Positive predictive value and impact of misdiagnosis of a heart failure diagnosis in administrative registers among patients admitted to a University Hospital cardiac care unit.
To evaluate the positive predictive value (PPV) of a diagnosis of heart failure (HF) in the Danish National Registry of Patients (NRP) among patients admitted to a University Hospital cardiac care unit, and to evaluate the impact of misdiagnosing HF. The NRP was used to identify patients with heart failure from July 1, 2005 to June 30, 2007. Heart failure was defined in accordance with European Society of Cardiology (ESC) guidelines. The recorded diagnoses from the NRP were compared with clinical data from the medical records. We identified 758 patients with a diagnosis of heart failure in the NRP. The PPV of a heart failure discharge diagnosis was 84.0% (95% confidence interval: 81.2-86.6). Patients with a discharge diagnosis of HF in the NRP without fulfilling the ESC criteria for HF had a better survival rate, a lower rate of rehospitalization, none were followed in the outpatient clinic, and they had a lower consumption of anticongestive medicine after discharge. We found a relatively high PPV of the HF diagnosis in the NRP, and the NRP can therefore be a valuable tool for identification of patients with HF. However, using the NRP alone will not give a true picture of the cost and total burden of the disease.


Mononuclear salen-gallium complexes for iso-selective ring-opening polymerization (ROP) of rac-lactide.
A series of mononuclear salen-supported gallium amido/alkoxide derivatives were prepared and structurally characterized and subsequently used as initiators in rac-lactide ring-opening polymerisation (ROP). The reaction of variously substituted salen ligands (1a-1f) with 0.5 equiv. of Ga2(NMe2)6 allowed the isolation of the corresponding (salen)Ga-NMe2 chelates (2b-2d, 2f) via an amine elimination route, as poorly soluble compounds in common solvents. The (salen)Ga-OBn derivatives (3a-3e) may be readily accessed by an amine-elimination/alcoholysis sequence and the molecular structures of 3a, 3d and 3e were confirmed through X-ray crystallography diffraction analysis. The present (salen)Ga-X species may effectively mediate the iso-selective ROP of rac-LA in a controlled manner (Pm up to 0.77 using a 1/1 2f/BnOH mixture as ROP initiator), with a ROP activity greatly dependent upon steric hindrance and geometrical constraints imposed by the variously substituted salen ligands. Based on the present study, salen ligands with limited steric hindrance and a certain degree of flexibility appear best suited for iso-selective ROP by (salen)Ga chelates. The salen-gallium complex 3a is also effective for the controlled ROP of ε-caprolactone (CL) and the production of PCL-b-PLA copolymers.


Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice.
We recently reported that brain-specific human β-secretase 1 (BACE1) knock-in (PLB4), a mouse model of sporadic Alzheimer's disease (AD), also develops a severe diabetic phenotype characterised by impaired glucose homeostasis, decreased insulin sensitivity and a fatty liver phenotype. Hence, we here aimed to assess if targeted anti-diabetic therapies (Liraglutide and Fenretinide) would attenuate the diabetic and behavioural phenotype of these mice. PLB4 mice and wild-type (WT) controls were administered Liraglutide or Fenretinide for ten consecutive weeks alongside vehicle-treated mice. Physiological (body weight and mass composition, glucose tolerance, serum hormone concentration), behavioural (locomotor activity) and molecular assessments were performed in mice pre- and post-treatment. Liraglutide and Fenretinide treatments inhibited adiposity gain and decreased circulating serum triglyceride (with Liraglutide) and leptin (with Fenretinide) levels in PLB4 mice. We also found that PLB4 mice exhibited increased levels of serum dipeptidyl peptidase 4 (DPP4), together with up-regulated hepatic expression of Dpp4, retinol binding protein 4 (Rbp4) and sterol regulatory element-binding 1c (Srebp1c), which was normalised by both treatments. Interestingly, Liraglutide treatment slowed down habituation to a novel environment and increased secondary night activity peak in WT mice, suggesting an impact on circadian activity regulation. However, neither treatment improved glucose homeostasis in PLB4 mice, implying that impaired glucose metabolism in this genotype may not be associated with glucagon like peptide 1 (GLP-1) and/or RBP4-mediated pathways. In summary, this study provides new insights into molecular mechanisms underlying neuronal BACE1-mediated metabolic regulation and implicates BACE1 as a putative regulator of systemic DPP4 levels.


Activation of nuclear factor-kappaB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide.
Doxorubicin (DOX) is a widely used anti-tumour drug. Cardiotoxicity is a major toxic side effect of DOX therapy. Although recent studies implicated an apoptotic pathway in DOX-induced cardiotoxicity, the mechanism of DOX-induced apoptosis remains unclear. In the present study, we investigated the role of reactive oxygen species and the nuclear transcription factor nuclear factor kappaB (NF-kappaB) during apoptosis induced by DOX in bovine aortic endothelial cells (BAECs) and adult rat cardiomyocytes. DOX-induced NF-kappaB activation is both dose- and time-dependent, as demonstrated using electrophoretic mobility-shift assay and luciferase and p65 (Rel A) nuclear-translocation assays. Addition of a cell-permeant iron metalloporphyrin significantly suppressed NF-kappaB activation and apoptosis induced by DOX. Overexpression of glutathione peroxidase, which detoxifies cellular H(2)O(2), significantly decreased DOX-induced NF-kappaB activation and apoptosis. Inhibition of DOX-induced NF-kappaB activation by a cell-permeant peptide SN50 that blocks translocation of the NF-kappaB complex into the nucleus greatly diminished DOX-induced apoptosis. Apoptosis was inhibited when IkappaB mutant vector, another NF-kappaB inhibitor, was added to DOX-treated BAECs. These results suggest that NF-kappaB activation in DOX-treated endothelial cells and myocytes is pro-apoptotic, in contrast with DOX-treated cancer cells, where NF-kappaB activation is anti-apoptotic. Removal of intracellular H(2)O(2) protects endothelial cells and myocytes from DOX-induced apoptosis, possibly by inhibiting NF-kappaB activation. These findings suggest a novel mechanism for enhancing the therapeutic efficacy of DOX.


Characterization of fatty acid synthase in cell lines derived from experimental mammary tumors.
The lipogenic enzyme fatty acid synthase (FAS) is elevated in various human primary cancers and certain human cancer cell lines. FAS overexpression in human neoplasia has clinical relevance because of its association with tumor aggression and potential chemotherapeutic intervention. Here, we surveyed FAS in cell lines established from normal murine mammary epithelium (NMuMG) and from mammary tumors induced by either rodent polyoma (Py) virus or murine mammary tumor virus (MMTV). Western blotting revealed greater content of FAS in Py-transformed A1-1 and T1 than NMuMG or MMTV-transformed Mm5MT, RIIIMT and MMT060562. These data suggest that signaling events mediated by Py transformation may increase cellular amounts of FAS. Although FAS content was elevated to similar levels in A1-1 and T1, specific activities were significantly different as enzyme activity in T1 was 3-fold higher than A1-1. Likewise, FAS activity in NMuMG was about 0.5-fold higher than the MMTV-transformed lines, even though enzyme content was similar. Immunoprecipitation studies employing anti-phosphoamino acid antibodies followed by immunoblot analysis with anti-FAS antisera (and vice versa) were used to characterize the constitutive phosphorylation state of the enzyme. Phosphoserine and phosphothreonine residues were detected in the more active FAS from T1 and NMuMG, but not in the less active FAS from Mm5MT or A1-1. Discovery of phosphorylated FAS suggests that the enzyme may have more immediate control over lipogenesis than previously thought. High-dose (10-4 M) dexamethasone induced FAS content and activity in NMuMG and MMTV-transformed lines but not Py-transformed cells. Lower concentrations (10-8, 10-6 M) of dexamethasone also activated FAS but without concomitant elevation of its protein content, which was consistent with a phosphorylated form of FAS. Finally, cell lines were treated with the FAS inhibitor cerulenin: almost all breast cancer lines were growth inhibited at significantly lower amounts of drug than normal cell lineages, suggesting that FAS plays a greater role in viability of tumor cells than normal cells. Pretreatment with palmitate (a primary end-product of FAS) prior to cerulenin rescued A1-1 cells only slightly from growth inhibition, whereas pretreatment with oleate (a monounsaturated fatty acid synthesized from palmitate) synergized cerulenin's cytotoxic effects.


