Reaction-diffusion systems with constant diffusivities: conditional symmetries and form-preserving transformations

Q-conditional symmetries (nonclassical symmetries) for a general class of two-component reaction-diffusion systems with constant diffusivities are studied. Using the recently introduced notion of Q-conditional symmetries of the first type (R. Cherniha J. Phys. A: Math. Theor., 2010. vol. 43., 405207), an exhaustive list of reaction-diffusion systems admitting such symmetry is derived. The form-preserving transformations for this class of systems are constructed and it is shown that this list contains only non-equivalent systems. The obtained symmetries permit to reduce the reaction-diffusion systems under study to two-dimensional systems of ordinary differential equations and to find exact solutions. As a non-trivial example, multiparameter families of exact solutions are explicitly constructed for two nonlinear reaction-diffusion systems. A possible interpretation to a biologically motivated model is presented

Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction

BACKGROUND: PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3β/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3β signaling and cell survival. CONCLUSIONS: PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI

Perinatal and sociodemographic factors at birth predicting conduct problems and violence to age 18 years: comparison of Brazilian and British birth cohorts.

This is the final published version. It was first published by Wiley at http://dx.doi.org/10.1111/jcpp.12369BACKGROUND: Many low- and middle-income countries have high levels of violence. Research in high-income countries shows that risk factors in the perinatal period are significant precursors of conduct problems which can develop into violence. It is not known whether the same early influences are important in lower income settings with higher rates of violence. This study compared perinatal and sociodemographic risk factors between Brazil and Britain, and their role in explaining higher rates of conduct problems and violence in Brazil. METHODS: Prospective population-based birth cohort studies were conducted in Pelotas, Brazil (N = 3,618) and Avon, Britain (N = 4,103). Eleven perinatal and sociodemographic risk factors were measured in questionnaires completed by mothers during the perinatal period. Conduct problems were measured in questionnaires completed by mothers at age 11, and violence in self-report questionnaires completed by adolescents at age 18. RESULTS: Conduct problems were predicted by similar risk factors in Brazil and Britain. Female violence was predicted by several of the same risk factors in both countries. However, male violence in Brazil was associated with only one risk factor, and several risk factor associations were weaker in Brazil than in Britain for both females and males. Almost 20% of the higher risk for conduct problems in Brazil compared to Britain was explained by differential exposure to risk factors. The percentage of the cross-national difference in violence explained by early risk factors was 15% for females and 8% for males. CONCLUSIONS: A nontrivial proportion of cross-national differences in antisocial behaviour are related to perinatal and sociodemographic conditions at the start of life. However, risk factor associations are weaker in Brazil than in Britain, and influences in other developmental periods are probably of particular importance for understanding male youth violence in Brazil.The 1993 Pelotas Birth Cohort Study is currently supported by the Wellcome Trust through the programme entitled Major Awards for Latin America on Health Consequences of Population Change (Grant: 086974/Z/08/Z). The European Union, National Support Program for Centers of Excellence (PRONEX), the Brazilian National Research Council (CNPq), and the Brazilian Ministry of Health supported previous phases of the study. The UK Medical Research Council and the Wellcome Trust (Grant: 092731) and the University of Bristol provide core support for ALSPAC. Additional support for the data collected at age 18 in this paper was provided by UK Medical Research Council (Grants G0800612 and G0802736).The research for this specific article was funded by the Wellcome Trust (Grant: 089963/Z/09/Z). The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. Yulia Shenderovich helped prepare the tables. The authors have declared that they have no competing or potential conflicts of interest

Endothelial and cardiomyocyte PI3Kβ divergently regulate cardiac remodelling in response to ischaemic injury

AIMS: Cardiac remodeling in the ischemic heart determines prognosis in patients with ischemic heart disease (IHD), while enhancement of angiogenesis and cell survival has shown great potential for IHD despite translational challenges. Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway plays a critical role in promoting angiogenesis and cell survival. However, the effect of PI3Kβ in the ischemic heart is poorly understood. This study investigates the role of endothelial and cardiomyocyte PI3Kβ in post-infarct cardiac remodeling. METHODS AND RESEARCH: PI3Kβ catalytic subunit-p110β level was increased in infarcted murine and human hearts. Using cell type-specific loss-of-function approaches, we reported novel and distinct actions of p110β in endothelial cells versus cardiomyocytes in response to myocardial ischemic injury. Inactivation of endothelial p110β resulted in marked resistance to infarction and adverse cardiac remodeling with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured endothelial cells with p110β knockout or inhibition displayed preferential PI3Kα/Akt/eNOS signaling that consequently promoted protective signaling and angiogenesis. In contrast, mice with cardiomyocyte p110β-deficiency exhibited adverse post-infarct ventricular remodeling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of cardiomyocytes to ischemia-mediated cell death. Disruption of cardiomyocyte p110β signaling compromised nuclear p110β and phospho-Akt levels leading to perturbed gene expression and elevated pro-cell death protein levels, increasing the susceptibility to cardiomyocyte death. A similar divergent response of PI3Kβ endothelial and cardiomyocyte mutant mice was seen using a model of myocardial ischemia-reperfusion injury. CONCLUSIONS: These data demonstrate novel, differential, and cell-specific functions of PI3Kβ in the ischemic heart. While loss of endothelial PI3Kβ activity produces cardioprotective effects, cardiomyocyte PI3Kβ is protective against myocardial ischemic injury

Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke:an individual patient data meta-analysis of randomised controlled trials

SummaryBackgroundMany international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke.MethodsWe obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome “dead or dependent” in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis.FindingsPatients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59–0·67) and for haemorrhagic events was 0·60 (0·55–0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events.InterpretationThere was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised.FundingMRC

A question of scale: Human migrations writ large and small

Several recent papers illustrate the importance of migration and gene flow in molding the patterns of genetic variation observed in humans today. We place the varied demographic processes covered by these terms into a more general framework, and discuss some of the challenges facing attempts to reconstruct past human mobility and determine its influence on our genetic heritage

Musculoskeletal impairment survey in Rwanda: Design of survey tool, survey methodology, and results of the pilot study (a cross sectional survey)

BACKGROUND: Musculoskeletal impairment (MSI) is an important cause of morbidity and mortality worldwide, especially in developing countries. Prevalence studies for MSI in the developing world have used varying methodologies and are seldom directly comparable. This study aimed to develop a new tool to screen for and diagnose MSI and to pilot test the methodology for a national survey in Rwanda. METHODS: A 7 question screening tool to identify cases of MSI was developed through literature review and discussions with healthcare professionals. To validate the tool, trained rehabilitation technicians screened 93 previously identified gold standard 'cases' and 86 'non cases'. Sensitivity, specificity and positive predictive value were calculated. A standardised examination protocol was developed to determine the aetiology and diagnosis of MSI for those who fail the screening test. For the national survey in Rwanda, multistage cluster random sampling, with probability proportional to size procedures will be used for selection of a cross-sectional, nationally representative sample of the population. Households to be surveyed will be chosen through compact segment sampling and all individuals within chosen households will be screened. A pilot survey of 680 individuals was conducted using the protocol. RESULTS: The screening tool demonstrated 99% sensitivity and 97% specificity for MSI, and a positive predictive value of 98%. During the pilot study 468 out of 680 eligible subjects (69%) were screened. 45 diagnoses were identified in 38 persons who were cases of MSI. The subjects were grouped into categories based on diagnostic subgroups of congenital (1), traumatic (17), infective (2) neurological (6) and other acquired(19). They were also separated into mild (42.1%), moderate (42.1%) and severe (15.8%) cases, using an operational definition derived from the World Health Organisation's International Classification of Functioning, Disability and Health. CONCLUSION: The screening tool had good sensitivity and specificity and was appropriate for use in a national survey. The pilot study showed that the survey protocol was appropriate for measuring the prevalence of MSI in Rwanda. This survey is an important step to building a sound epidemiological understanding of MSI, to enable appropriate health service planning

The relevance of nanoscale biological fragments for ice nucleation in clouds

Most studies of the role of biological entities as atmospheric ice-nucleating particles have focused on relatively rare supermicron particles such as bacterial cells, fungal spores and pollen grains. However, it is not clear that there are sufficient numbers of these particles in the atmosphere to strongly influence clouds. Here we show that the ice-nucleating activity of a fungus from the ubiquitous genus Fusarium is related to the presence of nanometre-scale particles which are far more numerous, and therefore potentially far more important for cloud glaciation than whole intact spores or hyphae. In addition, we quantify the ice-nucleating activity of nano-ice nucleating particles (nano-INPs) washed off pollen and also show that nano-INPs are present in a soil sample. Based on these results, we suggest that there is a reservoir of biological nano-INPs present in the environment which may, for example, become aerosolised in association with fertile soil dust particles

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Pathological and ecological host consequences of infection by an introduced fish parasite

The infection consequences of the introduced cestode fish parasite Bothriocephalus acheilognathi were studied in a cohort of wild, young-of-the-year common carp Cyprinus carpio that lacked co-evolution with the parasite. Within the cohort, parasite prevalence was 42% and parasite burdens were up to 12% body weight. Pathological changes within the intestinal tract of parasitized carp included distension of the gut wall, epithelial compression and degeneration, pressure necrosis and varied inflammatory changes. These were most pronounced in regions containing the largest proportion of mature proglottids. Although the body lengths of parasitized and non-parasitized fish were not significantly different, parasitized fish were of lower body condition and reduced weight compared to non-parasitized conspecifics. Stable isotope analysis (δ15N and δ13C) revealed trophic impacts associated with infection, particularly for δ15N where values for parasitized fish were significantly reduced as their parasite burden increased. In a controlled aquarium environment where the fish were fed ad libitum on an identical food source, there was no significant difference in values of δ15N and δ13C between parasitized and non-parasitized fish. The growth consequences remained, however, with parasitized fish growing significantly slower than non-parasitized fish, with their feeding rate (items s−1) also significantly lower. Thus, infection by an introduced parasite had multiple pathological, ecological and trophic impacts on a host with no experience of the parasite