 16S rRNAs distinct from those of common skin and gut flora. These findings suggest that the prostate can harbor microorganisms that are not detectable by traditional approaches. These organisms may be associated with inflammation in the expressed prostatic secretions. Molecular methods hold great promise for identifying culture-resistant microorganisms in patients with chronic prostatitis.


Equity of access to specialist chronic fatigue syndrome (CFS/ME) services in England (2008-2010): a national survey and cross-sectional study.
Provision of National Health Service (NHS) specialist chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) services in England has been deemed patchy and inconsistent. Our objective was to explore variation in the provision of NHS specialist CFS/ME services and to investigate whether access is related to measures of deprivation and inequality. Survey of all CFS/ME clinical teams in England, plus cross-sectional data from a subset of teams. Secondary care. We used clinic activity data from CFS/ME clinical teams in England to describe provision of specialist CFS/ME services (referral, assessment and diagnosis rates per 1000 adults per year) during 2008-2011 according to Primary Care Trust (PCT) population estimates, and to investigate whether use of services was related to PCT-level measures of deprivation and inequality. We used postcode data from seven services to investigate variation in provision by deprivation. Clinic activity data were obtained from 93.9% (46/49) of clinical teams in England which between them received referrals from 84.9% (129/152) of PCTs. 12 PCTs, covering a population of 2.08 million adults, provided no specialist CFS/ME service. There was a six-fold variation in referral and assessment rates between services which could not be explained by PCT-level measures of deprivation and inequality. The median assessment rate in 2010 was 0.25 (IQR 0.17, 0.35) per 1000 adults per year. 91.9% (IQR 76.5%, 100.0%) of adults assessed were diagnosed with CFS/ME. Postcode data from seven clinical teams showed that assessment rates were equal across deprivation quartiles for four teams but were 40-50% lower in the most deprived compared with the most affluent areas for three teams. Two million adults in England do not have access to a specialist CFS/ME service. In some areas which do have a specialist service, access is inequitable. This inequity may worsen with the impending fragmentation of NHS commissioning across England.


Characterization of western European field isolates and vaccine strains of avian infectious laryngotracheitis virus by restriction fragment length polymorphism and sequence analysis.
Infectious laryngotracheitis is a dramatic disease of the upper respiratory tract in poultry caused by a herpesvirus. In this study we investigated the characteristics of western European field isolates of infectious laryngotracheitis virus (ILTV) to gain more information on their diversity. The examined 104 isolates, collected from acute outbreaks during the last 35 years, originated from eight different countries: Switzerland (48), Germany (21), Sweden (14), the United Kingdom (9), Italy (5), Belgium (4), Austria (2), and Norway (1). Two vaccines, a chicken embryo origin product and a tissue culture origin product, were included in the survey. Polymerase chain reaction (PCR) was performed to amplify a 2.1-kb DNA fragment of ILTV using primers generated for the thymidine kinase (TK) gene. After digestion of the resulting PCR products by restriction endonuclease HaeIII, restriction fragment length polymorphism analysis was carried out. PCR amplicons of three field isolates and both vaccine strains were selected for sequencing. Here 98 field isolates showed the same cleavage pattern and were identical to both vaccine strains (clone 1). They differed from five Swiss isolates with identical cleavage pattern (clone 2) and one Swedish isolate (clone 3). The present study demonstrated that at least three clones of ILTV have been circulating in western Europe during the last 35 years. The 104 isolates analyzed showed a high genetic similarity regarding the TK gene, and a large majority of the field isolates (98/104) were genetically related to the vaccine strains.


Altered DNA methylation profile in Norwegian patients with Autoimmune Addison's Disease.
Autoimmune Addison's Disease (AAD) is an endocrine and immunological disease of uncertain pathogenesis resulting from the immune system's destruction of the hormone producing cells of the adrenal cortex. The underlying molecular mechanisms are largely unknown, but it is commonly accepted that a combination of genetic susceptibility and environmental impact is critical. In the present study, we identified multiple hypomethylated gene promoter regions in patients with isolated AAD using DNA isolated from CD4+ T cells. The identified differentially methylated regions were distributed evenly across the 10.5-kb-promoter regions covered by the array, and a substantial number localized to promoters of genes involved in immune regulation and autoimmunity. This study reveals a hypomethylated status in CD4+ T cells from AAD patients and indicates differential methylation of promoters of key genes involved in immune responses.


Autophagy regulates adipose mass and differentiation in mice.
The relative balance between the quantity of white and brown adipose tissue can profoundly affect lipid storage and whole-body energy homeostasis. However, the mechanisms regulating the formation, expansion, and interconversion of these 2 distinct types of fat remain unknown. Recently, the lysosomal degradative pathway of macroautophagy has been identified as a regulator of cellular differentiation, suggesting that autophagy may modulate this process in adipocytes. The function of autophagy in adipose differentiation was therefore examined in the current study by genetic inhibition of the critical macroautophagy gene autophagy-related 7 (Atg7). Knockdown of Atg7 in 3T3-L1 preadipocytes inhibited lipid accumulation and decreased protein levels of adipocyte differentiation factors. Knockdown of Atg5 or pharmacological inhibition of autophagy or lysosome function also had similar effects. An adipocyte-specific mouse knockout of Atg7 generated lean mice with decreased white adipose mass and enhanced insulin sensitivity. White adipose tissue in knockout mice had increased features of brown adipocytes, which, along with an increase in normal brown adipose tissue, led to an elevated rate of fatty acid, beta-oxidation, and a lean body mass. Autophagy therefore functions to regulate body lipid accumulation by controlling adipocyte differentiation and determining the balance between white and brown fat.


Theoretical screening of -NH2-, -OH-, -CH3-, -F-, and -SH-substituted porphyrins as sensitizer candidates for dye-sensitized solar cells.
Following former studies, the donor-acceptor combinations of -NH(2)-substituted porphyrin donor and the acceptors C, D, E, F, H and G, those of -OH-, -CH(3)- and -Ph-substituted porphyrins as well as porphine donors and the acceptors E, G, and H, and those of -F- and -SH-substituted porphyrin donors and the acceptor G as novel sensitizer candidates have been designed and calculated at the density functional B3LYP level. The result shows that -NH(2)-, -OH- and -CH(3)-substituted porphyrins as donors combined with the acceptor G are very promising to provide good performances as sensitizers because of their smaller HOMO-LUMO gaps, much red-shifted absorption bands, and good frontier molecular orbital spatial distributions. They are all promising to challenge the current photon-to-current conversion efficiency record 7.1% of porphyrin-sensitized solar cells in which the -NH(2)-substituted porphyrins as donors combined with the acceptor G are the best systems.


Placing RNA in context and space - methods for spatially resolved transcriptomics.
Single-cell transcriptomics provides us with completely new insights into the molecular diversity of different cell types and the different states they can adopt. The technique generates inventories of cells that constitute the building blocks of multicellular organisms. However, since the method requires isolation of discrete cells, information about the original location within tissue is lost. Therefore, it is not possible to draw detailed cellular maps of tissue architecture and their positioning in relation to other cells. In order to better understand the cellular and tissue function of multicellular organisms, we need to map the cells within their physiological, morphological, and anatomical context and space. In this review, we will summarize and compare the different methods of in situ RNA analysis and the most recent developments leading to more comprehensive and highly multiplexed spatially resolved transcriptomic approaches. We will discuss their highlights and advantages as well as their limitations and challenges and give an outlook on promising future applications and directions both within basic research as well as clinical integration.


Sequencing of high-complexity DNA pools for identification of nucleotide and structural variants in regions associated with complex traits.
We have used targeted genomic sequencing of high-complexity DNA pools based on long-range PCR and deep DNA sequencing by the SOLiD technology. The method was used for sequencing of 286 kb from four chromosomal regions with quantitative trait loci (QTL) influencing blood plasma lipid and uric acid levels in DNA pools of 500 individuals from each of five European populations. The method shows very good precision in estimating allele frequencies as compared with individual genotyping of SNPs (r(2) = 0.95, P < 10(-16)). Validation shows that the method is able to identify novel SNPs and estimate their frequency in high-complexity DNA pools. In our five populations, 17% of all SNPs and 61% of structural variants are not available in the public databases. A large fraction of the novel variants show a limited geographic distribution, with 62% of the novel SNPs and 59% of novel structural variants being detected in only one of the populations. The large number of population-specific novel SNPs underscores the need for comprehensive sequencing of local populations in order to identify the causal variants of human traits.


