SN 2005cs in M51-II. Complete evolution in the optical and the near-infrared

We present the results of the one-year long observational campaign of the type 11 plateau SN 2005cs, which exploded in the nearby spiral galaxy M51 (the Whirlpool galaxy). This extensive data set makes SN 2005cs the best observed low-luminosity, Ni-56-poor type II plateau event so far and one of the best core-collapse supernovae ever. The optical and near-infrared spectra show narrow P-Cygni lines characteristic of this SN family, which are indicative of a very low expansion velocity (about 1000 km s(-1)) of the ejected material. The optical light curves cover both the plateau phase and the late-time radioactive tail, until about 380 d after core-collapse. Numerous unfiltered observations obtained by amateur astronomers give us the rare opportunity to monitor the fast rise to maximum light, lasting about 2 cl. In addition to optical observations, we also present near-infrared light curves that (together with already published ultraviolet observations) allow us to construct for the first time a reliable bolometric light Curve for an object of this class. Finally. comparing the observed data withthose derived front it semi-analytic model, we infer for SN 2005cs a Ni-56 mass of about 3 x 10(-3) M-circle dot a total ejected mass of 8-13 M-circle dot and an explosion energy of about 3 x 10(50) erg.

Binding site of AMPA-receptor allosteric modulator

The computer molecular docking of piperonyl acid piperidide (BDP) and some its analogs already known as ampakins was conducted for estimating their possible binding with AMPA-receptor glutamate domains in cyclothiazide binding area and for further design of new structures maximally complimentary to the receptor. On the base of the conducted docking it can be suggested that the binding site of BDP (amides of benzodioxane-6-carboxylic and piperonyl acids) analogs is located in AMPA-receptor cyclothiazide binding pocket. It is shown that formation of protein-ligand complexes of AMPA-receptor with benzodioxane-6-carboxylic and piperonyl acid derivatives, similarly to cyclothiazide, proceeds with interaction with Ser497, Leu751, which significance is confirmed by site-specific mutagenesis.

Balancing Inflammatory, Lipid, and Xenobiotic Signaling Pathways by VSL#3, a Biotherapeutic Agent, in the Treatment of Inflammatory Bowel Disease

Background: The interleukin 10 knockout mouse (IL10-KO) is a model of human inflammatory bowel disease (IBD) used to Study host microbial interactions and the action of potential therapeutics. Using Affymetrix data analysis, important signaling pathways and transcription factors relevant to gut inflammation and antiinflammatory probiotics were identified.

Methods: Affymetrix microarray analysis on both wildtype (WT) and IL10-KO mice orally administered with and without the probiotic VSL#3 was performed and the results validated by real-time polymerase chain reaction (PCR), immunocytochemistry, proteomics, and histopathology. Changes in metabolically active bacteria were assessed with denaturing gradient gel electrophoresis (DGGE).

Results: Inflammation in IL10-KO mice was characterized by differential regulation of inflammatory, nuclear receptor, lipid, and xenobiotic signaling pathways. Probiotic intervention resulted in downregulation of CXCL9 (fold change [FC] = -3.98, false discovery rate [FDR] = 0.019), CXCL10 (FC = -4.83, FDR = 0.0008), CCL5 (FC -3.47 FDR = 0.017), T-cell activation (Itgal [FC = -4.72, FDR = 0.00009], Itgae [FC = -2.54 FDR = 0.0044]) and the autophagy gene IRGM (FC = -1.94, FDR = 0.01), a recently identified susceptibility gene in human IBD. Consistent with a marked reduction in integrins, probiotic treatment decreased the number of CCL5+ CD3+ double-positive T Cells and upregulated galectin2, which triggers apoptosis of activated T cells. Importantly, genes associated with lipid and PPAR signaling (PPAR alpha [FC = 2.36, FDR = 0.043], PPARGC1 alpha [FC 2.58, FDR = 0.016], Nrld2 [FC = 3.11, FDR = 0.0067]) were also upregulated. Altered microbial diversity was noted in probiotic-treated mice.

Conclusions: Bioinformatics analysis revealed important immune response. phagocytic and inflammatory pathways dominated by elevation of T-helper cell 1 type (TH1) transcription factors in IL10-KO mice. Probiotic intervention resulted in a site-specific reduction of these pathways but importantly upregulated PPAR, xenobiotic, and lipid signaling genes. potential antagonists of NF-kappa B inflammatory pathways.

