Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts

Aims: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. Methods and Results: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. Conclusion: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia

Heat treatment significantly increases the sharpness of silcrete stone tools

Humans were regularly heat-treating stone tool raw materials as early as 130,000 years ago. The late Middle Stone Age (MSA) and Late Stone Age (LSA) of South Africa's Western Cape region provides some of the earliest and most pervasive archaeological evidence for this behaviour. While archaeologists are beginning to understand the flaking implications of raw material heat treatment, its potential functional benefits remain unanswered. Using silcrete from the Western Cape region, we investigate the impact of heat treatment on stone tool cutting performance. We quantify the sharpness of silcrete in its natural, unheated form, before comparing it with silcrete heated in three different conditions. Results show that heat-treated silcrete can be significantly sharper than unheated alternatives, with cutting forces halving and energy requirements reducing by approximately two-thirds. The data suggest that silcrete may have been heat treated during the South African MSA and LSA to increase the sharpness and performance of stone cutting edges. This early example of material engineering has implications for understanding Stone Age populations’ technological capabilities, inventiveness and raw material choices. We predict that heat-treatment behaviours in other prehistoric and ethnographic contexts may also be linked to increases in edge sharpness and concerns about functional performance

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications

The genome of the seagrass <i>Zostera marina</i> reveals angiosperm adaptation to the sea

Seagrasses colonized the sea on at least three independent occasions to form the basis of one of the most productive and widespread coastal ecosystems on the planet. Here we report the genome of Zostera marina (L.), the first, to our knowledge, marine angiosperm to be fully sequenced. This reveals unique insights into the genomic losses and gains involved in achieving the structural and physiological adaptations required for its marine lifestyle, arguably the most severe habitat shift ever accomplished by flowering plants. Key angiosperm innovations that were lost include the entire repertoire of stomatal genes, genes involved in the synthesis of terpenoids and ethylene signalling, and genes for ultraviolet protection and phytochromes for far-red sensing. Seagrasses have also regained functions enabling them to adjust to full salinity. Their cell walls contain all of the polysaccharides typical of land plants, but also contain polyanionic, low-methylated pectins and sulfated galactans, a feature shared with the cell walls of all macroalgae and that is important for ion homoeostasis, nutrient uptake and O2/CO2 exchange through leaf epidermal cells. The Z. marina genome resource will markedly advance a wide range of functional ecological studies from adaptation of marine ecosystems under climate warming, to unravelling the mechanisms of osmoregulation under high salinities that may further inform our understanding of the evolution of salt tolerance in crop plants

MicroRNA Expression Profiling Identifies Activated B Cell Status in Chronic Lymphocytic Leukemia Cells

Chronic lymphocytic leukemia (CLL) is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA) expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA) identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70+ and IgVH unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL

The art of indigeneity: Aesthetics and competition in Mexican economies of culture

On the basis of ethnographic research with woodcarvers in Oaxaca, Mexico, this paper investigates the role that aesthetic practices play in economic competition in cultural markets. I explain how one family has become the most successful artisans in their village by aesthetically referencing the indigenous art that is highly sought after by the North American ethnic art market. By reformulating Bourdieu's analysis of artistic fields, I argue that aesthetic competition should be theorised at the level of genres, which allow insight into how individual aesthetic innovations may transform the fields in which art is produced and circulated. I show that by referencing indigeneity, this successful family not only accesses a new market but also renders their work more authoritative than the carvings of their neighbours, which aesthetically reference Mexican ‘artesanías’ (craftwork). In so doing, they not only earn more money but also change the ways that Oaxacan woodcarvings are valued in general

MicroRNA-296 is enriched in cancer cells and downregulates p21WAF1 mRNA expression via interaction with its 3′ untranslated region

MicroRNAs (miRNAs) are a class of noncoding small RNAs that act as negative regulators of gene expression. To identify miRNAs that may regulate human cell immortalization and carcinogenesis, we performed comparative miRNA array profiling of human normal and SV40-T antigen immortalized cells. We found that miR-296 was upregulated in immortalized cells that also had activation of telomerase. By an independent experiment on genomic analysis of cancer cells we found that chromosome region (20q13.32), where miR-296 is located, was amplified in 28/36 cell lines, and most of these showed enriched miR-296 expression. Overexpression of miR-296 in human cancer cells, with and without telomerase activity, had no effect on their telomerase function. Instead, it suppressed p53 function that is frequently downregulated during human cell immortalization and carcinogenesis. By monitoring the activity of a luciferase reporter connected to p53 and p21WAF1 (p21) untranslated regions (UTRs), we demonstrate that miR-296 interacts with the p21-3′UTR, and the Hu binding site of p21-3′UTR was identified as a potential miR-296 target site. We demonstrate for the first time that miR-296 is frequently upregulated during immortalization of human cells and contributes to carcinogenesis by downregulation of p53-p21WAF1 pathway

A Pilot Study of Abnormal Growth in Autism Spectrum Disorders and Other Childhood Psychiatric Disorders

The aims of the current study were to examine whether early growth abnormalities are (a) comparable in autism spectrum disorders (ASD) and other childhood psychiatric disorders, and (b) specific to the brain or generalized to the whole body. Head circumference, height, and weight were measured during the first 19 months of life in 129 children with ASD and 59 children with non-ASD psychiatric disorders. Both groups showed comparable abnormal patterns of growth compared to population norms, especially regarding height and head circumference in relation to height. Thus abnormal growth appears to be related to psychiatric disorders in general and is mainly expressed as an accelerated growth of height not matched by an increase in weight or head circumference

Inhibition of MicroRNA miR-222 with LNA Inhibitor Can Reduce Cell Proliferation in B Chronic Lymphoblastic Leukemia

MicroRNAs (miRNAs) are small regulatory molecules that negatively regulate gene expression by base-pairing with their target mRNAs. miRNAs have contribute significantly to cancer biology and recent studies have demonstrated the oncogenic or tumor-suppressing role in cancer cells. In many tumors up-regulation miRNAs has been reported especially miR-222 has been shown to be up-regulated in B chronic lymphocytic leukemia (B-CLL). In this study we assessed the effected inhibition of miR-222 in cell viability of B-CLL. We performed inhibition of mir-222 in B-CLL cell line (183-E95) using locked nucleic acid (LNA) antagomir. At different time points after LNA-anti-mir-222 transfection, miR-222 quantitation and cell viability were assessed by qRT-real time polymerase chain reaction and MTT assays. The data were analyzed by independent t test and one way ANOVA. Down-regulation of miR-222 in B-CLL cell line (183-E95) with LNA antagomir decreased cell viability in B-CLL. Cell viability gradually decreased over time as the viability of LNA-anti-mir transfected cells was <47 % of untreated cells at 72 h post-transfection. The difference in cell viability between LNA-anti-miR and control groups was statistically significant (p < 0.042). Based on our findings, the inhibition of miR-222 speculate represent a potential novel therapeutic approach for treatment of B-CLL