Expanding heterochromatin reveals discrete subtelomeric domains delimited by chromatin landscape transitions.
The eukaryotic genome is divided into chromosomal domains of heterochromatin and euchromatin. Transcriptionally silent heterochromatin is found at subtelomeric regions, leading to the telomeric position effect (TPE) in yeast, fly, and human. Heterochromatin generally initiates and spreads from defined loci, and diverse mechanisms prevent the ectopic spread of heterochromatin into euchromatin. Here, we overexpressed the silencing factor Sir3 at varying levels in yeast and found that Sir3 spreads into extended silent domains (ESDs), eventually reaching saturation at subtelomeres. We observed the spread of Sir3 into subtelomeric domains associated with specific histone marks in wild-type cells, and stopping at zones of histone mark transitions including H3K79 trimethylation levels. Our study shows that the conserved H3K79 methyltransferase Dot1 is essential in restricting Sir3 spread beyond ESDs, thus ensuring viability upon overexpression of Sir3. Last, our analyses of published data demonstrate how ESDs unveil uncharacterized discrete domains isolating structural and functional subtelomeric features from the rest of the genome. Our work offers a new approach on how to separate subtelomeres from the core chromosome.


Association of ACTN3 R577X but not ACE I/D gene variants with elite rugby union player status and playing position.
We aimed to quantify the ACE I/D and ACTN3 R577X (rs1815739) genetic variants in elite rugby athletes (rugby union and league) and compare genotype frequencies to controls and between playing positions. The rugby athlete cohort consisted of 507 Caucasian men, including 431 rugby union athletes that for some analyses were divided into backs and forwards and into specific positional groups: front five, back row, half backs, centers, and back three. Controls were 710 Caucasian men and women. Real-time PCR of genomic DNA was used to determine genotypes using TaqMan probes and groups were compared using χ(2) and odds ratio (OR) statistics. Correction of P values for multiple comparisons was according to Benjamini-Hochberg. There was no difference in ACE I/D genotype between groups. ACTN3 XX genotype tended to be underrepresented in rugby union backs (15.7%) compared with forwards (24.8%, P = 0.06). Interestingly, the 69 back three players (wings and full backs) in rugby union included only six XX genotype individuals (8.7%), with the R allele more common in the back three (68.8%) than controls (58.0%; χ(2) = 6.672, P = 0.04; OR = 1.60) and forwards (47.5%; χ(2) = 11.768, P = 0.01; OR = 2.00). Association of ACTN3 R577X with playing position in elite rugby union athletes suggests inherited fatigue resistance is more prevalent in forwards, while inherited sprint ability is more prevalent in backs, especially wings and full backs. These results also demonstrate the advantage of focusing genetic studies on a large cohort within a single sport, especially when intrasport positional differences exist, instead of combining several sports with varied demands and athlete characteristics.


Nationwide Survey of Post-Transplant Glomerular Diseases, Based on the Japan Renal Biopsy Registry (J-RBR).
BACKGROUND Nationwide data on allograft kidney biopsies have been limited in number, in contrast to the large amount of accumulated data on native kidney biopsies. In this context, we have surveyed transplant biopsy data based on the nationwide database, the Japan Renal Biopsy Registry (J-RBR). MATERIAL AND METHODS A total of 2430 transplant biopsy cases were registered in the web-based J-RBR from January 2007 to January 2018. We categorized the entries regarding both the purpose of the biopsy and pathological diagnosis, and confirmed transplant glomerular diseases based on the clinical and pathological diagnosis. RESULTS Of the 2430 total transplant biopsy cases, 637 cases, including 9 cases of baseline biopsy, 216 cases of protocol biopsy, and 232 cases of episode biopsy, had a pathological diagnosis, including glomerular diseases, rejection, calcineurin inhibitor nephropathy, and interstitial fibrosis and tubular atrophy. Of these, 127 cases presented with glomerular disease, including 8 cases of baseline biopsy, 23 of protocol biopsy, 59 of episode biopsy, and 37 of unknown purpose). A total of 127 biopsies with glomerular disease revealed a high prevalence of immunoglobulin A nephropathy (n=38, 29.9%), followed by mesangial proliferative glomerulonephritis (n=29, 22.8%) and focal segmental glomerulosclerosis (n=8, 6.3%) when focused on protocol and episode biopsies. CONCLUSIONS The nationwide transplant biopsy database demonstrated the pathological characteristics of 637 cases, including 127 cases of post-transplant glomerular disease. The protocol and episode biopsies included high prevalence rates of IgAN, followed by FSGS.


The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors.
The BBSome, a complex of eight Bardet-Biedl syndrome (BBS) proteins involved in cilia function, has emerged as an important regulator of energy balance, but the underlying cellular and molecular mechanisms are not fully understood. Here, we show that the control of energy homeostasis by the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons require intact BBSome. Targeted disruption of the BBSome by Bbs1 gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the Bbs1 gene in POMC neurons is associated with hyperphagia. Mechanistically, we present evidence implicating the BBSome in the trafficking of G protein-coupled neuropeptide Y Y2 receptor (NPY2R) and serotonin 5-hydroxytryptamine (HT)2C receptor (5-HT2CR) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HT2CR, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HT2cR agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HT2CR to be stalled in the late endosome. Our results demonstrate the significance of the hypothalamic BBSome for the control of energy balance through regulation of trafficking of important metabolic receptors.


Study of the potential spermatogonial stem cell compartment in dogfish testis, Scyliorhinus canicula L.
In the lesser-spotted dogfish (Scyliorhinus canicula), spermatogenesis takes place within spermatocysts made up of Sertoli cells associated with stage-synchronized germ cells. As shown in testicular cross sections, cysts radiate in maturational order from the germinative area, where they are formed, to the opposite margin of the testis, where spermiation occurs. In the germinative zone, which is located in a specific area between the tunica albuginea of the testis and the dorsal testicular vessel, individual large spermatogonia are surrounded by elongated somatic cells. The aim of this study has been to define whether these spermatogonia share characteristics with spermatogonial stem cells described in vertebrate and non-vertebrate species. We have studied their ultrastructure and their mitotic activity by 5'-bromo-2'-deoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) immunodetection. Additionally, immunodetection of c-Kit receptor, a marker of differentiating spermatogonia in rodents, and of alpha- and beta-spectrins, as constituents of the spectrosome and the fusome, has been performed. Ultrastructurally, nuclei of stage I spermatogonia present the same mottled aspect in dogfish as undifferentiated spermatogonia nuclei in rodents. Moreover, intercellular bridges are not observed in dogfish spermatogonia, although they are present in stage II spermatogonia. BrdU and PCNA immunodetection underlines their low mitotic activity. The presence of a spectrosome-like structure, a cytological marker of the germline stem cells in Drosophila, has been observed. Our results constitute the first step in the study of spermatogonial stem cells and their niche in the dogfish.


Improvement in neonatal intensive care unit care: a cluster randomised controlled trial of active dissemination of information.
Research findings are not rapidly or fully implemented into policies and practice in care. To assess whether an 'active' strategy was more likely to lead to changes in policy and practice in preterm baby care than traditional information dissemination. Cluster randomised trial. 180 neonatal units (87 active, 93 control) in England; clinicians from active arm units; babies born <27 weeks gestation. CONTROL ARM: Dissemination of research report; slides; information about newborn care position statement. ACTIVE ARM: As above plus offer to become 'regional 'champion' (attend two workshops, support clinicians to implement research evidence regionally), or attend one workshop, promote implementation of research evidence locally. timing of surfactant administration; admission temperature; staffing of resuscitation team present at birth. 48/87 Lead clinicians in the active arm attended one or both workshops. There was no evidence of difference in post-intervention policies between trial arms. Practice outcomes based on babies in the active (169) and control arms (186), in 45 and 49 neonatal units respectively, showed active arm babies were more likely to have been given surfactant on labour ward (RR=1.30; 95% CI 0.99 to 1.70); p=0.06); to have a higher temperature on admission to neonatal intensive care unit (mean difference=0.29(o)C; 95% CI 0.22 to 0.55; p=0.03); and to have had the baby's trunk delivered into a plastic bag (RR=1.27; 95% CI 1.01 to 1.60; p=0.04) than the control group. The effect on having an 'ideal' resuscitation team at birth was in the same direction of benefit for the active arm (RR=1.18; 95% CI 0.97 to 1.43; p=0.09). The costs of the intervention were modest. This is the first trial to evaluate methods for transferring information from neonatal research into local policies and practice in England. An active approach to research dissemination is both feasible and cost-effective. Current controlled trials ISRCTN89683698.