Topoisomerase IIα promotes activation of RNA polymerase I transcription by facilitating pre-initiation complex formation

Type II DNA topoisomerases catalyse DNA double-strand cleavage, passage and re-ligation to effect topological changes. There is considerable interest in elucidating topoisomerase II roles, particularly as these proteins are targets for anti-cancer drugs. Here we uncover a role for topoisomerase IIa in RNA polymerase I-directed ribosomal RNA gene transcription, which drives cell growth and proliferation and is upregulated in cancer cells. Our data suggest that topoisomerase IIa is a component of the initiation-competent RNA polymerase Iß complex and interacts directly with RNA polymerase I-associated transcription factor RRN3, which targets the polymerase to promoter-bound SL1 in pre-initiation complex formation. In cells, activation of rDNA transcription is reduced by inhibition or depletion of topoisomerase II, and this is accompanied by reduced transient double-strand DNA cleavage in the rDNA-promoter region and reduced pre-initiation complex formation. We propose that topoisomerase IIa functions in RNA polymerase I transcription to produce topological changes at the rDNA promoter that facilitate efficient de novo pre-initiation complex formation.

Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the Acute Respiratory Distress Syndrome (ARDS). In animal models of ARDS, Keratinocyte Growth Factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.

Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS.

Methods: Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50μg lipopolysaccharide. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.

Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of Surfactant Protein D (SP-D), MMP-9, IL-1Ra, GM-CSF and CRP. In vitro, BAL fluid from KGF-treated subjects (KGF BAL) inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF pre-treated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.

Conclusions: KGF treatment increases BAL SP-D, a marker of type II alveolar epithelial cell proliferation in a human model of ALI. Additionally KGF increases alveolar concentrations of the anti-inflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).

Predicting the ecological impacts of a new freshwater invader:Functional responses and prey selectivity of the 'killer shrimp', Dikerogammarus villosus, compared to the native Gammarus pulex

The ability to predict the likely ecological impacts of invasive species in fresh waters is a pressing research requirement. Whilst comparisons of species traits and considerations of invasion history have some efficacy in this respect, we require robust methods that can compare the effects of native and invasive species. Here, we utilise comparative functional responses and prey selectivity experiments to understand and predict the ecological impact of an invader as compared to a native. We compared the predatory functional responses of an emerging invasive species in Europe, the 'killer shrimp', Dikerogammarus villosus, and an analogous native species, Gammarus pulex, towards three representative prey species: Asellus aquaticus, Daphnia magna and Chironomus sp. Furthermore, as ecological impact may be greater for invasive species with more indiscriminate feeding habits, we compared the selectivity for the three prey types between the invasive and native species. In both the presence and absence of experimental habitats, large D. villosus, and those matched for body size with G. pulex, generally showed higher (Type II) functional responses than G. pulex, with the invasive species exhibiting higher maximum feeding rates. Further, D. villosus exhibited significantly more indiscriminate prey selection compared with G. pulex, a trait that became more evident as the invader increased in size. Differences in functional responses and prey selectivity were prey species specific, with higher to lower predicted impacts in the order A. aquaticus, D. magna and Chironomus sp. This is in accord with the impact of this invasive species on macroinvertebrates in the field. We thus provide understanding of the known ecological impact of D. villosus and discuss the utility of the phenomenological use of comparative functional responses and resource use as a tool through which the potential ecological impacts of invasive species may be identified. © 2013 John Wiley & Sons Ltd.

Cadaveric fascia lata pubovaginal slings:early results on safety, efficacy and patient satisfaction

Objective To prospectively evaluate and quantify the efficacy of cadaveric fascia lata (CFL) as an allograft material in pubovaginal sling placement to treat stress urinary incontinence (SUI).

Patients and methods Thirty-one women with SUI (25 type II and six type III; mean age 63 years, range 40-75) had a CFL pubovaginal sling placed transvaginally. The operative time, blood loss, surgical complications and mean hospital stay were all documented. Before and at 4 months and 1 year after surgery each patient completed a 3-day voiding diary and validated voiding questionnaires (functional inquiry into voiding habits, Urogenital Distress Inventory and Incontinence Impact Questionnaire, including visual analogue scales).