Self-template construction of hollow Co3O4 microspheres from porous ultrathin nanosheets and efficient noble metal-free water oxidation catalysts.
Developing noble metal-free water oxidation catalysts is essential for many energy conversion/storage processes (e.g., water splitting). Herein, we report the facile synthesis of hollow Co3O4 microspheres composed of porous, ultrathin (<5 nm), single-crystal-like nanosheets via a novel "self-template" route. The successful preparation of these hollow Co3O4 nanomaterials includes three main steps: (1) the synthesis of solid cobalt alkoxide microspheres, (2) their subsequent self-template conversion into hollow cobalt hydroxide microspheres composed of ultrathin nanosheets, and finally (3) thermal treatment of hollow cobalt hydroxide microspheres into the hollow Co3O4 material. The as-obtained hollow Co3O4 nanomaterial possesses a high BET surface area (∼180 m(2) g(-1)), and can serve as an active and stable water oxidation catalyst under both electrochemical and photochemical reaction conditions, owing to its unique structural features. In the electrochemical water oxidation, this catalyst affords a current density of 10 mA cm(-2) (a value related to practical relevance) at an overpotential of ∼0.40 V. Moreover, with the assistance of a sensitizer [Ru(bpy)3](2+) (bpy = 2,2'-bipyridine), this nanomaterial can catalyze water oxidation reactions under visible light irradiation with an O2 evolution rate of ∼12 218 μmol g(-1) h(-1). Our results suggest that delicate nanostructuring can offer unique advantages for developing efficient water oxidation catalysts.


Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration.
In elderly people particularly in postmenopausal women, inadequate bone formation by osteoblasts originating from bone marrow mesenchymal stem cells (BMSCs) for compensation of bone resorption by osteoclasts is a major reason for osteoporosis. Enhancing osteoblastic differentiation of BMSCs is a feasible therapeutic strategy for osteoporosis. Here, bone marrow stromal cell (ST)-derived exosomes (STExos) are found to remarkably enhance osteoblastic differentiation of BMSCs in vitro. However, intravenous injection of STExos is inefficient in ameliorating osteoporotic phenotypes in an ovariectomy (OVX)-induced postmenopausal osteoporosis mouse model, which may be because STExos are predominantly accumulated in the liver and lungs, but not in bone. Hereby, the STExo surface is conjugated with a BMSC-specific aptamer, which delivers STExos into BMSCs within bone marrow. Intravenous injection of the STExo-Aptamer complex enhances bone mass in OVX mice and accelerates bone healing in a femur fracture mouse model. These results demonstrate the efficiency of BMSC-specific aptamer-functionalized STExos in targeting bone to promote bone regeneration, providing a novel promising approach for the treatment of osteoporosis and fracture.


Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression.
Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance and has been implicated in DNA damage response and aging. Telomere dysfunction induced by TRF2 inhibition can accelerate cellular senescence in human fibroblasts. While previous work has demonstrated that a variety of factors can regulate TRF2 expression transcriptionally and post-translationally, whether microRNAs (miRNAs) also participate in post-transcriptionally modulating TRF2 levels remains largely unknown. To better understand the regulatory pathways that control TRF2, we carried out a large-scale luciferase reporter screen using a miRNA expression library and identified four miRNAs that could target human TRF2 and significantly reduce the level of endogenous TRF2 proteins. In particular, our data revealed that miR-23a could directly target the 3' untranslated region (3'UTR) of TRF2. Overexpression of miR-23a not only reduced telomere-bound TRF2 and increased telomere dysfunction-induced foci (TIFs), but also accelerated senescence of human fibroblast cells, which could be rescued by ectopically expressed TRF2. Our findings demonstrate that TRF2 is a specific target of miR-23a, and uncover a previously unknown role for miR-23a in telomere regulation and cellular senescence.


A State of Alcohol Hangover Impedes Everyday Prospective Memory.
The aim of the current study was to investigate what impact a state of alcohol hangover (AH) has upon everyday prospective memory (PM; memory for future events/intentions). Previous research has shown that the AH has a detrimental effect upon cognitive abilities, including memory and attentional deficits. No published research articles to date have focused upon what impact AH might have upon everyday memory, of which PM is a good example. The current study compared an AH group (AHG) with a non-hangover group (NHG) on PM. Since other drug use, anxiety and depression can affect PM independent of the AH, these covariates were controlled for in the study. Fifty-eight young adults studying at university participated in this between-subjects design study-25 in the AHG and 33 in the NHG. The Prospective Remembering Video Procedure (PRVP) measured PM. The Acute Hangover Rating Scale confirmed a state of AH and a Digital Breath Analyzer Test measured their BAC. The Hospital Anxiety and Depression Scale gauged levels of anxiety and depression and a Recreational Drug Use Questionnaire (RDUQ) measured alcohol and other drug use. Anyone who reported having used an illicit substance (e.g., cannabis, ecstasy) or who smoked, were excluded from the study. After controlling for age, alcohol units per week, years spent drinking alcohol, anxiety and depression scores, a one-way analysis of covariance (ANCOVA) revealed that the AHG (mean = 5.16) recalled significantly fewer items on the PRVP than the NHG (mean = 7.51)-F (1,52) = 5.69, p < 0.05. Overall, it appeared that a state of AH significantly impaired PM, which was not attributable to age, alcohol use, or anxiety or depression indices. Given the importance of PM to everyday activities, such as remembering to keep appointments or to take an important medication on time, this finding may have farther-reaching implications. These findings should also be used to educate young adults and health professionals dealing with the consequences with regards the dangers of alcohol misuse.


Notch signaling in pediatric soft tissue sarcomas.
Pediatric soft tissue sarcomas are rare tumors of childhood, frequently characterized by specific chromosome translocations. Despite improvements in treatment, their clinical management is often challenging due to the low responsiveness of metastatic forms and aggressive variants to conventional therapeutic approaches, which leads to poor overall survival. It is widely thought that soft tissue sarcomas derive from mesenchymal progenitor cells that, during embryonic life, have developed chromosomal aberrations with de-regulation of the main pathways governing tissue morphogenesis. The Notch signaling pathway is one of the most important molecular networks involved in differentiation processes. Emerging evidence highlights the role of Notch signaling de-regulation in the biology of these pediatric sarcomas. In this review, we present an outline of recently gathered evidence on the role of Notch signaling in soft tissue sarcomas, highlighting its importance in tumor cell biology. The potential challenges and opportunities of targeting Notch signaling in the treatment of pediatric soft tissue sarcomas are also discussed.


Priming of plant resistance by natural compounds. Hexanoic acid as a model.
Some alternative control strategies of currently emerging plant diseases are based on the use of resistance inducers. This review highlights the recent advances made in the characterization of natural compounds that induce resistance by a priming mechanism. These include vitamins, chitosans, oligogalacturonides, volatile organic compounds, azelaic and pipecolic acid, among others. Overall, other than providing novel disease control strategies that meet environmental regulations, natural priming agents are valuable tools to help unravel the complex mechanisms underlying the induced resistance (IR) phenomenon. The data presented in this review reflect the novel contributions made from studying these natural plant inducers, with special emphasis placed on hexanoic acid (Hx), proposed herein as a model tool for this research field. Hx is a potent natural priming agent of proven efficiency in a wide range of host plants and pathogens. It can early activate broad-spectrum defenses by inducing callose deposition and the salicylic acid (SA) and jasmonic acid (JA) pathways. Later it can prime pathogen-specific responses according to the pathogen's lifestyle. Interestingly, Hx primes redox-related genes to produce an anti-oxidant protective effect, which might be critical for limiting the infection of necrotrophs. Our Hx-IR findings also strongly suggest that it is an attractive tool for the molecular characterization of the plant alarmed state, with the added advantage of it being a natural compound.


Allocentric kin recognition is not affected by facial inversion.
Typical judgments involving faces are disrupted by inversion, with the Thatcher illusion serving as a compelling example. In two experiments, we examined how inversion affects allocentric kin recognition-the ability to judge the degree of genetic relatedness of others. In the first experiment, participants judged whether pairs of photographs of children portrayed siblings or unrelated children. Half of the pairs were siblings, half were unrelated. In three experimental conditions, photographs were viewed in upright orientation, flipped around a horizontal axis, or rotated 180°. Neither rotation nor flipping had any detectable effect on allocentric kin recognition. In the second experiment, participants judged pairs of photographs of adult women. Half of the pairs were sisters, half were unrelated. We again found no significant effect of facial inversion. Unlike almost all other face judgments, judgments of kinship from facial appearance do not rely on perceptual cues disrupted by inversion, suggesting that they rely more on spatially localized cues rather than "holistic" cues. We conclude that kin recognition is not simply a byproduct of other face perception abilities. We discuss the implications for cue combination models of other facial judgments that are affected by inversion.


Butterfly abundance declines over 20 years of systematic monitoring in Ohio, USA.
Severe insect declines make headlines, but they are rarely based on systematic monitoring outside of Europe. We estimate the rate of change in total butterfly abundance and the population trends for 81 species using 21 years of systematic monitoring in Ohio, USA. Total abundance is declining at 2% per year, resulting in a cumulative 33% reduction in butterfly abundance. Three times as many species have negative population trends compared to positive trends. The rate of total decline and the proportion of species in decline mirror those documented in three comparable long-term European monitoring programs. Multiple environmental changes such as climate change, habitat degradation, and agricultural practices may contribute to these declines in Ohio and shift the makeup of the butterfly community by benefiting some species over others. Our analysis of life-history traits associated with population trends shows an impact of climate change, as species with northern distributions and fewer annual generations declined more rapidly. However, even common and invasive species associated with human-dominated landscapes are declining, suggesting widespread environmental causes for these trends. Declines in common species, although they may not be close to extinction, will have an outsized impact on the ecosystem services provided by insects. These results from the most extensive, systematic insect monitoring program in North America demonstrate an ongoing defaunation in butterflies that on an annual scale might be imperceptible, but cumulatively has reduced butterfly numbers by a third over 20 years.