A dominantly acting murine allele of Mcm4 causes chromosomal abnormalities and promotes tumorigenesis.
Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance, while mice homozygous for the mutation die early during embryonic development. Sdl mice exhibit an increase in the frequency of micronucleated reticulocytes, and T-ALLs from Sdl mice harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Using exome sequencing it was determined that Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4(D573H)). MCM4 is part of the heterohexameric complex of MCM2-7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at replication forks. Previous studies in murine models have discovered that genetic reductions of MCM complex levels promote tumor formation by causing genomic instability. However, Sdl mice possess normal levels of Mcms, and there is no evidence for loss-of-heterozygosity at the Mcm4 locus in Sdl leukemias. Studies in Saccharomyces cerevisiae indicate that the Sdl mutation produces a biologically inactive helicase. Together, these data support a model in which chromosomal abnormalities in Sdl mice result from the ability of MCM4(D573H) to incorporate into MCM complexes and render them inactive. Our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences by causing chromosomal abnormalities.


Engagement and retention: measuring breadth and depth of participant use of an online intervention.
The Internet provides us with tools (user metrics or paradata) to evaluate how users interact with online interventions. Analysis of these paradata can lead to design improvements. The objective was to explore the qualities of online participant engagement in an online intervention. We analyzed the paradata in a randomized controlled trial of alternative versions of an online intervention designed to promote consumption of fruit and vegetables. Volunteers were randomized to 1 of 3 study arms involving several online sessions. We created 2 indirect measures of breadth and depth to measure different dimensions and dynamics of program engagement based on factor analysis of paradata measures of Web pages visited and time spent online with the intervention materials. Multiple regression was used to assess influence of engagement on retention and change in dietary intake. Baseline surveys were completed by 2513 enrolled participants. Of these, 86.3% (n = 2168) completed the follow-up surveys at 3 months, 79.6% (n = 2027) at 6 months, and 79.4% (n = 1995) at 12 months. The 2 tailored intervention arms exhibited significantly more engagement than the untailored arm (P < .01). Breadth and depth measures of engagement were significantly associated with completion of follow-up surveys (odds ratios [OR] = 4.11 and 2.12, respectively, both P values < .001). The breadth measure of engagement was also significantly positively associated with a key study outcome, the mean increase in fruit and vegetable consumption (P < .001). By exploring participants' exposures to online interventions, paradata are valuable in explaining the effects of tailoring in increasing participant engagement in the intervention. Controlling for intervention arm, greater engagement is also associated with retention of participants and positive change in a key outcome of the intervention, dietary change. This paper demonstrates the utility of paradata capture and analysis for evaluating online health interventions. NCT00169312; http://clinicaltrials.gov/ct2/show/NCT00169312 (Archived by WebCite at http://www.webcitation.org/5u8sSr0Ty).


Effect of the threat of a disulfiram-ethanol reaction on cue reactivity in alcoholics.
Little is known about the effect of disulfiram on subjective and autonomic nervous system cue reactivity in the laboratory. The dissuasive psychological effect manifested as a threat would seem to prevail over the pharmacological effect. The primary objective was to determine whether there was a difference in cue reactivity responses during a threat condition compared to a neutral condition during alcohol cue exposure. In a crossover randomized study, participants received threat and neutral messages during two cue exposure sessions. The threat condition consisted of leading the patients to believe they had ingested 500 mg of disulfiram and the neutral condition of informing them that they had ingested a placebo, while in both condition they received the same placebo. Physiological cue reactivity was demonstrated by a decrease in diastolic blood pressure during the threat compared to the neutral condition (p=0.04). Heart rate and subjective cue reactivity measures remained unchanged. There was a negative affect (assessed by the Positive and Negative Affect Scale) by condition by exposure interaction. The threat of a disulfiram-ethanol reaction appears to affect cue reactivity physiologically rather than subjectively. While the data does not show changes in subjective ratings, it is possible that there are alternative beneficial effects arising from other cognitive processes that are not captivated by self-reported craving scales, reflected by decreases in negative affect and blood pressure. From this perspective, disulfiram might be recast to be more acceptable to patients.


Hydrogen bonding described using dispersion-corrected density functional theory.
In recent works, dispersion-corrected atom-centered potentials (DCACPs) were developed as a method to account for long-range dispersion forces between molecules in density functional theory calculations within the generalized gradient approximation (GGA). Here, we test the ability of DCACPs to improve the GGA treatment of hydrogen-bonded systems. We assessed both BLYP and dispersion-corrected BLYP with respect to benchmark calculations for the hydrogen bond lengths and binding energies of 20 complexes containing the elements C, H, N, O, and S. Benchmark data included geometries calculated using MP2 and CCSD(T) and binding energies using W2, W1, CBS-QB3, and other CCSD(T) extrapolation schemes. With respect to benchmark methods, dispersion-corrected BLYP exhibited a mean signed error of 0.010 A in the hydrogen bond length and a mean relative error of 5.1% in the hydrogen bond binding energy. By comparison, uncorrected BLYP exhibited error statistics of 0.036 A and 15.9%, respectively. We conclude that DCACPs robustly improve the BLYP description of hydrogen-bonded systems at small additional computational cost. New benchmark geometries (MP2/aug-cc-pVTZ) and new benchmark binding energies (W1) are presented for seven complexes, and the remaining benchmark data were taken from previous literature.


Segmentation and analysis of the three-dimensional redistribution of nuclear components in human mesenchymal stem cells.
To better understand the impact of changes in nuclear architecture on nuclear functions, it is essential to quantitatively elucidate the three-dimensional organization of nuclear components using image processing tools. We have developed a novel image segmentation method, which involves a contrast enhancement and a subsequent thresholding step. In addition, we have developed a new segmentation method of the nuclear volume using the fluorescent background signal of a probe. After segmentation of the nucleus, a first-order normalization is performed on the signal positions of the component of interest to correct for the shape of the nucleus. This method allowed us to compare various signal positions within a single nucleus, and also on pooled data obtained from multiple nuclei, which may vary in size and shape. The algorithms have been tested by analyzing the spatial localization of nuclear bodies in relation to the nuclear center. Next, we used this new tool to study the change in the spatial distribution of nuclear components in cells before and after caspase-8 activation, which leads to cell death. Compared to the morphological TopHat method, this method gives similar but significantly faster results. A clear shift in the radial distribution of centromeres has been found, while the radial distribution of telomeres was changed much less. In addition, we have used this new tool to follow changes in the spatial distribution of two nuclear components in the same nucleus during activation of apoptosis. We show that after caspase-8 activation, when centromeres shift to a peripheral localization, the spatial distribution of PML-NBs does not change while that of centromeres did. We propose that the use of this new image segmentation method will contribute to a better understanding of the 3D spatial organization of the cell nucleus.


Historical and contemporary population genetic connectivity of the European short-snouted seahorse Hippocampus hippocampus and implications for management.
This first genetic study of Hippocampus hippocampus covers the species' entire geographic range and employs two mtDNA markers (control region and cytochrome b) to establish patterns of population structuring. A total of 255 specimens from 21 locations were used to obtain 89 concatenated haplotypes. The common haplotype was present in all but one population, however, most haplotypes were unique. The haplotype network had a star-like construction, suggesting expansion from a bottleneck event. F(ST) and AMOVA revealed population subdivision into three geographic regions (English Channel + Bay of Biscay, Mediterranean Sea + Atlantic Ocean Iberian coast + Macaronesian Islands, and West Africa) with barriers to gene flow indentified at Cape Finisterre and the Cape Verde frontal zone. Neutrality tests and nested clade analysis suggest a complex demographic history, with both historic events and contemporary processes shaping patterns of genetic differentiation. The genetic population subdivision detected in this study indicates that H. hippocampus should be managed as three separate units. This is especially pertinent as H. hippocampus populations within the West African region are the only ones known to be specifically targeted for exploitation.