Results The mean (range) operative time was 71 (50-120) min, blood loss 78.7 (20-250) mL and hospital stay 1.2 (1-2) days; there were no surgical complications. Over the mean follow-up of 13.5 months, complete resolution of SUI was reported by 29 (93%) patients. Overactive bladder symptoms were present in 23 (74%) patients before surgery, 21 (68%) at 4 months and two (6%) at 1 year; 80% of patients with low (<15 cmH (2) O) voiding pressures before surgery required self-catheterization afterward, as did 36% at 4 months, but only one (3%) at 1 year. Twenty-four (77%) patients needed to adopt specific postures to facilitate voiding. After surgery there was a significant reduction in daytime frequency, leakage episodes and pad use (P <0.05). The severity of leak and storage symptoms was also significantly less (P <0.002), whilst the severity of obstructive symptoms remained unchanged. Mean subjective levels of improvement were 69% at 4 months and 85% at 1 year, with corresponding objective satisfaction levels of 61% and 69%, respectively. At 1 year, approximate to 80% of the patients said they would undergo the procedure again and/or recommend it to a friend.

Conclusion Placing a pubovaginal sling of CFL allograft is a highly effective, safe surgical approach for resolving SUI, with a short operative time and rapid recovery. Storage symptoms are significantly improved, and subjective improvement and satisfaction rates are high.

The molecular basis of galactosemia - Past, present and future

Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100years has seen considerable progress in understanding the underlying genetics and biochemistry of this condition. Initial studies concentrated on increasing the understanding of the clinical manifestations of the disease. However, Leloir's discovery of the pathway of galactose catabolism in the 1940s and 1950s enabled other scientists, notably Kalckar, to link the disease to a specific enzymatic step in the pathway. Kalckar's work established that defects in galactose 1-phosphate uridylyltransferase (GALT) were responsible for the majority of cases of galactosemia. However, over the next three decades it became clear that there were two other forms of galactosemia: type II resulting from deficiencies in galactokinase (GALK1) and type III where the affected enzyme is UDP-galactose 4'-epimerase (GALE). From the 1970s, molecular biology approaches were applied to galactosemia. The chromosomal locations and DNA sequences of the three genes were determined. These studies enabled modern biochemical studies. Structures of the proteins have been determined and biochemical studies have shown that enzymatic impairment often results from misfolding and consequent protein instability. Cellular and model organism studies have demonstrated that reduced GALT or GALE activity results in increased oxidative stress. Thus, after a century of progress, it is possible to conceive of improved therapies including drugs to manipulate the pathway to reduce potentially toxic intermediates, antioxidants to reduce the oxidative stress of cells or use of "pharmacological chaperones" to stabilise the affected proteins.

Multidimensional rehabilitation programmes for adult cancer survivors

Background: Multidimensional rehabilitation programmes (MDRPs) have developed in response to the growing number of people living with and surviving cancer. MDRPs comprise a physical component and a psychosocial component. Studies of the effectiveness of these programmes have not been reviewed and synthesised.

Objectives: To conduct a systematic review of studies examining the effectiveness of MDRPs in terms of maintaining or improving the physical and psychosocial well-being of adult cancer survivors.

Search methods: We conducted electronic searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsychINFO up to February 2012.

Selection criteria: Selection criteria focused on randomised controlled trials (RCTs) of multidimensional interventions for adult cancer survivors. Interventions had to include a physical component and a psychosocial component and to have been carried out on two or more occasions following completion of primary cancer treatment. Outcomes had to be assessed using validated measures of physical health and psychosocial well-being. Non-English language papers were included.

Data collection and analysis: Pairs of review authors independently selected trials, rated their methodological quality and extracted relevant data. Although meta-analyses of primary and secondary endpoints were planned there was a high level of study heterogeneity and only one common outcome measure (SF-36) could be statistically synthesised. In addition, we conducted a narrative analysis of interventions, particularly in terms of inspecting and identifying intervention components, grouping or categorising interventions and examining potential common links and outcomes.