In-depth proteomic analysis of Varroa destructor: Detection of DWV-complex, ABPV, VdMLV and honeybee proteins in the mite.
We investigated pathogens in the parasitic honeybee mite Varroa destructor using nanoLC-MS/MS (TripleTOF) and 2D-E-MS/MS proteomics approaches supplemented with affinity-chromatography to concentrate trace target proteins. Peptides were detected from the currently uncharacterized Varroa destructor Macula-like virus (VdMLV), the deformed wing virus (DWV)-complex and the acute bee paralysis virus (ABPV). Peptide alignments revealed detection of complete structural DWV-complex block VP2-VP1-VP3, VDV-1 helicase and single-amino-acid substitution A/K/Q in VP1, the ABPV structural block VP1-VP4-VP2-VP3 including uncleaved VP4/VP2, and VdMLV coat protein. Isoforms of viral structural proteins of highest abundance were localized via 2D-E. The presence of all types of capsid/coat proteins of a particular virus suggested the presence of virions in Varroa. Also, matches between the MWs of viral structural proteins on 2D-E and their theoretical MWs indicated that viruses were not digested. The absence/scarce detection of non-structural proteins compared with high-abundance structural proteins suggest that the viruses did not replicate in the mite; hence, virions accumulate in the Varroa gut via hemolymph feeding. Hemolymph feeding also resulted in the detection of a variety of honeybee proteins. The advantages of MS-based proteomics for pathogen detection, false-positive pathogen detection, virus replication, posttranslational modifications, and the presence of honeybee proteins in Varroa are discussed.


Expression of hepatitis C virus proteins interferes with the antiviral action of interferon independently of PKR-mediated control of protein synthesis.
Hepatitis C virus (HCV) of genotype 1 is the most resistant to interferon (IFN) therapy. Here, we have analyzed the response to IFN of the human cell line UHCV-11 engineered to inducibly express the entire HCV genotype 1a polyprotein. IFN-treated, induced UHCV cells were found to better support the growth of encephalomyocarditis virus (EMCV) than IFN-treated, uninduced cells. This showed that expression of the HCV proteins allowed the development of a partial resistance to the antiviral action of IFN. The nonstructural 5A (NS5A) protein of HCV has been reported to inhibit PKR, an IFN-induced kinase involved in the antiviral action of IFN, at the level of control of protein synthesis through the phosphorylation of the initiation factor eIF2alpha (M. Gale, Jr., C. M. Blakely, B. Kwieciszewski, S. L. Tan, M. Dossett, N. M. Tang, M. J. Korth, S. J. Polyak, D. R. Gretch, and M. G. Katze, Mol. Cell. Biol. 18:5208-5218, 1998). Accordingly, cell lines inducibly expressing NS5A were found to rescue EMCV growth (S. J. Polyak, D. M. Paschal, S. McArdle, M. J. Gale, Jr., D. Moradpour, and D. R. Gretch, Hepatology 29:1262-1271, 1999). In the present study we analyzed whether the resistance of UHCV-11 cells to IFN could also be attributed to inhibition of PKR. Confocal laser scanning microscopy showed no colocalization of PKR, which is diffuse throughout the cytoplasm, and the induced HCV proteins, which localize around the nucleus within the endoplasmic reticulum. The effect of expression of HCV proteins on PKR activity was assayed in a reporter assay and by direct analysis of the in vivo phosphorylation of eIF2alpha after treatment of cells with poly(I)-poly(C). We found that neither PKR activity nor eIF2alpha phosphorylation was affected by coexpression of the HCV proteins. In conclusion, expression of HCV proteins in their biological context interferes with the development of the antiviral action of IFN. Although the possibility that some inhibition of PKR (by either NS5A or another viral protein) occurs at a very localized level cannot be excluded, the resistance to IFN, resulting from the expression of the HCV proteins, cannot be explained solely by inhibition of the negative control of translation by PKR.


Endometrial effect of progesterone delivered by vaginal rings in estrogen-treated postmenopausal women.
The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women. Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium. Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group. The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.


mRNA localization studies suggest that murine FGF-5 plays a role in gastrulation.
During gastrulation in the mouse, the pluripotent embryonic ectoderm cells form the three primary germ layers, ectoderm, mesoderm and endoderm. Little is known about the mechanisms responsible for these processes, but evidence from previous studies in amphibians, as well as expression studies in mammals, suggest that signalling molecules of the Fibroblast Growth Factor (FGF) family may play a role in gastrulation. To determine whether this might be the case for FGF-5 in the mouse embryo, we carried out RNA in situ hybridization studies to determine when and where in the early postimplantation embryo the Fgf-5 gene is expressed. We chose to study this particular member of the FGF gene family because we had previously observed that its pattern of expression in cultures of teratocarcinoma cell aggregates is consistent with the proposal that Fgf-5 plays a role in gastrulation in vivo. The results reported here show that Fgf-5 expression increases dramatically in the pluripotent embryonic ectoderm just prior to gastrulation, is restricted to the cells forming the three primary germ layers during gastrulation, and is not detectable in any cells in the embryo once formation of the primary germ layers is virtually complete. Based on this provocative expression pattern and in light of what is known about the functions in vitro of other members of the FGF family, we hypothesize that in the mouse embryo Fgf-5 functions in an autocrine manner to stimulate the mobility of the cells that contribute to the embryonic germ layers or to render them competent to respond to other inductive or positional signals.


Use of low-dose pregabalin in patients undergoing laparoscopic cholecystectomy.
The objective of this study was to examine the effects of low-dose pregabalin on the analgesic efficacy, side-effects, and recovery profile in patients undergoing laparoscopic cholecystectomy. One hundred and sixty-two patients aged 18-65 yr, of ASA physical status I-III, undergoing elective outpatient laparoscopic cholecystectomy were recruited and randomized in this prospective, placebo-controlled, double-blind study to receive one of the following study medications orally: pregabalin 50 mg, pregabalin 75 mg, or placebo, 1 h before surgery and then every 12 h after operation for a total of three doses. Postoperative numeric pain scores, analgesic consumption, recovery score (QoR-40), and side-effects (opioid-related symptom distress scale) were assessed in the early postoperative period (every 15 min during the first hour, at 90, 120 min, 6, and 12 h) and at days 1, 2, and 7. Data were analysed using an intention-to-treat method. Compared with the placebo group, the pain scores were lower in the pregabalin 75 mg group in the first 90 min after surgery (P<0.05). Pregabalin 50 mg resulted in pain reduction at 30 and 45 min (P<0.05) relative to placebo. The analgesic consumption, side-effects, and recovery scores were similar among the three groups. Perioperative administration of pregabalin 75 mg provided limited analgesic benefit in the postoperative period. An updated meta-analysis confirms this finding (see Supplementary material).


Stochastic patterns of polymorphism after a selective sweep over a subdivided population.
The geographic structure of a population, which is modelled as a network of several small random-mating populations or demes exchanging migrants between them, limits the rapid spread of a beneficial allele under strong directional selection to the entire population. This weakens or modifies the hitchhiking effect of the beneficial allele on the pattern of genetic variation at linked neutral loci. Previous studies suggested that the characteristic patterns of polymorphism arise with selective sweeps in such a subdivided population. However, they did not fully address the stochastic pattern, as expected in an actual sample of DNA sequence, of such patterns. This study uses a novel method of individual-based forward-in-time simulation to generate multi-locus neutral polymorphism after a selective sweep in a moderately subdivided population. Population subdivision is shown to cause frequency spectrum to shift slightly such that Tajima's D becomes less negative than expected under a panmictic population. Similarly, the pattern of linkage disequilibrium showed very small change due to population subdivision. On the other hand, the value of Wright's F ST at closely linked neutral loci relative to that at unlinked loci greatly increased by population subdivision as predicted by previous studies. Finally, the distribution of the gradient of heterozygosity along the migration path of beneficial mutation, previously suggested to allow the inference of the direction of spread, was investigated. The variance of difference in heterozygosity was much larger than the mean, suggesting that such an inference may not be practical.