Antioxidants in eggs of great tits Parus major from Chernobyl and hatching success.
Antioxidants are powerful protectors against the damaging effects of free radicals that constitute the inevitable by-products of aerobic metabolism. Growing embryos are particularly susceptible to the damaging effects of free radicals produced during rapid growth, and mothers of many species provide protection against such damage by allocating antioxidants to their eggs. Birds living in radioactively contaminated areas use dietary antioxidants to cope with the damaging effects of radiation, but females also allocate dietary antioxidants to eggs, potentially enforcing a physiological trade-off between self-maintenance and reproductive investment. Here we tested whether female great tits Parus major breeding in radioactively contaminated study areas near Chernobyl allocated less dietary antioxidants to eggs, and whether such reduced allocation of dietary antioxidants to eggs had fitness consequences. Concentrations of total yolk carotenoids and vitamins A and E were depressed near Chernobyl compared to concentrations in a less contaminated Ukrainian study area and a French control study area, and all antioxidants showed dose-dependent relationships with all three dietary antioxidants decreasing with increasing level of radiation at nest boxes. These effects held even when controlling statistically for potentially confounding habitat variables and covariation among antioxidants. Laying date was advanced and clutch size increased at nest boxes with high dose rates. Hatching success increased with increasing concentration of vitamin E, implying that hatching success decreased at boxes with high levels of radiation, eventually eliminating and even reversing the higher potential reproductive output associated with early reproduction and large clutch size. These findings are consistent with the hypothesis that radioactive contamination reduced levels of dietary antioxidants in yolks, with negative consequences for hatching success and reproductive success.


Evaluation of myocardial viability with iodine-123-BMIPP in a canine model.
The tracer 123I-BMIPP was examined for its ability to reflect myocardial lipid metabolism. Studies in mice indicate that myocardial BMIPP uptake correlates with ATP content. Details, however, of myocardial accumulation in the ischemic period with either infarct or ischemia are not well documented. Sixteen adult mongrel dogs were investigated. The occluded left anterior descending artery (LAD) alone was reperfused to make the ischemic area, and the first diagonal branch of the LAD was kept occluded to make the infarct area. Regional wall motion was evaluated by echocardiography in the short-axial view from the epicardium. Tissue blood flow was calculated using nonradioactive colored microspheres. Changes in blood glucose levels, lipid levels and lactate extraction were examined in blood collected from the aorta and great cardiac vein (GCV). The ATP concentration and BMIPP count were determined by high-performance liquid chromatography and gamma-counter, respectively. Two hours after reperfusion, blood flow decreased to 20% +/- 5% in the infarct area and 64% +/- 9% in the ischemic area (p < 0.05), despite comparable wall-motion reduction (32% +/- 5% and 42% +/- 12% in the infarct and ischemic areas, respectively). BMIPP content and ATP concentration showed parallel reduction: 40% +/- 7% and 75% +/- 4% (p < 0.05) of BMIPP and 32% +/- 9% and 69% +/- 7% (p < 0.05) of ATP in the infarct and ischemic areas, respectively. The nonesterified fatty acid extraction, defined as flow x ([artery] - [GCV]), decreased to 87% +/- 5.6% during occlusion and 75% +/- 20.1% 2 hr after reperfusion, as compared with the control value. BMIPP uptake correlated well with lipid metabolism and tissue ATP levels and may prove useful in differentiating myocardial infarction from ischemia in the acute phase of ischemic episodes.


Antioxidant properties of alpha-lipoic acid: effects on red blood membrane permeability and adaptation of isolated rat heart to reversible ischemia.
The aim of our work was to study (1) the antioxidant properties of lipoic acid (LA) and its reduced metabolite dihydrolipoic acid (DHLA) formed by reduction of LA and (2) the effects of treatment with LA and DHLA on (a) K(+) efflux from human red blood cells and (b) post-ischemic recovery and oxidative stress in isolated perfused rat hearts challenged with an ischemia-reperfusion (IR) sequence. In vitro, we used xanthine and xanthine oxidase to generate superoxide anion, which is not directly measurable by electron paramagnetic resonance (EPR), but specifically oxidizes the spin probe CPH into an EPR-detectable long lasting CP(*) nitroxide radical. While 5 mM of LA was ineffective in reducing the kinetics of CP(*) nitroxide formation, DHLA was shown to lessen this rate in a dose-dependent manner and at 30 mM was even more efficient than 300 UI/ml SOD. These results are in agreement with the fact that DHLA is able to directly scavenge superoxide anion. Red cells are a good model to investigate oxidative damage in biological membranes; hence, we used a suspension of erythrocytes incubated with 2,2(')-azobis(2-amidinopropane) hydrochloride (AAPH) which generates in vitro free radicals. DHLA provided more effective protection of red cells membranes than LA; DHLA was comparable to Trolox for its antioxidant potency. In vivo, treatment of rats (50 mg/kg/day i.p. for 7 days) with LA induced a slight increase in coronary flow (CF) in isolated perfused hearts, after 30 min of global total ischemia. This effect was not associated with an improvement in contractile function and reduction of myocardial oxidative stress. In conclusion, because of their ability to scavenge free radicals, LA and to an even greater degree DHLA were able to protect the membranes of red blood cells. This finding suggests that LA and DHLA might be useful in the treatment of diseases associated with oxidative stress such as diabetes.


Comparative therapeutic evaluation of different topicals and narrow band ultraviolet B therapy combined with systemic methotrexate in the treatment of palmoplantar psoriasis.
The incidence of uncomplicated psoriasis is 1-3% in the general population. The involvement of palm and sole is seen in 7-14.5% of cases. There are different topicals and systemic therapies available for treating the case of psoriasis but none is satisfactory for longer duration. The study involved the comparative therapeutic evaluation of the different topical regimens and narrow band ultraviolet B (NB-UVB) therapy in combination with systemic methotrexate. The study was held in out-patient department of Skin, VD and Leprosy of B.R.D. Medical College, Gorakhpur, from July 2007 to December 2008. The group included 98 new cases of palmoplantar psoriasis. These cases were divided into eight groups according to the eight regimens involved in the study. The severity of psoriasis was assessed by the ESIF (erythema, scaling, induration and fissuring) score. The study showed that all the regimens had significant response rates. The combination of NB-UVB with systemic methotrexate had maximum response rate (64.85±4.52%) that was statistically significant (paired "t" at 16d.f. = 33.329, P<0.001) with minimum number of recurrences after stopping the treatment. The combination of halobetasol ointment with systemic methotrexate also had significant response rate (paired "t" at 19d.f. = 13.5183, P<0.001) but had maximum number of cases with recurrence (70%) after stopping the treatment. These results suggest that the combination of every regimen with systemic methotrexate resulted in an early and a good improvement in the quality of life of patients suffering from psoriasis. It also shows that NB-UVB in combination with systemic methotrexate is more efficacious and has minimum recurrence rate and side effects in the treatment of palmoplantar psoriasis.


Oral treatment with royal jelly improves memory and presents neuroprotective effects on icv-STZ rat model of sporadic Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in cognitive function. Intracerebroventricular injection of streptozotocin (icv-STZ) has been used as an experimental model of Sporadic AD (SAD) in rodents and represents a promising tool for etiopathogenic analysis and evaluation of new therapeutic proposals for AD. The icv-STZ model shows many aspects of SAD abnormalities, resulting in decreased brain glucose and energy metabolism, cognitive impairment, oxidative stress, neuronal loss, and amyloid angiopathy. Royal jelly (RJ), a substance produced by worker honeybees of the Apis mellifera species, has been popularly used for more than 30 years in areas related to health eating and natural medicine. Researches indicate that RJ has a several pharmacological activities, including neuroprotective and improvement of cognitive function. The objective of this study was to investigate the effects of oral treatment with royal jelly during 2 weeks in Wistar rats submitted to icv-STZ on a working memory and neuroprotection, as evaluated by neurogenesis, neurodegeneration and oxidative stress. In this study, icv-STZ injection induced deleterious effects in the hippocampus, associated with cognitive impairments, and developed marked neurodegeneration, besides the reduction of neurogenesis and increased oxidative stress. On the other hand, RJ long-term oral administration induced beneficial effects in animals injured by icv-STZ injection, increasing retention time for working spatial memory, reducing neurodegeneration and oxidative stress level and increasing the proliferation of new neurons in the hippocampus. Thus, RJ promotes beneficial effects on cognitive functions and exhibits a neuroprotective action in the STZ experimental model of SAD.