Main results: Twelve RCTs (comprising 1669 participants) met the eligibility criteria. We judged five studies to have a moderate risk of bias and assessed the remaining seven as having a high risk of bias. It was possible to include SF-36 physical health component scores from five studies in a meta-analysis. Participating in a MDRP was associated with an increase in SF-36 physical health component scores (mean difference (MD) 2.22, 95% confidence interval (CI) 0.12 to 4.31, P = 0.04). The findings from the narrative analysis suggested that MDRPs with a single domain or outcome focus appeared to be more successful than programmes with multiple aims. In addition, programmes that comprised participants with different types of cancer compared to cancer site-specific programmes were more likely to show positive improvements in physical outcomes. The most effective mode of service delivery appeared to be face-to-face contact supplemented with at least one follow-up telephone call. There was no evidence to indicate that MDRPs which lasted longer than six months improved outcomes beyond the level attained at six months. In addition, there was no evidence to suggest that services were more effective if they were delivered by a particular type of health professional.

Authors' conclusions: There is some evidence to support the effectiveness of brief, focused MDRPs for cancer survivors. Rigorous and methodologically sound clinical trials that include an economic analysis are required.

Low luminosity TypeII supernovae-II. Pointing towards moderate mass precursors

We present new data for five underluminous Type II-plateau supernovae (SNe IIP), namely SN 1999gn, SN 2002gd, SN 2003Z, SN 2004eg and SN 2006ov. This new sample of lowluminosity SNe IIP (LL SNe IIP) is analysed together with similar objects studied in the past. All of them show a flat light-curve plateau lasting about 100 d, an underluminous late-time exponential tail, intrinsic colours that are unusually red, and spectra showing prominent and narrow P Cygni lines. A velocity of the ejected material below 10³ km s^-1 is inferred from measurements at the end of the plateau. The 56Ni masses ejected in the explosion are very small (≤10^-2 M⊙). We investigate the correlations among ⁵⁶Ni mass, expansion velocity of the ejecta and absolute magnitude in the middle of the plateau, confirming the main findings of Hamuy, according to which events showing brighter plateau and larger expansion velocities are expected to produce more 56Ni. We propose that these faint objects represent the LL tail of a continuous distribution in parameters space of SNe IIP. The physical properties of the progenitors at the explosion are estimated through the hydrodynamical modelling of the observables for two representative events of this class, namely SN 2005cs and SN 2008in. We find that the majority of LL SNe IIP, and quite possibly all, originate in the core collapse of intermediate-mass stars, in the mass range 10-15 M⊙. 

Supernovae and radio transients in M82

We present optical and near-infrared (NIR) photometry and NIR spectroscopy of SN 2004am, the only optically detected supernova (SN) in M82. These demonstrate that SN 2004am was a highly reddened Type II-P SN similar to the low-luminosity Type II-P events such as SNe 1997D and 2005cs. We show that SN 2004am was located coincident with the obscured super star cluster M82-L, and from the cluster age infer a progenitor mass of 12{^{+ 7}_{- 3}} M⊙. In addition to this, we present a high spatial resolution Gemini-North Telescope K-band adaptive optics image of the site of SN 2008iz and a second transient of uncertain nature, both detected so far only at radio wavelengths. Using image subtraction techniques together with archival data from the Hubble Space Telescope, we are able to recover a NIR transient source coincident with both objects. We find the likely extinction towards SN 2008iz to be not more than AV ˜ 10. The nature of the second transient remains elusive and we regard an extremely bright microquasar in M82 as the most plausible scenario.

Tumor necrosis factor receptor expression and signaling in renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC), a tubular epithelial cell (TEC) malignancy, frequently secretes tumor necrosis factor (TNF). TNF signals via two distinct receptors (TNFRs). TNFR1, expressed in normal kidney primarily on endothelial cells, activates apoptotic signaling kinase 1 and nuclear factor-kappaB (NF-kappaB) and induces cell death, whereas TNFR2, inducibly expressed on endothelial cells and on TECs by injury, activates endothelial/epithelial tyrosine kinase (Etk), which trans-activates vascular endothelial growth factor receptor 2 (VEGFR2) to promote cell proliferation. We investigated TNFR expression in clinical samples and function in short-term organ cultures of ccRCC tissue treated with wild-type TNF or specific muteins selective for TNFR1 (R1-TNF) or TNFR2 (R2-TNF). There is a significant increase in TNFR2 but not TNFR1 expression on malignant TECs that correlates with increasing malignant grade. In ccRCC organ cultures, R1-TNF increases TNFR1, activates apoptotic signaling kinase and NF-kappaB, and promotes apoptosis in malignant TECs. R2-TNF increases TNFR2, activates NF-kappaB, Etk, and VEGFR2 and increases entry into the cell cycle. Wild-type TNF induces both sets of responses. R2-TNF actions are blocked by pretreatment with a VEGFR2 kinase inhibitor. We conclude that TNF, acting through TNFR2, is an autocrine growth factor for ccRCC acting via Etk-VEGFR2 cross-talk, insights that may provide a more effective therapeutic approach to this disease.