Population Genetics of Plasmodium vivax in Four Rural Communities in Central Vietnam.
The burden of malaria in Vietnam has drastically reduced, prompting the National Malaria Control Program to officially engage in elimination efforts. Plasmodium vivax is becoming increasingly prevalent, remaining a major problem in the country's central and southern provinces. A better understanding of P. vivax genetic diversity and structure of local parasite populations will provide baseline data for the evaluation and improvement of current efforts for control and elimination. The aim of this study was to examine the population genetics and structure of P. vivax isolates from four communities in Tra Leng commune, Nam Tra My district in Quang Nam, Central Vietnam. P. vivax mono infections collected from 234 individuals between April 2009 and December 2010 were successfully analyzed using a panel of 14 microsatellite markers. Isolates displayed moderate genetic diversity (He = 0.68), with no significant differences between study communities. Polyclonal infections were frequent (71.4%) with a mean multiplicity of infection of 1.91 isolates/person. Low but significant genetic differentiation (FST value from -0.05 to 0.18) was observed between the community across the river and the other communities. Strong linkage disequilibrium ([Formula: see text] = 0.113, p < 0.001) was detected across all communities, suggesting gene flow within and among them. Using multiple approaches, 101 haplotypes were grouped into two genetic clusters, while 60.4% of haplotypes were admixed. In this area of Central Vietnam, where malaria transmission has decreased significantly over the past decade, there was moderate genetic diversity and high occurrence of polyclonal infections. Local human populations have frequent social and economic interactions that facilitate gene flow and inbreeding among parasite populations, while decreasing population structure. Findings provide important information on parasites populations circulating in the study area and are relevant to current malaria elimination efforts.


Physical rehabilitation interventions for adult patients with critical illness across the continuum of recovery: an overview of systematic reviews protocol.
Patients admitted to the intensive care unit with critical illness often experience significant physical impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation interventions that enhance restoration of physical function have been evaluated across the continuum of recovery following critical illness including within the intensive care unit, following discharge to the ward and beyond hospital discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating these physical rehabilitation interventions, although there appears to be variability in review methodology and quality. We aim to conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive care patients across the continuum of recovery. This protocol has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. We will search the Cochrane Systematic Review Database, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, Excerpta Medica Database and Cumulative Index to Nursing and Allied Health Literature databases. We will include systematic reviews of randomised controlled trials of adult patients, admitted to the intensive care unit and who have received physical rehabilitation interventions at any time point during their recovery. Data extraction will include systematic review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal method. Primary outcomes of interest will focus on findings reflecting recovery of physical function. Quality of reporting and methodological quality will be appraised using the PRISMA checklist and the Assessment of Multiple Systematic Reviews tool. We anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post-critical illness patients across the continuum of recovery. PROSPERO CRD42015001068.


The role of mislocalized phototransduction in photoreceptor cell death of retinitis pigmentosa.
Most of inherited retinal diseases such as retinitis pigmentosa (RP) cause photoreceptor cell death resulting in blindness. RP is a large family of diseases in which the photoreceptor cell death can be caused by a number of pathways. Among them, light exposure has been reported to induce photoreceptor cell death. However, the detailed mechanism by which photoreceptor cell death is caused by light exposure is unclear. In this study, we have shown that even a mild light exposure can induce ectopic phototransduction and result in the acceleration of rod photoreceptor cell death in some vertebrate models. In ovl, a zebrafish model of outer segment deficiency, photoreceptor cell death is associated with light exposure. The ovl larvae show ectopic accumulation of rhodopsin and knockdown of ectopic rhodopsin and transducin rescue rod photoreceptor cell death. However, knockdown of phosphodiesterase, the enzyme that mediates the next step of phototransduction, does not. So, ectopic phototransduction activated by light exposure, which leads to rod photoreceptor cell death, is through the action of transducin. Furthermore, we have demonstrated that forced activation of adenylyl cyclase in the inner segment leads to rod photoreceptor cell death. For further confirmation, we have also generated a transgenic fish which possesses a human rhodopsin mutation, Q344X. This fish and rd10 model mice show photoreceptor cell death caused by adenylyl cyclase. In short, our study indicates that in some RP, adenylyl cyclase is involved in photoreceptor cell death pathway; its inhibition is potentially a logical approach for a novel RP therapy.


Diacylglycerol kinase control of protein kinase C.
The diacylglycerol kinases (DGK) are lipid kinases that transform diacylglycerol (DAG) into phosphatidic acid (PA) in a reaction that terminates DAG-based signals. DGK provide negative regulation to conventional and novel protein kinase C (PKC) enzymes, limiting local DAG availability in a tissue- and subcellular-restricted manner. Defects in the expression/activity of certain DGK isoforms contribute substantially to cognitive impairment and mental disorders. Abnormal DGK overexpression in tumors facilitates invasion and resistance to chemotherapy preventing tumor immune destruction by tumor-infiltrating lymphocytes. Effective translation of these findings into therapeutic approaches demands a better knowledge of the physical and functional interactions between the DGK and PKC families. DGKζ is abundantly expressed in the nervous and immune system, where physically and functionally interacts with PKCα. The latest discoveries suggest that PDZ-mediated interaction facilitates spatial restriction of PKCα by DGKζ at the cell-cell contact sites in a mechanism where the two enzymes regulate each other. In T lymphocytes, DGKζ interaction with Sorting Nexin 27 (SNX27) guarantees the basal control of PKCα activation. SNX27 is a trafficking component required for normal brain function whose deficit has been linked to Alzheimer's disease (AD) pathogenesis. The enhanced PKCα activation as the result of SNX27 silencing in T lymphocytes aligns with the recent correlation found between gain-of-function PKCα mutations and AD and suggests that disruption of the mechanisms that provides a correct spatial organization of DGKζ and PKCα may lie at the basis of immune and neuronal synapse impairment.


Engineered proteins with desired specificity: DARPins, other alternative scaffolds and bispecific IgGs.
Specific binding proteins have become essential for diagnostic and therapeutic applications, and traditionally these have been antibodies. Nowadays an increasing number of alternative scaffolds have joined these ranks. These additional folds have raised a lot of interest and expectations within the last decade. It appears that they have come of age and caught up with antibodies in many fields of applications. The last years have seen an exploration of possibilities in research, diagnostics and therapy. Some scaffolds have received further improvements broadening their fields of application, while others have started to occupy their respective niche. Protein engineering, the prerequisite for the advent of all alternative scaffolds, remains the driving force in this process, for both non-immunoglobulins and immunoglobulins alike.


Effects of pre-partum dietary crude protein level on colostrum fat globule membrane proteins and the performance of Hu ewes and their offspring.
Dietary proteins play important roles in the growth and reproduction of sheep, and the ewe's demand for proteins increases dramatically during late pregnancy. This research aimed to investigate the effect of dietary crude protein (CP) levels during late pregnancy on colostrum fat globule membrane (MFGM) protein and the growth performance of Hu sheep and their offspring, and provide a reference for the protein intake of ewes during late pregnancy. A total of 108 multiparous Hu sheep (45.6 ± 1.18 kg) were selected for this study, then 60 pregnant ewes confirmed by B-scan ultrasonography were randomly divided into three treatments (20 ewes/treatment) and fed by total mixed ration pellet with CP levels at 9.00% (LP), 12.0% (MP), and 15.0% (HP) during late pregnancy, respectively. The weight and dry matter intake of ewes during late pregnancy were recorded to calculate the average daily gain (ADG) and feed conversion ratio (FCR). Twin lambs were weighed on days 0, 7, 14, 30, 60, and 180 after birth to calculate ADG. Meanwhile, the colostrum of ewes was collected within 12 h after delivery. The colostrum MFGM proteins were identified and quantified by the isobaric tag for relative and absolute quantification (iTRAQ) coupled with liquid chromatography-tandem mass spectrometry methods. In addition, biological functions of differentially expressed proteins (DEPs) were annotated by Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The results revealed that a 15.0% CP level had significant effects on the BW of lambs on days 0, 7, and 30 (P < 0.05). Notably, a total of 1,529 MFGM proteins were identified and 286 DEPs were found among three treatments. Functional analysis showed that DEPs were mainly involved in cell growth, differentiation, and tissue repair, and involved in metabolic pathways, such as the porphyrin and chlorophyll metabolism pathways. In this study, lambs in HP treatment had better growth performance; moreover, dietary 15.0% CP level also affected the colostrum MFGM proteins composition of Hu ewes. These observations can facilitate future studies on the feeding regimen of ewes during late pregnancy.


Characterization of a trinuclear ruthenium species in catalytic water oxidation by Ru(bda)(pic)2 in neutral media.
A Ru(III)-O-Ru(IV)-O-Ru(III) type trinuclear species was crystallographically characterized in water oxidation by Ru(bda)(pic)2 (H2bda = 2,2'-bipyridine-6,6'-dicarboxylic acid; pic = 4-picoline) under neutral conditions. The formation of a ruthenium trimer due to the reaction of Ru(IV)[double bond, length as m-dash]O with Ru(II)-OH2 was fully confirmed by chemical, electrochemical and photochemical methods. Since the oxidation of the trimer was proposed to lead to catalyst decomposition, the photocatalytic water oxidation activity was rationally improved by the suppression of the formation of the trimer.