Stent Maps--Comparative Visualization for the Prediction of Adverse Events of Transcatheter Aortic Valve Implantations.
Transcatheter aortic valve implantation (TAVI) is a minimally-invasive method for the treatment of aortic valve stenosis in patients with high surgical risk. Despite the success of TAVI, side effects such as paravalvular leakages can occur postoperatively. The goal of this project is to quantitatively analyze the co-occurrence of this complication and several potential risk factors such as stent shape after implantation, implantation height, amount and distribution of calcifications, and contact forces between stent and surrounding structure. In this paper, we present a two-dimensional visualization (stent maps), which allows (1) to comprehensively display all these aspects from CT data and mechanical simulation results and (2) to compare different datasets to identify patterns that are typical for adverse effects. The area of a stent map represents the surface area of the implanted stent - virtually straightened and uncoiled. Several properties of interest, like radial forces or stent compression, are displayed in this stent map in a heatmap-like fashion. Important anatomical landmarks and calcifications are plotted to show their spatial relation to the stent and possible correlations with the color-coded parameters. To provide comparability, the maps of different patient datasets are spatially adjusted according to a corresponding anatomical landmark. Also, stent maps summarizing the characteristics of different populations (e.g. with or without side effects) can be generated. Up to this point several interesting patterns have been observed with our technique, which remained hidden when examining the raw CT data or 3D visualizations of the same data. One example are obvious radial force maxima between the right and non-coronary valve leaflet occurring mainly in cases without leakages. These observations confirm the usefulness of our approach and give starting points for new hypotheses and further analyses. Because of its reduced dimensionality, the stent map data is an appropriate input for statistical group evaluation and machine learning methods.


Binary mixtures of disks and elongated particles: Texture and mechanical properties.
We analyze the shear strength and microstructure of binary granular mixtures consisting of disks and elongated particles by varying systematically both the mixture ratio and degree of homogeneity (from homogeneous to fully segregated). The contact dynamics method is used for numerical simulations with rigid particles interacting by frictional contacts. A counterintuitive finding of this work is that the shear strength, packing fraction, and, at the microscopic scale, the fabric, force, and friction anisotropies of the contact network are all nearly independent of the degree of homogeneity. In other words, homogeneous mixtures have the same strength properties as segregated packings of the two particle shapes. In contrast, the shear strength increases with the proportion of elongated particles correlatively with the increase of the corresponding force and fabric anisotropies. By a detailed analysis of the contact network topology, we show that various contact types contribute differently to force transmission and friction mobilization.


Is Healthy Neuroticism Associated with Longevity? A Coordinated Integrative Data Analysis.
Individual differences in the Big Five personality traits have emerged as predictors of health and longevity. Although there are robust protective effects for higher levels of conscientiousness, results are mixed for other personality traits. In particular, higher levels of neuroticism have significantly predicted an increased risk of mortality, no-risk at all, and even a reduced risk of dying. The current study hypothesizes that one potential reason for the discrepancy in these findings for neuroticism is that interactions among neuroticism and other key personality traits have largely been ignored. Thus, in the current study we focus on testing whether the personality traits neuroticism and conscientiousness interact to predict mortality. Specifically, we borrow from recent evidence of "healthy neuroticism" to explore whether higher levels of neuroticism are only a risk factor for increased mortality risk when conscientiousness levels are low. We conducted a pre-registered integrative data analysis using 12 different cohort studies (total N = 44,702). Although a consistent pattern emerged of higher levels of conscientiousness predicting a reduced hazard of dying, neuroticism did not show a consistent pattern of prediction. Moreover, no study provided statistical evidence of a neuroticism by conscientiousness interaction. The current findings do not support the idea that the combination of high conscientiousness and high neuroticism can be protective for longevity. Future work is needed to explore different protective factors that may buffer the negative effects of higher levels of neuroticism on health, as well as other behaviors and outcomes that may support the construct of healthy neuroticism.


Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis.
We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc1 complex and the risk of targeting energy metabolism with new drugs.


Data on the working population in Spain related to training, workplace conditions and accident rates.
Obtaining data on worker accident rates is necessary in order to analyze the causes and variables involved in the occurrence of said accidents. The majority of these data, collected after the accident occurs, do not consider the employee׳s working conditions. Here are presented the data on workplace accidents and the conditions of the workers by analyzing the generic data supplied as part of the 7th National Survey of Workplace Conditions (EWCS) in Spain, conducted in 2011. These data will yield the variables needed to determine if the information on workplace risks provided by the survey respondents has an appreciable effect on the occurrence of occupational accidents in the working population, and will also be used to explore other variables.


The motor system contributes to comprehension of abstract language.
If language comprehension requires a sensorimotor simulation, how can abstract language be comprehended? We show that preparation to respond in an upward or downward direction affects comprehension of the abstract quantifiers "more and more" and "less and less" as indexed by an N400-like component. Conversely, the semantic content of the sentence affects the motor potential measured immediately before the upward or downward action is initiated. We propose that this bidirectional link between motor system and language arises because the motor system implements forward models that predict the sensory consequences of actions. Because the same movement (e.g., raising the arm) can have multiple forward models for different contexts, the models can make different predictions depending on whether the arm is raised, for example, to place an object or raised as a threat. Thus, different linguistic contexts invoke different forward models, and the predictions constitute different understandings of the language.


Cloning and characterization of pectate lyases expressed in the esophageal gland of the pine wood nematode Bursaphelenchus xylophilus.
Two pectate lyase genes (Bx-pel-1 and Bx-pel-2) were cloned from the pine wood nematode, Bursaphelenchus xylophilus. The deduced amino acid sequences of these pectate lyases are most similar to polysaccharide lyase family 3 proteins. Recombinant BxPEL1 showed highest activity on polygalacturonic acid and lower activity on more highly methylated pectin. Recombinant BxPEL1 demonstrated full dependency on Ca2+ for activity and optimal activity at 55 degrees C and pH 8 to 10 like other pectate lyases of polysaccharide lyase family 3. The protein sequences have predicted signal peptides at their N-termini and the genes are expressed solely in the esophageal gland cells of the nematode, indicating that the pectate lyases could be secreted into plant tissues to help feeding and migration in the tree. This study suggests that pectate lyases are widely distributed in plant-parasitic nematodes and play an important role in plant-nematode interactions.


Comparison of methods of teaching children proper lifting techniques.
This study was designed to determine the effects of two teaching methods on children's ability to demonstrate and recall their mastery of proper lifting techniques. Seventy-six third and fifth grade public school children were divided by grade into three groups. Two of the groups (experimental) were taught the correct method for lifting a heavy object, either by lecture demonstration or guided discovery teaching format; one group (control) was not taught. The students' knowledge was measured pretest, one-week posttest, and eight-week posttest with a written and practical test. The students in the experimental groups in both grades significantly (p less than or equal to .001) increased their scores on the written portion of the test over those of the control groups on the one-week posttest. No group, however, showed significant gains on the practical portion. No differences were found between teaching methods. Results of this study stress the importance of evaluating verbally learned motor skills in a practical application format in school settings and in clinical patient education.