Overweight and obesity on the island of Ireland: an estimation of costs

Objectives The increasing prevalence of overweight and obesity worldwide continues to compromise population health and creates a wider societal cost in terms of productivity loss and premature mortality. Despite extensive international literature on the cost of overweight and obesity, findings are inconsistent between Europe and the USA, and particularly within Europe. Studies vary on issues of focus, specific costs and methods. This study aims to estimate the healthcare and productivity costs of overweight and obesity for the island of Ireland in 2009, using both top-down and bottom-up approaches.

Methods Costs were estimated across four categories: healthcare utilisation, drug costs, work absenteeism and premature mortality. Healthcare costs were estimated using Population Attributable Fractions (PAFs). PAFs were applied to national cost data for hospital care and drug prescribing. PAFs were also applied to social welfare and national mortality data to estimate productivity costs due to absenteeism and premature mortality.

Results The healthcare costs of overweight and obesity in 2009 were estimated at €437 million for the Republic of Ireland (ROI) and €127.41 million for NI. Productivity loss due to overweight and obesity was up to €865 million for ROI and €362 million for NI. The main drivers of healthcare costs are cardiovascular disease, type II diabetes, colon cancer, stroke and gallbladder disease. In terms of absenteeism, low back pain is the main driver in both jurisdictions, and for productivity loss due to premature mortality the primary driver of cost is coronary heart disease.

Conclusions The costs are substantial, and urgent public health action is required in Ireland to address the problem of increasing prevalence of overweight and obesity, which if left unchecked will lead to unsustainable cost escalation within the health service and unacceptable societal costs.

SN 2011dh: DISCOVERY OF A TYPE IIb SUPERNOVA FROM A COMPACT PROGENITOR IN THE NEARBY GALAXY M51

On 2011 May 31 UT a supernova (SN) exploded in the nearby galaxy M51 (the Whirlpool Galaxy). We discovered this event using small telescopes equipped with CCD cameras and also detected it with the Palomar Transient Factory survey, rapidly confirming it to be a Type II SN. Here, we present multi-color ultraviolet through infrared photometry which is used to calculate the bolometric luminosity and a series of spectra. Our early-time observations indicate that SN 2011dh resulted from the explosion of a relatively compact progenitor star. Rapid shock-breakout cooling leads to relatively low temperatures in early-time spectra, compared to explosions of red supergiant stars, as well as a rapid early light curve decline. Optical spectra of SN 2011dh are dominated by H lines out to day 10 after explosion, after which He I lines develop. This SN is likely a member of the cIIb (compact IIb) class, with progenitor radius larger than that of SN 2008ax and smaller than the eIIb (extended IIb) SN 1993J progenitor. Our data imply that the object identified in pre-explosion Hubble Space Telescope images at the SN location is possibly a companion to the progenitor or a blended source, and not the progenitor star itself, as its radius (~1013 cm) would be highly inconsistent with constraints from our post-explosion spectra.

Galactokinase promiscuity: a question of flexibility?

Galactokinase catalyses the first committed step of the Leloir pathway, i.e. the ATP-dependent phosphorylation of α-D-galactose at C1-OH. Reduced galactokinase activity results in the inherited metabolic disease type II galactosaemia. However, inhibition of galactokinase is considered a viable approach to treating more severe forms of galactosaemia (types I and III). Considerable progress has been made in the identification of high affinity, selective inhibitors. Although the structure of galactokinase from a variety of species is known, its catalytic mechanism remains uncertain. Although the bulk of evidence suggests that the reaction proceeds via an active site base mechanism, some experimental and theoretical studies contradict this. The enzyme has potential as a biocatalyst in the production of sugar 1-phosphates. This potential is limited by its high specificity. A variety of approaches have been taken to identify galactokinase variants which are more promiscuous. These have broadened galactokinase's specificity to include a wide range of D- and L-sugars. Initial studies suggest that some of these alterations result in increased flexibility at the active site. It is suggested that modulation of protein flexibility is at least as important as structural modifications in determining the success or failure of enzyme engineering.