Comparison of slope-intercept with single plasma sample methods in estimating glomerular filtration rate using radionuclides.
To evaluate the accuracy of different single plasma sample methods (SPSM) 99m Tc-DTPA clearances and to test whether the SPSM can replace the dual plasma samples method (DPSM) in the measurement of glomerular filtration rate (GFR), we studied 430 subjects counting renal patients and donors (240 male, 190 female; mean age 43.40 ± 16.30 years). All the subjects underwent dynamic renal scintigraphy after injection of 99m Tc-DTPA; the GFR was calculated by seven SPSMs in addition to DPSM as a reference. Each of the SPSM clearance was compared with the DPSM measurement. There was a high correlation of all the SPSMs and the DPSM. The limits of agreement (95%) were found between the DPSM and all the SPSMs. Overall, the best method among the SPSMs, which is closest to the DPSM, is Fleming's single method as it has a statistically significant low mean difference (bias), low standard error, close mean ± SD to the reference method, good limits of agreement and high correlation co-efficient. This study concludes that, among the SPSMs, Fleming can reflect GFR more accurately than other methods, particularly when the expected serum creatinine is normal.


Fascial tissue research in sports medicine: from molecules to tissue adaptation, injury and diagnostics: consensus statement.
The fascial system builds a three-dimensional continuum of soft, collagen-containing, loose and dense fibrous connective tissue that permeates the body and enables all body systems to operate in an integrated manner. Injuries to the fascial system cause a significant loss of performance in recreational exercise as well as high-performance sports, and could have a potential role in the development and perpetuation of musculoskeletal disorders, including lower back pain. Fascial tissues deserve more detailed attention in the field of sports medicine. A better understanding of their adaptation dynamics to mechanical loading as well as to biochemical conditions promises valuable improvements in terms of injury prevention, athletic performance and sports-related rehabilitation. This consensus statement reflects the state of knowledge regarding the role of fascial tissues in the discipline of sports medicine. It aims to (1) provide an overview of the contemporary state of knowledge regarding the fascial system from the microlevel (molecular and cellular responses) to the macrolevel (mechanical properties), (2) summarise the responses of the fascial system to altered loading (physical exercise), to injury and other physiological challenges including ageing, (3) outline the methods available to study the fascial system, and (4) highlight the contemporary view of interventions that target fascial tissue in sport and exercise medicine. Advancing this field will require a coordinated effort of researchers and clinicians combining mechanobiology, exercise physiology and improved assessment technologies.


Chromosomes exhibit preferential positioning in nuclei of quiescent human cells.
The relative spatial positioning of chromosomes 7, 8, 16, X and Y was examined in nuclei of quiescent (noncycling) diploid and triploid human fibroblasts using fluorescence in situ hybridization (FISH) with chromosome-specific DNA probes and digital imaging. In quiescent diploid cells, interhomolog distances and chromosome homolog position maps revealed a nonrandom, preferential topology for chromosomes 7, 8 and 16, whereas chromosome X approximated a more random distribution. Variations in the orientation of nuclei on the culture substratum tended to hinder detection of an ordered chromosome topology at interphase by biasing homolog position maps towards random distributions. Using two chromosome X homologs as reference points in triploid cells (karyotype = 69, XXY), the intranuclear location of chromosome Y was found to be predictable within remarkably narrow spatial limits. Dual-FISH with various combinations of chromosome-specific DNA probes and contrasting fluorochromes was used to identify adjacent chromosomes in mitotic rosettes and test whether they are similarly positioned in interphase nuclei. From among the combinations tested, chromosomes 8 and 11 were found to be closely apposed in most mitotic rosettes and interphase nuclei. Overall, results suggest the existence of an ordered interphase chromosome topology in quiescent human cells in which at least some chromosome homologs exhibit a preferred relative intranuclear location that may correspond to the observed spatial order of chromosomes in rosettes of mitotic cells.


Mechanical and free living comparisons of four generations of the Actigraph activity monitor.
More studies include multiple generations of the Actigraph activity monitor. So far no studies have compared the output including the newest generation and investigated the impact on the output of the activity monitor when enabling the low frequency extension (LFE) option. The aims were to study the responses of four generations (AM7164, GT1M, GT3X and GT3X+) of the Actigraph activity monitor in a mechanical setup and a free living environment with and without enabling the LFE option. The monitors were oscillated in a mechanical setup using two radii in the frequency range 0.25-3.0 Hz. Following the mechanical study a convenience sample (N = 20) wore three monitors (one AM7164 and two GT3X) for 24 hours. The AM7164 differed from the newer generations across frequencies (p < 0.05) in the mechanical setup. The AM7164 produced a higher output at the lower and at the highest intensities, whereas the output was lower at the middle intensities in the mid-range compared to the newer generations. The LFE option decreased the differences at the lower frequencies, but increased differences at the higher. In free living, the mean physical activity level (PA) of the GT3X was 18 counts per minute (CPM) (8%) lower compared to the AM7164 (p < 0.001). Time spent in sedentary intensity was 26.6 minutes (95% CI 15.6 to 35.3) higher when assessed by the GT3X compared to the AM7164 (p < 0.001). Time spend in light and vigorous PA were 23.3 minutes (95% CI 31.8 to 14.8) and 11.7 minutes (95% CI 2.8 to 0.7) lower when assessed by the GT3X compared to the AM7164 (p < 0.05). When enabling the LFE the differences in the sedentary and light PA intensity (<333 counts*10 sec-1) were attenuated (p > 0.05 for differences between generations) thus attenuated the difference in mean PA (p > 0.05) when the LFE option was enabled. However, it did not attenuate the difference in time spend in vigorous PA and it introduced a difference in time spend in moderate PA (+ 3.0 min (95% CI 0.4 to 5.6)) between the generations. We observed significant differences between the AM7164 and the newer Actigraph GT-generations (GT1M, GT3X and GT3X+) in a mechanical setup and in free-living. Enabling the LFE option attenuated the differences in mean PA completely, but induced a bias in the moderate PA intensities.


Exploratory genomic analysis of high-grade neuroendocrine neoplasms across diverse primary sites.
High-grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n = 46), whole exome (n = 40), and gene copy number (n = 43) sequencing on G3 NEN formalin-fixed, paraffin-embedded samples from diverse organs (in total, 17 were lung, 16 were gastroenteropancreatic, and 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1, and CDKN2A were significantly mutated. The CDK4/6 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutations/MB), with 20% having >10 mutations/MB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types: focal deletion 22q13.31 (HR, 7.82; P = 0.034) and arm amplification 19q (HR, 4.82; P = 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.


Hypothetical acceptability of hospital-based post-mortem pediatric minimally invasive tissue sampling in Malawi: The role of complex social relationships.
Child mortality rates remain unacceptably high in low-resource settings. Cause of death (CoD) is often unknown. Minimally invasive tissue sampling (MITS)-using biopsy needles to obtain post-mortem samples-for histopathological and microbiologic investigation is increasingly being promoted to improve child and adult CoD attribution. "MITS in Malawi" is a sub-study of the Childhood Acute Illness & Nutrition (CHAIN) Network, which aims to identify biological and socioeconomic mortality risk factors among young children hospitalized for acute illness or undernutrition. MITS in Malawi employs standard MITS and a novel post-mortem endoscopic intestinal sampling approach to better understand CoD among children with acute illness and/or malnutrition who die during hospitalization. To understand factors that may impact MITS acceptability and inform introduction of the procedure to ascertain CoD among children with acute illness or malnutrition who die during hospitalization in Malawi. We conducted eight focus group discussions with key hospital staff and community members (religious leaders and parents of children under 5) to explore attitudes towards MITS and inform consent processes prior to commencing the MITS in Malawi study. We used thematic content analysis drawing on a conceptual framework developed from emergent themes and MITS acceptability literature. Feelings of power over decision-making within the hospital and household, trust in health systems, and open and respectful health worker communication with parents were important dimensions of MITS acceptability. Other facilitating factors included the potential for MITS to add CoD information to aid sense-making of death and contribute to medical knowledge and new interventions. Potential barriers to acceptability included fears of organ and blood harvesting, disfigurement to the body, and disruption to transportation and burial plans. Social relationships and power dynamics within healthcare systems and households are a critical component of MITS acceptability, especially given the sensitivity of death and autopsy.


Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates.
Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited. During 2004-08 the China Kadoorie Biobank recruited 512,891 men and women aged 30-79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately. Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers. The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.


Valid facial cues to cooperation and trust: male facial width and trustworthiness.
Decisions about whom to trust are biased by stable facial traits such as attractiveness, similarity to kin, and perceived trustworthiness. Research addressing the validity of facial trustworthiness or its basis in facial features is scarce, and the results have been inconsistent. We measured male trustworthiness operationally in trust games in which participants had options to collaborate for mutual financial gain or to exploit for greater personal gain. We also measured facial (bizygomatic) width (scaled for face height) because this is a sexually dimorphic, testosterone-linked trait predictive of male aggression. We found that men with greater facial width were more likely to exploit the trust of others and that other players were less likely to trust male counterparts with wide rather than narrow faces (independent of their attractiveness). Moreover, manipulating this facial-width ratio with computer graphics controlled attributions of trustworthiness, particularly for subordinate female evaluators.