Toward population impact from early childhood psychological interventions.
Acting alone, psychologists rarely achieve population impact on important mental health and well-being outcomes for families and young children. The traditional Institute of Medicine model of moving from efficacy trials to effectiveness trials to scaling up has not succeeded, partly due to degradation of program quality and impact during scale-up and partly due to a failure to consider system-context issues at the outset. Analysis of barriers to population impact leads to the proposal of a new comprehensive system of care that includes both top-down coordination among community agencies providing services and bottom-up outreach to every family to connect them with services. The North Carolina Smart Start Initiative is a top-down approach to improving the community-level quality of early childcare and education services. A natural experiment demonstrates that it improves population indicators of children's education outcomes. Family Connects is a bottom-up approach that reaches all families giving birth in a community through brief home visits to assess needs and connect families with community resources. A randomized controlled trial reveals increased community connectedness, lower maternal anxiety, reduced emergency health episodes, and lower rates of investigations for child abuse. These initiatives point toward the promise of population impact through psychological interventions in early life that are delivered in a collaborative system of care. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Biosynthesis of phenylnannolone A, a multidrug resistance reversal agent from the halotolerant myxobacterium Nannocystis pusilla B150.
The myxobacterial strain Nannocystis pusilla B150 synthesizes the structurally new polyketides phenylnannolone A–C. Apart from some common volatiles and siderophores, these are the first natural products from the genus Nannocystis. Phenylnannolone A shows inhibitory activity towards the ABCB1 gene product P-glycoprotein and reverses daunorubicin resistance in cancer cells. To decipher the biochemical reactions leading to the formation of phenylnannolone A, the putative biosynthetic genes were identified (phn1, phn2). Phn2 is a polyketide synthase (PKS) with an NRPS-like loading module, and its domain order is consistent with the phenylnannolone A structure. The functionality and substrate selectivity of the loading module were determined by means of a γ-18O4-ATP pyrophosphate exchange and a phosphopantetheine ejection assay. A specific activation of cinnamic acid by the AMP-ligase was detected. Phn1 is a putative butyryl-CoA carboxylase (BCC), providing ethylmalonyl-CoA for the formation of the ethyl-substituted part of phenylnannolone A. Phn1 is the first BCC found in biosynthetic genes for an ethyl-substituted natural compound. Biosynthesis of phenylnannolone A, putatively encoded by phn1 and phn2, thus utilizes the first biosynthetic machinery in which both a BCC and a PKS are involved.


Numerical processing of speckle photography data by Fourier transform.
Using a 1-D analysis of a double-exposed specklegram, we explore the influence of the diffraction halo removal in the numerical processing of data when it is done via discrete Fourier transform. Relative errors in displacements appear if the removal is not done, and they increase as fringe visibility and fringe density decrease. These errors are <0.5% for fringe densities larger than six fringes within the diffraction halo.


Robustness of model-based high-resolution prediction of forest biomass against different field plot designs.
Participatory forest monitoring has been promoted as a means to engage local forest-dependent communities in concrete climate mitigation activities as it brings a sense of ownership to the communities and hence increases the likelihood of success of forest preservation measures. However, sceptics of this approach argue that local community forest members will not easily attain the level of technical proficiency that accurate monitoring needs. Thus it is interesting to establish if local communities can attain such a level of technical proficiency. This paper addresses this issue by assessing the robustness of biomass estimation models based on air-borne laser data using models calibrated with two different field sample designs namely, field data gathered by professional forester teams and field data collected by local communities trained by professional foresters in two study sites in Nepal. The aim is to find if the two field sample data sets can give similar results (LiDAR models) and whether the data can be combined and used together in estimating biomass. Results show that even though the sampling designs and principles of both field campaigns were different, they produced equivalent regression models based on LiDAR data. This was successful in one of the sites (Gorkha). At the other site (Chitwan), however, major discrepancies remained in model-based estimates that used different field sample data sets. This discrepancy can be attributed to the complex terrain and dense forest in the site which makes it difficult to obtain an accurate digital elevation model (DTM) from LiDAR data, and neither set of data produced satisfactory results. Field sample data produced by professional foresters and field sample data produced by professionally trained communities can be used together without affecting prediction performance provided that the correlation between LiDAR predictors and biomass estimates is good enough.


Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.
The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.


Accelerating Pathology Image Data Cross-Comparison on CPU-GPU Hybrid Systems.
As an important application of spatial databases in pathology imaging analysis, cross-comparing the spatial boundaries of a huge amount of segmented micro-anatomic objects demands extremely data- and compute-intensive operations, requiring high throughput at an affordable cost. However, the performance of spatial database systems has not been satisfactory since their implementations of spatial operations cannot fully utilize the power of modern parallel hardware. In this paper, we provide a customized software solution that exploits GPUs and multi-core CPUs to accelerate spatial cross-comparison in a cost-effective way. Our solution consists of an efficient GPU algorithm and a pipelined system framework with task migration support. Extensive experiments with real-world data sets demonstrate the effectiveness of our solution, which improves the performance of spatial cross-comparison by over 18 times compared with a parallelized spatial database approach.


Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.
Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML.


Development and evaluation of a dual density insole for people standing for long periods of time at work.
Appropriate footwear is important for those who stand for prolonged periods of time at work, enabling them to remain comfortable, healthy and safe. Preferences for different footwear cushioning or hardness are often person specific and one shoe or insole will not be the choice for all. The aim of this study was to develop a range of insole options to maintain comfort during long periods of standing at work and test insole material preferences in the workplace. The study consisted of two parts. Part one evaluated 9 insoles of the same geometry that varied in hardness under 2 different plantar regions (n = 34). Insole preference, plantar pressure and selected anthropometric foot measures were taken. Three insole designs based on the most preferred options were identified from this part. In part two, these three insoles were evaluated with 22 workers immediately after trying them on (1 min) and after a working day. Foot anthropometric measures and subjective questions concerning material hardness preferences and self-reported foot characteristics were used to investigate whether either had a relationship with insole preference. Part one found insole preference predominantly varied according to material hardness under the medial arch rather than the heel/forefoot. Softer material under the heel and forefoot was associated with a reduction in peak pressures in these regions (p < 0.05). The most preferred insole had lower pressures under the hallux and first metatarsal phalangeal joint, and greater pressures and contact area under the medial midfoot (p < 0.05) compared to the least preferred insole. Height and foot anthropometrics were related to insole preference. In part two, under real world conditions, insole preference changed for 65% of participants between the immediate assessment (1 min) and after a whole workday, with dorsum height related to the latter (p < 0.05). Subjective questions for self-assessed arch height and footwear feel identified 66.7% of the insole preferences after 1 day at work, compared to 36% using immediate assessment of insole preference. Preference for material hardness varies underneath the medial arch of the foot and is time dependent. Simple foot measures and questions about comfort can guide selection of preferred insoles.


Design and analysis of radial imaging capsule endoscope (RICE) system.
In this study, a radial imaging capsule endoscope (RICE) system is designed, which differs from a conventional front imaging capsule endoscope (FICE) system. To observe the wrinkled intima of the intestine, which spreads without folding around the circumference of the capsule when a capsule endoscope with a diameter that slightly exceeds that of the intestine passes through it, the RICE uses a cone mirror, a radial window shell, and a focus optical module that comprise the radial imaging system. This concept was demonstrated in a packaged optical simulator. The RICE optical model also has been established and verified by many simulations and experiments. In minimizing the sagittal and tangential aberrations, the optical module of the RICE has achieved an F-number of 4.2, a viewing angle of 65.08°, and an RMS radius of the 4th to 6th fields of less than 17 um. A comparison of these characteristics with those of the focus optical module that is used in FICE lenses reveals that the spot size is 50% larger for each field, and the modulation transfer function (MTF) is remarkably improved from 7% to 36% at 100 lp/mm on the 5th field of the sagittal plane.


Obstructive sleep apnea and cardiac arrhythmias.
Sleep-disordered breathing (SDB), which includes obstructive sleep apnea (OSA) as its most extreme variant, is characterized by intermittent episodes of partial or complete obstruction of the upper airway, leading to cessation of breathing while asleep. Cardiac arrhythmias are common problems in OSA patients, although the true prevalence and clinical relevance of cardiac arrhythmias remains to be determined. The presence and complexity of tachyarrhythmias and bradyarrhythmias may influence morbidity, mortality and quality of life for patients with OSA. Although the exact mechanisms underlying the link between OSA and cardiac arrhythmias are not well established, they could be some of the same proposed mechanisms relating OSA to different cardiovascular diseases, such as repetitive pharyngeal collapse during sleep, which leads to markedly reduced or absent airflow, followed by oxyhemoglobin desaturation, persistent inspiratory efforts against an occluded airway and termination by arousal from sleep. These mechanisms elicit a variety of autonomic, hemodynamic, humoral and neuroendocrine responses that evoke acute and chronic changes in cardiovascular function. However, despite substantial research effort, the goals of determining in advance which patients will respond most favorably to certain treatment options (such as continuous positive airway pressure, tracheostomy or cardioversion) and the developing alternative treatments remain largely elusive. Therefore, this literature review aims to summarize a broad array of the pathophysiological mechanisms underlying the relationship between OSA and cardiac arrhythmias and the extent of this association from an epidemiological perspective, thereby attempting to assess the effects of OSA treatment on the presence of cardiac arrhythmias.


