Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses

The signalling pathways initiated by members of the transforming growth factor-β (TGFβ) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial-mesenchymal transition (EMT) and apoptosis. TGFβ signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGFβ signalling pathway, we performed a pharmacological screen by using a cell line engineered to report the endogenous transcription of the TGFβ-responsive target gene PAI-1. The screen revealed that small molecule inhibitors of salt-inducible kinases (SIKs) attenuate TGFβ-mediated transcription of PAI-1 without affecting receptor-mediated SMAD phosphorylation, SMAD complex formation or nuclear translocation. We provide evidence that genetic inactivation of SIK isoforms also attenuates TGFβ-dependent transcriptional responses. Pharmacological inhibition of SIKs by using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGFβ stimulation. Our data therefore provide evidence for a novel function of SIKs in modulating TGFβ-mediated transcriptional and cellular responses.</p

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury

Atlantic Ocean influence on a shift in European climate in the 1990s

European climate exhibits variability on a wide range of timescales. Understanding the nature and drivers of this variability is an essential step in developing robust climate predictions and risk assessments. The Atlantic Ocean has been suggested as an important driver of variability in European climate on decadal timescales1, but the importance of this influence in recent decades has been unclear, partly because of difficulties in separating the influence of the Atlantic Ocean from other contributions, for example, from the tropical Pacific Ocean and the stratosphere. Here we analyse four data sets derived from observations to show that, during the 1990s, there was a substantial shift in European climate towards a pattern characterized by anomalously wet summers in northern Europe, and hot, dry, summers in southern Europe, with related shifts in spring and autumn. These changes in climate coincided with a substantial warming of the North Atlantic Ocean, towards a state last seen in the 1950s. The patterns of European climate change in the 1990s are consistent with earlier changes attributed to the influence of the North Atlantic Ocean, and provide compelling evidence that the Atlantic Ocean was the key driver. Our results suggest that the recent pattern of anomalies in European climate will persist as long as the North Atlantic Ocean remains anomalously warm

Advancing Decadal-Scale Climate Prediction in the North Atlantic Sector

The climate of the North Atlantic region exhibits fluctuations on decadal timescales that have large societal consequences. Prominent examples include hurricane activity in the Atlantic1, and surface-temperature and rainfall variations over North America2, Europe3 and northern Africa4. Although these multidecadal variations are potentially predictable if the current state of the ocean is known5, 6, 7, the lack of subsurface ocean observations8 that constrain this state has been a limiting factor for realizing the full skill potential of such predictions9. Here we apply a simple approach—that uses only sea surface temperature (SST) observations—to partly overcome this difficulty and perform retrospective decadal predictions with a climate model. Skill is improved significantly relative to predictions made with incomplete knowledge of the ocean state10, particularly in the North Atlantic and tropical Pacific oceans. Thus these results point towards the possibility of routine decadal climate predictions. Using this method, and by considering both internal natural climate variations and projected future anthropogenic forcing, we make the following forecast: over the next decade, the current Atlantic meridional overturning circulation will weaken to its long-term mean; moreover, North Atlantic SST and European and North American surface temperatures will cool slightly, whereas tropical Pacific SST will remain almost unchanged. Our results suggest that global surface temperature may not increase over the next decade, as natural climate variations in the North Atlantic and tropical Pacific temporarily offset the projected anthropogenic warming

Risk factors for recurrent injurious falls that require hospitalization for older adults with dementia: a population based study

Background: Older adults with dementia are at an increased risk of falls, however, little is known about risk factors for recurrent injurious falls (a subsequent fall after the first fall has occurred) among this group. This study aimed to identify risk factors for recurrent injurious falls requiring hospitalization among adults aged 60+ years with dementia. Methods: This retrospective, whole-population cohort study was conducted using the Western Australian Hospital Morbidity Data System and Western Australian Death Registrations from 2001 to 2013. Survival analysis using a stratified conditional Cox model (type 1) was undertaken to identify risk factors for recurrent injurious falls requiring hospitalization. Results: There were 32,519 participants with an index hospital admission with dementia during the study period. Over 27 % (n = 8970) of the cohort experienced a total of 11,073 injurious falls requiring hospitalization during follow up with 7297 individuals experiencing a single fall, 1330 experiencing two falls and 343 experiencing three or more falls. The median follow-up time for each individual was 2.49 years. Females were at a significantly increased risk of 7 % for recurrent injurious falls resulting in hospitalization (adjusted hazard ratio 1.07, 95 % CI 1.01–1.12), compared to males. Increasing age, living in rural areas, and having an injurious fall in the year prior to the index hospital admission with dementia also increased the risk of recurrent injurious falls resulting in hospitalization. Conclusions: Screening those with dementia for injurious falls history could help to identify those most at risk of recurrent injurious falls. Improvement of heath care an

Elevated plasma CXCL12 alpha is associated with a poorer prognosis in pulmonary arterial hypertension.