Alteration of human erythrocyte membrane properties by complement fixation.
Erythrocyte survival studies of complement-coated radiolabeled erythrocytes have shown rapid removal of these cells from the peripheral blood with a return of these cells into the circulation within a few hours. We studied complement-coated human erythrocytes and measured surface charge and deformability, two parameters believed to be important in erythrocyte survival. Erythrocytes were coated with complement by two in vitro techniques: the addition of (a) low ionic strength sucrose, and (b) IgM cold agglutinins. Erythrocytes obtained from three patients with cold agglutinin disease were used as a source of in vivo complement-coated cells. No difference was found in surface charge as measured by electrophoretic mobility between erythrocytes from normal subjects and complement-coated erythrocytes from any of the three sources. When deformability was measured by filtration through 3-mum polycarbonate sieves, marked decreases in deformability were found in complement-coated erythrocytes. The filtration returned toward control levels by incubating the complement-coated erythrocytes in serum for 1 h and correlated with decreases in immune adherence. Using screen filtration pressure as a measure of deformability, a positive correlation between number of C3 molecules per erythrocyte and decreased deformability was found. C3b appeared responsible for the decreased deformability of the erythrocytes, since conversion of C3b to C3d resulted in a return of deformability toward normal. The data suggested that the sequestration of complement-coated human erythrocytes in the microvasculature can be explained in part by decreased deformability and changes in immune adherence.


West Nile Virus: is a vaccine needed?
West Nile virus (WNV) is a neurotropic Flavivirus that was associated with sporadic outbreaks of meningoencephalitis in Africa and the Middle East until 1999, when a more virulent strain emerged in the US that caused thousands of infections among humans and horses, with reported fatality rates between 10 and 50%. Although the epidemiology of WNV is changing into a more endemic pattern in the US, and the incidence of neuroinvasive disease is decreasing, the long-term effects of resolved WNV infections in humans, characterized as persistent movement disorders and various functional disabilities, are a significant cause of morbidity. In addition, the horse industry is also negatively impacted by WNV infections, resulting in significant economic losses. Together with the fact that WNV is a potential bioterrorism agent, these factors suggest that there is a need for the development of a safe and effective vaccine against WNV. The increased understanding of WNV pathogenesis and correlates of protection enables the rational design of such a vaccine. Several experimental vaccines have been tested in preclinical models and some have undergone clinical trials. The challenges related to the development of cheaper, safer and more effective vaccines for use in both humans and horses are likely to be overcome by new technological developments in the field of vaccinology.


Gordonia nitida sp. nov., a bacterium that degrades 3-ethylpyridine and 3-methylpyridine.
A bacterial strain, LE31T, which is capable of degrading 3-ethylpyridine and 3-methylpyridine, was isolated from an industrial wastewater and was taxonomically studied by using a polyphasic approach. Strain LE31T was identified as a member of the genus Gordonia on the basis of chemotaxonomic characteristics and phylogenetic inference-based 16S rDNA sequence. The cell wall contained meso-diaminopimelic acid, arabinose and galactose (wall chemotype IV). The predominant menaquinone was MK-9(H2). The mycolic acids contained 47-55 carbon atoms. The major fatty acids were C16:0, C18:1 omega9c, 10-methyl-C18:0 (TBSA). The G+C content of DNA was 67 mol%. The 16S rDNA sequence of strain LE31T was most similar to that of the type strain of Gordonia rubropertincta. The differences in some phenotypic characteristics and the genetic distinctiveness distinguish strain LE31T from the Gordonia species described previously. Therefore it is proposed that strain LE31T should be placed in the genus Gordonia as a new species. The name Gordonia nitida is proposed for strain LE31T. The type strain of the new species is strain LE31T (= KCTC 0605BPT = KCCM 80004T).


Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS. Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress. We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly. Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause. This work was supported by project grant funding from MND Scotland, the My Name'5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023\1100].


Condom use and self-efficacy among female sex workers with steady partners in China.
This study attempted to determine the association of self-efficacy with condom-use practice and to explore reasons of not using condoms among female sex workers (FSWs) with steady partners in China. Data from 309 establishment-based FSWs with steady partners in one Chinese county were collected through a cross-sectional study. Consistent condom use with steady partners was lower than with clients in entertainment establishments. Condom-use self-efficacy was positively associated with condom-use communication and condom-use frequency with clients but not with steady partners. It was positively associated with condom-use intention and skill with clients and steady partners. However, it was not associated with appropriate use of condoms. Significant differences of reasons about not using condom were also observed between the two partner types. The results may represent an important challenge to STD and HIV intervention programs aimed at achieving consistent condom use in FSWs. Health workers should focus on psychosocial factors affecting inconsistent condom use among FSWs with steady partners in China. In addition, intervention programs that can promote FSWs' self-efficacy through condom-use skill training will still be necessary.


Debriefing medical teams: 12 evidence-based best practices and tips.
Medical teams are commonly called on to perform complex tasks, and when those tasks involve saving the lives of critically injured patients, it is imperative that teams perform optimally. Yet, medical care settings do not always lend themselves to efficient teamwork. The human factors and occupational sciences literatures concerning the optimization of team performance suggest the usefulness of a debriefing process--either for critical incidents or recurring events. Although the debrief meeting is often used in the context of training medical teams, it is also useful as a continuous learning tool throughout the life of the team. WHAT ARE GOOD DEBRIEFS? The debriefing process allows individuals to discuss individual and team-level performance, identify errors made, and develop a plan to improve their next performance. THE DEBRIEF PROCESS: The list of 12 best practices and tips--4 for hospital leaders and the remainder for debrief facilitators or team leaders--should be useful for teams performing in various high-risk areas, including operating rooms, intensive care units, and emergency departments. The best practices and tips should help teams to identify weak areas of teamwork and develop new strategies to improve teamwork competencies. Moreover, they include practices that support both regular, recurring debriefs and critical-incident debriefings. Team members should follow these main guidelines--also provided in checklist form--which include ensuring that the organization creates a supportive learning environment for debriefs (concentrating on a few critical performance issues), providing feedback to all team members, and recording conclusions made and goals set during the debrief to facilitate future feedback.


Gut microbiota and therapeutic approaches for dysbiosis in irritable bowel syndrome: recent developments and future perspectives
Increased knowledge regarding the implications of gut microbiota in irritable bowel syndrome (IBS) suggests that a disturbed intestinal microenvironment (dysbiosis) might promote the development and maintenance of IBS symptoms and affects several pathways in the pathology of this multifactorial disease. Accordingly, manipulation of the gut microbiota in order to improve IBS symptoms has evolved as a novel treatment strategy in the last decade. Several different approaches have been investigated in order to improve the gut microbiota composition. Dietary modifications including supplementation with fibers, prebiotics, and probiotics are shown to improve symptoms and composition of gut microbiota in IBS; however, the exact probiotic mixture beneficial for each individual remains to be identified. The use of antibiotics still needs confirmation, although promising results have been reported with use of rifaximin. Fecal microbiota transplantation (FMT) has recently gained a lot of attention, and several placebo-controlled trials investigating FMT obtain promising results regarding symptom reduction and gut microbiota manipulation in IBS. However, more data regarding long-term effects are needed before FMT can be integrated as a customized treatment for IBS in the clinical routine.


Effect of intravenous frusemide on plasma renin concentration: suppression of response in hypertension.
1. Intravenous frusemide produced in normal subjects a prompt rise of plasma renin concentration which correlated with urinary sodium. 2. The renin response to frusemide was suppressed in patients with primary hyperaldosteronism. 3. In patients with low-renin hypertension and normal renin essential hypertension, the renin response to frusemide was similarly suppressed. 4. Suppression of the renin response to frusemide is therefore a feature of hypertension not confined to patients with primary hyperaldosteronism and low-renin hypertension. 5. Thus low-renin hypertension does not appear to constitute a distinct diagnostic entity. 6. It is suggested that suppression of the renin response is part of a long-term renal adaptation to high blood pressure.


Interaction of delaminations and matrix cracks in a CFRP plate, Part I: A test method for model validation.
Isolating and observing the damage mechanisms associated with low-velocity impact in composites using traditional experiments can be challenging, due to damage process complexity and high strain rates. In this work, a new test method is presented that provides a means to study, in detail, the interaction of common impact damage mechanisms, namely delamination, matrix cracking, and delamination-migration, in a context less challenging than a real impact event. Carbon fiber reinforced polymer specimens containing a thin insert in one region were loaded in a biaxial-bending state of deformation. As a result, three-dimensional damage processes, involving delaminations at no more than three different interfaces that interact with one another via transverse matrix cracks, were observed and documented using ultrasonic testing and x-ray computed tomography. The data generated by the test is intended for use in numerical model validation. Simulations of this test are included in Part II of this paper.