The IL-8 protease SpyCEP is detrimental for Group A Streptococcus host-cells interaction and biofilm formation.
SpyCEP-mediated chemokine degradation translates into more efficient spreading and increased severity of invasive Group A Streptococcus (GAS) infections, due to impaired neutrophil recruitment to the site of infection. SpyCEP is markedly up-regulated in invasive as compared to colonizing GAS isolates raising the question whether SpyCEP expression hinders bacterial attachment and thus colonization of the host. To address this question we used a molecular approach involving the use of homologous GAS strains either expressing or not SpyCEP or expressing an enzymatically inactive variant of SpyCEP. We found that expression of enzymatically functional SpyCEP lowered GAS adherence and invasion potential toward various epithelial and endothelial cells. SpyCEP also blunted biofilm formation capacity. Our data indicate that expression of SpyCEP decreases colonization and thus might be detrimental for the spreading of GAS.


Developing explanatory models of health inequalities in childhood dental caries.
Long-term aim is to determine optimum interventions to reduce dental caries in children in disadvantaged communities and minimise the effects of exclusion from health care systems, of ethnic diversity, and health inequalities. Generation of initial explanatory models, study protocol and development of two standardised measures. First, to investigate how parental attitudes may impact on their children's oral health-related behaviours and second, to assess how dentists' attitudes may impact on the provision of dental care. Core research team, lead methodologists, 44 consortium members from 18 countries. To complete the development of the questionnaire, the initial set of items was administered to parents (n = 23) with children in nursery schools in Dundee, Scotland and sent to the same parents one week later. A standardised measure examining barriers to providing dental care for children aged 3 to 6 years was developed. 20 dentists working in primary dental care in Scotland completed the measure on two different occasions separated by one week. Explanatory models were developed. Family questionnaire: test-retest reliability excellent (r = 0.93 p < or = 0.001) with very good internal reliability (alpha = 0.89). Dentists questionnaire: excellent test-re-test reliability r = 0.88, (alpha = 0.90). Interaction between consortium members enhanced the validity of the questionnaires and protocols for different cultural locations. There were challenges in developing and delivering this multi-centre study. Experience gained will support the development of substantive trials and longitudinal studies to address the considerable international health disparity of childhood dental caries.


Intraligamental Myomectomy Strategy Using Laparoscopy.
STUDY Intraligamental myomas (IMs) represent 6% to 10% of all uterine myomas. An IM growing from the lateral uterine wall into the broad ligament often presents as a large pelvic mass without symptoms. Removing a large IM can be difficult because of the limited operative field and poses challenges during conventional laparoscopic surgical approaches. The risk of injury to the ureter and uterine artery during myomectomy is greater than that during other types of myoma. Retrospective study (Canadian Task Force classification III). University-affiliated hospital. IM was classified into 3 types according to the location: (1) anterior intraligamental myoma (AIM), (2) posterior intraligamental myoma (PIM), and (3) lateral intraligamental myoma (LIM). From April 2007 to July 2015, 83 consecutive patients with IM underwent laparoscopic myomectomy at National Taiwan University Hospital, Taipei, Taiwan, including 23 AIM, 27 PIM, and 33 LIM. Several techniques are described, and videos are supplied for performing laparoscopic myomectomy safely and easily in different types of IM. Urinary frequency (31%) and a palpable abdominal mass (31%) were the 2 most common presenting symptoms. Most of the lesions were 33 LIM (40%) followed by 27 PIM (32%) and 23 AIM (28%). The mean myoma sizes were 11.0, 8.0, and 7.8 cm; the mean myoma weights were 478, 279, and 309 g; the mean operative times were 134, 108, and 104 minutes; and the mean blood loss during surgery was 224, 94, and 107 mL for LIM, PIM, and AIM, respectively. LIMs had relatively more blood loss because they were heavier and commonly rested alongside the uterine artery. The only complication was late postoperative hemorrhage in 1 case of LIM. Histopathology showed leiomyoma in all cases. Three patients were spontaneously conceived after myomectomy, and each had a successful pregnancy and cesarean delivery. Surgical treatment of IM is empirically difficult. It is important to use an approach that considers the location, size, and shape of the myoma. All types of IM presented with similar symptoms, and the highest blood loss occurred during laparoscopic myomectomy of a LIM.


Biomedical solid waste management in an Indian hospital: a case study.
The objectives of this study were: (i) to assess the waste handling and treatment system of hospital bio-medical solid waste and its mandatory compliance with Regulatory Notifications for Bio-medical Waste (Management and Handling) Rules, 1998, under the Environment (Protection Act 1986), Ministry of Environment and Forestry, Govt. of India, at the chosen KLE Society's J. N. Hospital and Medical Research Center, Belgaum, India and (ii) to quantitatively estimate the amount of non-infectious and infectious waste generated in different wards/sections. During the study, it was observed that: (i) the personnel working under the occupier (who has control over the institution to take all steps to ensure biomedical waste is handled without any adverse effects to human health and the environment) were trained to take adequate precautionary measures in handling these bio-hazardous waste materials, (ii) the process of segregation, collection, transport, storage and final disposal of infectious waste was done in compliance with the Standard Procedures, (iii) the final disposal was by incineration in accordance to EPA Rules 1998, (iv) the non-infectious waste was collected separately in different containers and treated as general waste, and (v) on an average about 520 kg of non-infectious and 101 kg of infectious waste is generated per day (about 2.31 kg per day per bed, gross weight comprising both infectious and non-infectious waste). This hospital also extends its facility to the neighboring clinics and hospitals by treating their produced waste for incineration.


Perception of surgical complications among patients, nurses and physicians: a prospective cross-sectional survey.
Several scores grade the severity of post-operative complications but it is unclear whether such scores truly reflect the perception of patients and practicing nurses and physicians. 227 patients, 143 nurses and 245 physicians independently rated the severity of 30 common post-operative complications on a numerical analogue scale from 0 (not severe at all) to 100 (extremely severe) while being blinded towards the Clavien-Dindo classification. We considered a difference in ratings of >10 to be clinically important in distinguishing between grades of severity and groups. We evaluated the level of reproducibility of responses by calculating intraclass correlation coefficients (ICC) and compared scores across severity grades and between groups using the generalized estimating equations. Reproducibility of the ratings was good for all three groups (ICCpatients 0.71 (95%-CI 0.64-0.76), ICCnurses 0.83 (0.78-0.87) and ICCphysicians 0.87 (0.83-0.90)). The participants' perceptions of the severity of complications reflected the Clavien-Dindo classification (median of grade I: 20 (IQR 10-30), grade II: 40 (31.3-52.5), grade IIIa: 50 (40-60), grade IIIb: 70 (60-75), grade IVa: 85 (80-90) and grade IVB: 95 (90-100)). Although patients' perception differed significantly from those of physicians (average difference -8.7 (95%-CI -10.4 to -6.9, p < 0.001) and nurses (difference -2.8 (-4.8 to -0.8, p = 0.007) they did not reach our thresholds for clinical importance. The severity of post-operative complications is perceived similarly by patients, nurses and physicians and reflects the Clavien-Dindo classification well. Our results support the use of Clavien-Dindo classification system as part of the shared or informed decision making process.


Spine-related disability following combat injury.
Spine-related disability for military personnel injured in combat is not known. The goal of this study was to characterize spine-related disability in a cohort of soldiers wounded in recent military operations. The authors reviewed the U.S. Army Physical Evaluation Board database medical discharge records of 450 wounded soldiers for long-term disability causing a medical discharge from active duty service. Fourteen percent of the cohort had at least one spine-related disability resulting in medical discharge from the military. For the 54 unfitting conditions attributed to back pain, 33% had no precipitating injury. Eighteen soldiers had a spinal cord injury, 10 of which were complete. The average percent disability for back pain was 11%, and the average disability for a spinal cord injury was 77%. Twenty-one percent of the soldiers with spine-related disability also had disability attributed to psychological conditions. Spine-related disability is common after combat injury, though not all spine disability is directly related to an actual injury. Spinal cord injury with persistent neurological dysfunction results in higher permanent disability.