Recent work in preclinical models suggests that signalling via the pro-angiogenic and proinflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortalit

Genetic Organisation, Mobility and Predicted Functions of Genes on Integrated, Mobile Genetic Elements in Sequenced Strains of Clostridium difficile

Background: Clostridium difficile is the leading cause of hospital-associated diarrhoea in the US and Europe. Recently the incidence of C. difficile-associated disease has risen dramatically and concomitantly with the emergence of 'hypervirulent' strains associated with more severe disease and increased mortality. C. difficile contains numerous mobile genetic elements, resulting in the potential for a highly plastic genome. In the first sequenced strain, 630, there is one proven conjugative transposon (CTn), Tn5397, and six putative CTns (CTn1, CTn2 and CTn4-7), of which, CTn4 and CTn5 were capable of excision. In the second sequenced strain, R20291, two further CTns were described.Results: CTn1, CTn2 CTn4, CTn5 and CTn7 were shown to excise from the genome of strain 630 and transfer to strain CD37. A putative CTn from R20291, misleadingly termed a phage island previously, was shown to excise and to contain three putative mobilisable transposons, one of which was capable of excision. In silico probing of C. difficile genome sequences with recombinase gene fragments identified new putative conjugative and mobilisable transposons related to the elements in strains 630 and R20291. CTn5-like elements were described occupying different insertion sites in different strains, CTn1-like elements that have lost the ability to excise in some ribotype 027 strains were described and one strain was shown to contain CTn5-like and CTn7-like elements arranged in tandem. Additionally, using bioinformatics, we updated previous gene annotations and predicted novel functions for the accessory gene products on these new elements.Conclusions: The genomes of the C. difficile strains examined contain highly related CTns suggesting recent horizontal gene transfer. Several elements were capable of excision and conjugative transfer. The presence of antibiotic resistance genes and genes predicted to promote adaptation to the intestinal environment suggests that CTns play a role in the interaction of C. difficile with its human host

Declining resilience of ecosystem functions under biodiversity loss

The composition of species communities is changing rapidly through drivers such as habitat loss and climate change, with potentially serious consequences for the resilience of ecosystem functions on which humans depend. To assess such changes in resilience, we analyse trends in the frequency of species in Great Britain that provide key ecosystem functions-specifically decomposition, carbon sequestration, pollination, pest control and cultural values. For 4,424 species over four decades, there have been significant net declines among animal species that provide pollination, pest control and cultural values. Groups providing decomposition and carbon sequestration remain relatively stable, as fewer species are in decline and these are offset by large numbers of new arrivals into Great Britain. While there is general concern about degradation of a wide range of ecosystem functions, our results suggest actions should focus on particular functions for which there is evidence of substantial erosion of their resilience

Personality of wild male crested macaques (Macaca nigra).

Animal personalities, i.e. consistent differences in behavior across time and/or context, have received increased attention of behavioral biologists over the last years. Recent research shows that personalities represent traits on which natural and sexual selection work and which can have substantial fitness consequences. The aim of this study is to establish the personality structure of crested macaque (Macaca nigra) males as foundation for future studies on its adaptive value. We collected behavioral data through focal animal sampling and additionally conducted two sets of playback experiments. Results of a factor analysis on the behavioral data revealed a four factor structure with components we labeled Anxiety, Sociability, Connectedness and Aggressiveness. Results from the experiments revealed an additional and independent Boldness factor but the absence of Neophilia. Overall, this structure resembles other macaque and animal species with the exception of Connectedness, which might be a consequence of the species' tolerant social style. Our results thus not only form the basis for future studies on the adaptive value of personality in crested macaques but also contribute an important data point for investigating the evolution of personality structure from a comparative perspective by refining, for example, which personality factors characterized the last common ancestor of hominids and macaques