Spatially differentiated regulation: Can it save the Baltic Sea from excessive N-loads?
The Baltic Sea Action Plan and the EU Water Framework Directive both require substantial additional reductions of nutrient loads (N and P) to the marine environment. Focusing on nitrogen, we present a widely applicable concept for spatially differentiated regulation, exploiting the large spatial variations in the natural removal of nitrate in groundwater and surface water. By targeting mitigation measures towards areas where nature's own capacity for removal is low, spatially differentiated regulation can be more cost-effective than the traditional uniform regulation. We present a methodology for upscaling local modelling results on targeted measures at field scale to Baltic Sea drainage basin scale. The paper assesses the potential gain and discusses key challenges related to implementation of spatially differentiated regulation, including the need for more scientific knowledge, handling of uncertainties, practical constraints related to agricultural practice and introduction of co-governance regimes.


Design of phase I combination trials: recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee.
Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker).


Eicosanoid Profile of Influenza A Virus Infected Pigs.
Respiratory tract infections caused by the Influenza A virus (IAV) are a worldwide problem for human and animal health. Within this study, we analyzed the impact of IAV infection on the immune-related lipidome (eicosanoids) of the pig as new infection model. For this purpose, we performed HPLC-MS/MS using dynamic multiple reaction monitoring and analyzed lung, spleen, blood plasma and bronchoalveolar lavages. IAV infection leads to collective changes in the levels of the analyzed hydroxyeicosatrienoic acids (HETEs), hydroxydocosahexaenoic acids (HDHAs) and epoxyeicosatrienoic acids (EETs), and moreover, unique eicosanoid changes in several sample types, even under mild infection conditions. In accordance with different mouse infection studies, we observed infection-related patterns for 12-HETE, 15-HETE and 17-HDHA, which seem to be common for IAV infection. Using a long-term approach of 21 days we established an experimental setup that can be used also for bacterial-viral coinfection experiments.


Real-time observation of tetrapyrrole binding to an engineered bacterial phytochrome.
Near-infrared fluorescent proteins (NIR FPs) engineered from bacterial phytochromes are widely used for structural and functional deep-tissue imaging in vivo. To fluoresce, NIR FPs covalently bind a chromophore, such as biliverdin IXa tetrapyrrole. The efficiency of biliverdin binding directly affects the fluorescence properties, rendering understanding of its molecular mechanism of major importance. miRFP proteins constitute a family of bright monomeric NIR FPs that comprise a Per-ARNT-Sim (PAS) and cGMP-specific phosphodiesterases - Adenylyl cyclases - FhlA (GAF) domain. Here, we structurally analyze biliverdin binding to miRFPs in real time using time-resolved stimulated Raman spectroscopy and quantum mechanics/molecular mechanics (QM/MM) calculations. Biliverdin undergoes isomerization, localization to its binding pocket, and pyrrolenine nitrogen protonation in <1 min, followed by hydrogen bond rearrangement in ~2 min. The covalent attachment to a cysteine in the GAF domain was detected in 4.3 min and 19 min in miRFP670 and its C20A mutant, respectively. In miRFP670, a second C-S covalent bond formation to a cysteine in the PAS domain occurred in 14 min, providing a rigid tetrapyrrole structure with high brightness. Our findings provide insights for the rational design of NIR FPs and a novel method to assess cofactor binding to light-sensitive proteins.


Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry.
We previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry. Extensive analysis of the tannins' mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses. CHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified.


Temperature dependence of DNA translocations through solid-state nanopores.
In order to gain a better physical understanding of DNA translocations through solid-state nanopores, we study the temperature dependence of λ-DNA translocations through 10 nm diameter silicon nitride nanopores, both experimentally and theoretically. The measured ionic conductance G, the DNA-induced ionic-conductance blockades [Formula: see text] and the event frequency Γ all increase with increasing temperature while the DNA translocation time τ decreases. G and [Formula: see text] are accurately described when bulk and surface conductances of the nanopore are considered and access resistance is incorporated appropriately. Viscous drag on the untranslocated part of the DNA coil is found to dominate the temperature dependence of the translocation times and the event rate is well described by a balance between diffusion and electrophoretic motion. The good fit between modeled and measured properties of DNA translocations through solid-state nanopores in this first comprehensive temperature study, suggest that our model captures the relevant physics of the process.


Impact of DSMES app interventions on medication adherence in type 2 diabetes mellitus: systematic review and meta-analysis.
To conduct systematic review and meta-analysis of interventional studies to investigate the impact of diabetes self-management education and support (DSMES) apps on adherence in patients with type 2 diabetes mellitus (T2D). PubMed, Embase, CENTRAL, Web of Science, Scopus and ProQuest were searched, in addition to references of identified articles and similar reviews. Experimental studies, reported in English, assessing DSMES app intervention's impact on adherence and clinical outcomes of patients with T2D compared with usual care were included. Study bias was assessed using Cochrane Risk of Bias V.2.0 tool. Analysis plan involved narrative synthesis, moderator and meta-analysis. Six randomised controlled trials were included, involving 696 participants (average age 57.6 years, SD 10.59). Mobile apps were mostly used for imputing clinical data, dietary intake or physical activity, and transmitting information to the provider. At 3 months, DSMES apps proved effective in improving medication adherence (standardized mean difference (SMD)=0.393, 95% CI 0.17 to 0.61), glycated haemoglobin (HbA1c) (mean difference (MD)=-0.314, 95% CI -0.477 to -0.151) and Body Mass Index (BMI) (MD=-0.28, 95% CI -0.545 to -0.015). All pooled estimates had low heterogeneity (I 2 0%). Four studies had moderate risk of bias while one each was judged to be low and high risks, respectively. DSMES apps had significant small to moderate effects on medication adherence, HbA1c and BMI of patients with T2D compared with usual care. Apps were described as reliable, easy to use and convenient, though participants were required to be phone literate. Evidence comes from feasibility trials with generally moderate risk of bias. Larger trials with longer follow-up periods using theory-based interventions are required to improve current evidence.


Isolation of ribosomes from cysts of entamoeba invadens.
A reproducible method for the preparation of 75S ribosomes from cysts of Entamoeba invadens is presented. The method depends on the inactivation of the cyst's ribonuclease by high levels of Bentonite. The ribosomes are found to be extremely sensitive to ribonuclease, and to be stabilized by the addition of manganous and calcium ions to the magnesium customarily employed. Reasons are given for equating these ribosomes with the particles of which the crystalline chromatoid bodies are made.


101 Dothideomycetes genomes: A test case for predicting lifestyles and emergence of pathogens.
Dothideomycetes is the largest class of kingdom Fungi and comprises an incredible diversity of lifestyles, many of which have evolved multiple times. Plant pathogens represent a major ecological niche of the class Dothideomycetes and they are known to infect most major food crops and feedstocks for biomass and biofuel production. Studying the ecology and evolution of Dothideomycetes has significant implications for our fundamental understanding of fungal evolution, their adaptation to stress and host specificity, and practical implications with regard to the effects of climate change and on the food, feed, and livestock elements of the agro-economy. In this study, we present the first large-scale, whole-genome comparison of 101 Dothideomycetes introducing 55 newly sequenced species. The availability of whole-genome data produced a high-confidence phylogeny leading to reclassification of 25 organisms, provided a clearer picture of the relationships among the various families, and indicated that pathogenicity evolved multiple times within this class. We also identified gene family expansions and contractions across the Dothideomycetes phylogeny linked to ecological niches providing insights into genome evolution and adaptation across this group. Using machine-learning methods we classified fungi into lifestyle classes with >95 % accuracy and identified a small number of gene families that positively correlated with these distinctions. This can become a valuable tool for genome-based prediction of species lifestyle, especially for rarely seen and poorly studied species.


Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth.
Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer.


Genome-wide analysis of androgen receptor binding and gene regulation in two CWR22-derived prostate cancer cell lines.
Prostate carcinoma (CaP) is a heterogeneous multifocal disease where gene expression and regulation are altered not only with disease progression but also between metastatic lesions. The androgen receptor (AR) regulates the growth of metastatic CaPs; however, sensitivity to androgen ablation is short lived, yielding to emergence of castrate-resistant CaP (CRCaP). CRCaP prostate cancers continue to express the AR, a pivotal prostate regulator, but it is not known whether the AR targets similar or different genes in different castrate-resistant cells. In this study, we investigated AR binding and AR-dependent transcription in two related castrate-resistant cell lines derived from androgen-dependent CWR22-relapsed tumors: CWR22Rv1 (Rv1) and CWR-R1 (R1). Expression microarray analysis revealed that R1 and Rv1 cells had significantly different gene expression profiles individually and in response to androgen. In contrast, AR chromatin immunoprecipitation (ChIP) combined with promoter DNA microarrays (ChIP-on-chip) studies showed that they have a similar AR-binding profile. Coupling of the microarray study with ChIP-on-chip analysis identified direct AR targets. The most prominent function of transcripts that were direct AR targets was transcriptional regulation, although only one transcriptional regulator, CCAAT/enhancer binding protein δ, was commonly regulated in both lines. Our results indicate that the AR regulates the expression of different transcripts in the two lines, and demonstrate the versatility of the AR-regulated gene expression program in prostate tumors.