Mammography screening: an incremental cost effectiveness analysis of two view versus one view procedures in London.
To compare the costs and effects of routine mammography screening by a single mediolateral-oblique view and two views (mediolateral-oblique plus craniocaudal) of each breast. A cost effectiveness analysis of a prospective non-randomised trial comparing one and two view mammography screening was carried out at St Margaret's Hospital, Epping. All women in the study had two view mammography. The mediolateral-oblique view was always the first image read by the radiologist. After reading the films for a clinic session, the same radiologist then went back and read both the mediolateral-oblique and craniocaudal views together. Each set of films was read by two radiologists. The main outcome measures were recall rates, number of cancers detected, screening and assessment costs, and cost effectiveness ratios. A total of 26,430 women who attended for breast screening using both one and two view mammography participated. A sample of 132 women attending for assessment provided data on the private costs incurred in attending for assessment. There was a reduction in the recall rate from 9.1% (2404 of 26,430) after one view screening to 6.7% (1760 of 26,430) after two view screening. The results also suggest that for every 10,000 women screened an additional five cancers would be detected earlier with two view screening. The additional health service screening cost associated with two view screening was estimated to be 3.63 pounds: the costs associated with one and two view screening policies were estimated to be 41.49 pounds and 32.99 pounds respectively. Private costs incurred were estimated to be 0.35 pounds per woman screened and 32.75 pounds per woman assessed. Two cost effectiveness ratios were calculated: an incremental health service cost per additional cancer detected of 4129 pounds and an incremental health service plus private cost per additional cancer detected of 2742 pounds. The sensitivity analysis suggested that the results were sensitive to relatively large changes in a number of parameters. These included screening costs, assessment costs, equipment life, and recall rates. Use of two view screening increased early cancer detection and also costs. The reduction in the recall rate with two views was not sufficiently large to make the cost of two view screening neutral. While these results are not completely generalisable, a framework is provided to allow other centres to estimate the cost effectiveness of two view screening in their locality.


Association between attitudes toward health promotion and opinions regarding organ transplants in Japan.
Health promotion activities to educate the public about health lifestyles have been performed widely in industrialized countries where chronic adult diseases have become prevalent. According to a basic principle of health promotion activities, the symptoms of many diseases are regarded as the result of inadequate health behavior, curable by modifying health behavior. It is thus possible that an exposure to health promotion activities might instill negative attitudes towards organ transplants, because program participants may conclude that persons who need an organ transplant have become unhealthy as the result of their own poor health habits. In this study, two types of surveys were undertaken to test this hypothesis. The subjects of the first cross-sectional study were 712 male and female Japanese citizens, and those of the second case-control study were 240 female company employees in Japan. In the first study, a logistic regression analysis was used and the following findings were obtained. (1) Compared with the persons who felt that they did not have enough practical knowledge about individual health practices, those who felt that they had adequate knowledge were 0.66 times less likely to support organ transplants. (2) Compared with those who were not willing to spend money on healthful things, the persons who were willing to do so were 0.51 times less likely to support organ transplants. In the second case-control study, it was revealed that the subjects who had negative attitudes towards organ transplants had consistently healthier lifestyles than did those who had positive attitudes towards organ transplants. Based upon the present findings and the nature of the basic principles of health promotion activities, we infer that community health promotion activities have a negative influence upon citizens' opinions of organ transplants. Since these findings have health policy implications, more studies are necessary to conclusively evaluate the effects of health promotion activities upon attitudes toward organ transplants.


Carbon nanotubes kirigami mechanical metamaterials.
Imparting elasticity and functionality to materials is one of the key objects of materials science research. Here, inspired by the art of kirigami, mechanical metamaterials comprising carbon nanotubes (CNTs) are hypothetically constructed. Using classical molecular dynamics (MD) simulations, a systematic study of the elastic limit, extensibility and yield stress of as-generated CNTs kirigami (CNT-k) is performed. Three designated kirigami patterns are employed to achieve high stretchability of CNTs. It is shown that CNT-k typically exhibits three distinct deformation stages, of which the first stage, which is referred to as geometric deformation, contributes quite a high proportion of the ductility. Various geometric parameters of CNT-k that influence the key mechanical properties of interest are respectively discussed. Three types of CNT-k with specifically identical geometric parameters exhibit distinct mechanical characteristics. This study provides an interesting example of interplay between the geometry, ductility, and mechanical characteristics of tubular materials.


Identification of Fabaceae plants using the DNA barcode matK.
In this study, we tested the applicability of the core DNA barcode MATK for identifying species within the Fabaceae family. Based on an evaluation of genetic variation, DNA barcoding gaps, and species discrimination power, MATK is a useful barcode for Fabaceae species. Of 1355 plant samples collected from 1079 species belonging to 409 diverse genera, MATK precisely identified approximately 80 % and 96 % of them at the species and genus levels, respectively. Therefore, our research indicates that the MATK region is a valuable marker for plant species within Fabaceae.


Optically active second-harmonic generation from a uniaxial fluid medium.
We have shown that optically active second-harmonic generation is allowed in a uniaxial fluid medium. A homeotropically aligned chiral smectic-A liquid crystal was used as an example. Phase matching was achievable by angle tuning. Chiral nonlinear susceptibility for the liquid crystal was deduced. The signal dropped precipitously as the sample underwent the transition from smectic-A to isotropic.


Contribution of the potassium-chloride co-transporter KCC2 to the modulation of lumbar spinal networks in mice.
Spontaneous activity is observed in most developing neuronal circuits, such as the retina, hippocampus, brainstem and spinal cord. In the spinal cord, spontaneous activity is important for generating embryonic movements critical for the proper development of motor axons, muscles and synaptic connections. A spontaneous bursting activity can be recorded in vitro from ventral roots during perinatal development. The depolarizing action of the inhibitory amino acids γ-aminobutyric acid and glycine is widely proposed to contribute to spontaneous activity in several immature systems. During development, the intracellular chloride concentration decreases, leading to a shift of equilibrium potential for Cl(-) ions towards more negative values, and thereby to a change in glycine- and γ-aminobutyric acid-evoked potentials from depolarization/excitation to hyperpolarization/inhibition. The up-regulation of the outward-directed Cl(-) pump, the neuron-specific potassium-chloride co-transporter type 2 KCC2, has been shown to underlie this shift. Here, we investigated whether spontaneous and locomotor-like activities are altered in genetically modified mice that express only 8-20% of KCC2, compared with wild-type animals. We show that a reduced amount of KCC2 leads to a depolarized equilibrium potential for Cl(-) ions in lumbar motoneurons, an increased spontaneous activity and a faster locomotor-like activity. However, the left-right and flexor-extensor alternating pattern observed during fictive locomotion was not affected. We conclude that neuronal networks within the spinal cord are more excitable in KCC2 mutant mice, which suggests that KCC2 strongly modulates the excitability of spinal cord networks.


GPR55 and its interaction with membrane lipids: comparison with other endocannabinoid-binding receptors.
A number of integral membrane G protein-coupled receptors (GPCRs) share common structural features (including palmytoilated aminoacid residues and consensus sequences specific for interaction with cholesterol) that allow them to interact with lipid rafts, membrane cholesterol-rich microdomains able to regulate GPCR signalling and functions. Among GPCRs, type-1 and type-2 cannabinoid receptors, the molecular targets of endocannabinoids (eCBs), control many physiological and pathological processes through the activation of several signal transduction pathways. Recently, the orphan GPR55 receptor has been proved to be activated by many eCBs, thus leading to the hypothesis that it might be the "type-3" cannabinoid receptor. While the biological activity of eCBs and the influence of membrane lipids on their functions are rather well established, information regarding GPR55 is still scarce and often controversial. Based on this background, here we shall review current data about GPR55 pharmacology and signalling, highlighting its involvement in several pathophysiological conditions. We shall also outline the structural features that allow GPR55 to interact with cholesterol and to associate with lipid rafts; how the latter lipid microdomains impact the biological activity of GPR55 is also addressed, as well as their potential for the discovery of new therapeutics useful for the treatment of those human diseases that might be associated with alterations of GPR55 activity.


Comparison of a restrictive versus liberal red cell transfusion policy for patients with myelodysplasia, aplastic anaemia, and other congenital bone marrow failure disorders.
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the efficacy and safety of a restrictive versus liberal red cell transfusion strategy for patients with long-term bone marrow failure. These include myelodysplasia, acquired aplastic anaemia, and other inherited bone marrow failure disorders.