An integrative and functional framework for the study of animal emotion and mood.
A better understanding of animal emotion is an important goal in disciplines ranging from neuroscience to animal welfare science. The conscious experience of emotion cannot be assessed directly, but neural, behavioural and physiological indicators of emotion can be measured. Researchers have used these measures to characterize how animals respond to situations assumed to induce discrete emotional states (e.g. fear). While advancing our understanding of specific emotions, this discrete emotion approach lacks an overarching framework that can incorporate and integrate the wide range of possible emotional states. Dimensional approaches that conceptualize emotions in terms of universal core affective characteristics (e.g. valence (positivity versus negativity) and arousal) can provide such a framework. Here, we bring together discrete and dimensional approaches to: (i) offer a structure for integrating different discrete emotions that provides a functional perspective on the adaptive value of emotional states, (ii) suggest how long-term mood states arise from short-term discrete emotions, how they also influence these discrete emotions through a bi-directional relationship and how they may function to guide decision-making, and (iii) generate novel hypothesis-driven measures of animal emotion and mood.


An evolutionary perspective on leaf economics: phylogenetics of leaf mass per area in vascular plants.
In plant leaves, resource use follows a trade-off between rapid resource capture and conservative storage. This "worldwide leaf economics spectrum" consists of a suite of intercorrelated leaf traits, among which leaf mass per area, LMA, is one of the most fundamental as it indicates the cost of leaf construction and light-interception borne by plants. We conducted a broad-scale analysis of the evolutionary history of LMA across a large dataset of 5401 vascular plant species. The phylogenetic signal in LMA displayed low but significant conservatism, that is, leaf economics tended to be more similar among close relatives than expected by chance alone. Models of trait evolution indicated that LMA evolved under weak stabilizing selection. Moreover, results suggest that different optimal phenotypes evolved among large clades within which extremes tended to be selected against. Conservatism in LMA was strongly related to growth form, as were selection intensity and phenotypic evolutionary rates: woody plants showed higher conservatism in relation to stronger stabilizing selection and lower evolutionary rates compared to herbaceous taxa. The evolutionary history of LMA thus paints different evolutionary trajectories of vascular plant species across clades, revealing the coordination of leaf trait evolution with growth forms in response to varying selection regimes.


Polymorphism of the major surface epitope of the CopB outer membrane protein of Moraxella catarrhalis.
The CopB outer membrane protein has been considered a vaccine candidate for the prevention of infections due to Moraxella catarrhalis. Monoclonal antibody 10F3 recognizes whole cells of about 70% of clinical isolates, suggesting that this epitope is reasonably conserved. To determine whether CopB has other surface epitopes, we analyzed M. catarrhalis isolates using polyclonal sera against recombinant CopB proteins from a 10F3 positive isolate and a 10F3 negative isolate, and polyclonal sera against synthetic peptides that contained the sequence corresponding to the 10F3 epitope region of three different isolates. Extensive cross-reactivity was observed with the anti-CopB sera towards purified recombinant CopB proteins in Western blot and antigen ELISA, implying that antigenic regions common to both proteins were present. However, anti-CopB sera resembled anti-CopB peptide sera in exhibiting similar binding specificity to whole cells, segregating M. catarrhalis isolates into four CopB groups. We subsequently cloned and sequenced the copB genes from representative isolates. The deduced CopB amino acid sequences and the degree of sequence identity also demonstrated the existence of the same four CopB groups. Each of the four groups had a unique sequence in the 10F3 epitope region and a fifth group had the epitope deleted. The polymorphism of the major surface epitope prompts further consideration regarding the utility of CopB as a vaccine component as well as the design of an efficacious CopB-based vaccine to achieve broad protection against Moraxella infection.


Fabrication tolerances of SOI based directional couplers and ring resonators.
In this work the effect of deviations of the waveguide shape introduced by manufacturing tolerances on the performance of lateral directional couplers and ring resonators based on SOI-rib-waveguides are investigated by using Full Wave 3D Finite Element Method. Beside dimensional deviations like waveguide width and slab thickness for the first time the influence of waveguide sidewall angle and wet chemical cleaning procedures on the device performance are carefully analyzed. Efficient measures against systematic process tolerances are proposed and possible actions to improve device stability and reproducibility are discussed.


Singular value analysis of the Mueller matrix in comparison with eigenvalue analysis of the coherency matrix in polarization characterization of media.
Singular values of the arbitrary Mueller matrix are determined to be indicators of some polarization properties of the medium such as depolarization and diattenuation. Whereas eigenvalue analysis of the coherency matrix may wrongly characterize media with simultaneous strong depolarization and diattenuation effects. The comparison between the patterns of changes in singular-value and eigenvalue trends of the coherency matrix in experimental Mueller matrices, shows that singular values of the Mueller matrix are more capable of discriminating media with close degrees of depolarization.


Porous Silicon-Based Catalysts for the Dehydration of Glycerol to High Value-Added Products.
Increasing worldwide biodiesel production has led to the generation of an important glycerol surplus, which needs to be valorized in order to improve the economic and environmental sustainability of the biodiesel industry. In this context, glycerol dehydration to acrolein by acid catalysis appears to be a potential route of glycerol valorization, since acrolein is an important intermediate for many chemical industries. The main drawback of this catalytic process is catalyst deactivation. Different alternatives have been proposed for overcoming it, such as the use of mesoporous materials in order to facilitate the diffusion of glycerol and reaction products, thus minimizing deactivation. This review compiles the main achievements of the use of mesoporous silica-containing materials that have been deployed either as a catalyst or for support in glycerol dehydration to acrolein. Thus, the effect of mesoporosity on both catalytic performance and deactivation will be discussed, as well as the blocking of pores by coke deposition.


Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma.
Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. In contrast with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.


Thinning and drilling laser-assisted hatching in thawed embryo transfer: A randomized controlled trial.
In frozen and thawed embryos, the zona pellucida (ZP) can be damaged due to hardening. Laser-assisted hatching (LAH) of embryos can increase the pregnancy rate. This study compared thinning and drilling of the ZP before frozen embryo transfer (FET). Patients were randomly allocated into two groups for LAH using thinning or drilling on day 2 after thawing. Twenty-five percent of the ZP circumference and 50% of the ZP thickness was removed in the thinning group, and a hole 40 µm in diameter was made in the drilling group. A total of 171 in vitro fertilization/intracytoplasmic sperm injection FET cycles, including 85 cycles with drilling LAH and 86 cycles with thinning LAH, were carried out. The thinning group had a similar β-human chorionic gonadotropin-positive rate (38.4% vs. 29.4%), implantation rate (16.5% vs. 14.4%), clinical pregnancy rate (36.0% vs. 25.9%), miscarriage rate (5.8% vs. 2.4%), ongoing pregnancy rate (30.2% vs. 23.5%), and multiple pregnancy rate (7.0% vs. 10.6%) to the drilling LAH group. There were no significant differences in pregnancy outcomes between subgroups defined based on age (older or younger than 35 years) or ZP thickness (greater or less than 17 µm) according to the LAH method. The present study demonstrated that partial ZP thinning or drilling resulted in similar outcomes in implantation and pregnancy rates using thawed embryos, irrespective of women's age or ZP thickness.


Development and validation of a symptom index for advanced hepatobiliary and pancreatic cancers: the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy (NCCN-FACT) Hepatobiliary-Pancreatic Symptom Index (NFHSI).
The 45-item Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire assesses health-related quality of life in patients with liver, bile duct, and pancreatic cancers. Although the FACT-Hep was initially derived from patient input, this study's researchers sought to verify adequate coverage of items by soliciting open-ended input from patients with advanced disease. As part of a larger study in collaboration with the National Comprehensive Cancer Network (NCCN), 50 people (60% male, 80% caucasian, average age 60.4 years) with stage 3 or 4 hepatobiliary or pancreatic cancer were recruited. Participants generated and ranked up to 10 important symptoms and concerns that physicians should monitor when assessing the value of chemotherapy. Patients were also able to provide open-ended, qualitative information that was evaluated systematically. Ten expert physicians also provided input on priority symptoms. The resulting 18-item NCCN-FACT Hepatobiliary-Pancreatic Symptom Index (NFHSI-18) demonstrated high internal consistency (α = .89) and moderate to strong correlations with measures of physical well-being (ρ = .76), emotional well-being (ρ = 0.52), and functional well-being (ρ = 0.57). Scores on the NFHSI-18 were also highly correlated with the original hepatobiliary scale of the FACT-Hep (ρ = .82; all P < .001). Compared with patients with better performance status, patients with poor performance status had worse NFHSI-18 symptom scores, F(3,47) = 9.74; P = .0003. The NFHSI-18 assesses symptoms of importance to patients with hepatobiliary and pancreatic cancers and demonstrates promising measurement properties. The scale is a good candidate for brief symptom assessment in clinical trials.