Use of p53-Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease.

Background Peripheral vascular disease is a major diabetes mellitus‐related complication. In this study, we noted that expressions of proapoptotic p53 gene and its downstream cascade gene such as p21 are upregulated in hyperglycemia. Therefore, we investigated whether p53‐ and p21‐silenced endothelial progenitor cells (EPCs) were able to survive in hyperglycemic milieu, and whether transplantation of either p53 knockout (KO) or p21KO or p53‐ and p21‐silenced EPCs could improve collateral vessel formation and blood flow in diabetic vaso‐occlusive peripheral vascular disease mouse models. Methods and Results We transplanted p53 and p21KO mouse EPCs (mEPCs) into streptozotocin–induced diabetic (type 1 diabetes mellitus model) C57BL/6J and db/db (B6.BKS(D)‐Leprdb/J) (type 2 model) post–femoral artery occlusion. Similarly, Ad‐p53–silenced and Ad‐p21–silenced human EPCs (CD34+) cells were transplanted into streptozotocin‐induced diabetic NOD.CB17‐Prkdcscid/J mice. We measured blood flow at 3, 7, and 10 days and hindlimb muscles were obtained postsacrifice for mRNA estimation and CD31 staining. Enhanced blood flow was noted with delivery of p53 and p21KO mEPCs in streptozotocin‐induced diabetic C57BL/6J mice. Similar results were obtained when human Ad‐p53shEPCs(CD34+) and Ad‐p21shEPCs(CD34+) were transplanted into streptozotocin‐induced nonobese diabetic severe combined immunodeficiency mice. Gene expression analysis of p53 and p21KO EPCs transplanted hindlimb muscles showed increased expression of endothelial markers such as endothelial nitric oxide synthase, vascular endothelial growth factor A, and platelet endothelial cell adhesion molecule 1. Similarly, quantitative reverse transcriptase polymerase chain reaction of human Ad‐p53shEPCs (CD34+)– and Ad‐p21shEPCs (CD34+)–transplanted hindlimb muscles also showed increased expression of endothelial markers such as vascular endothelial growth factor A, noted primarily in the p53‐silenced EPCs group. However, such beneficial effect was not noted in the db/db type 2 diabetic mouse models. Conclusions Transient silencing of p53 using adenoviral vector in EPCs may have a therapeutic role in diabetic peripheral vascular disease

The Relationship Between Problem Solving Skills Levels and Locus of Control in Nursing Students

Giriş: Problem çözme becerisi ve iç kontrol odağı hemşirelik eğitimi boyunca öğrencilerde geliştirilmesi istenen özelliklerdir. Amaç:Hemşirelik öğrencilerinin problem çözme beceri düzeyi ile kontrol odağı arasında ilişkinin değerlendirilmesidir. Yöntem: Araştırmanıntasarımı tanımlayıcı ve korelasyonel niteliktedir. Araştırmanın örneklemini Hemşirelik Yüksekokulunda öğrenim gören 289 öğrencioluşturmuştur. Veri toplama aracı olarak; Türkçe geçerlik güvenirliğini Şahin, Şahin ve Heppner'in (1993) yaptığı Problem Çözme Envanterive Dağ (2002) tarafından geliştirilen Kontrol Odağı Ölçeği kullanılmıştır. Bulgular: Problem çözme becerileri ile kontrol odağı puanlarıarasında pozitif yönde, orta düzeyde, istatistiksel düzeyde anlamlı ilişki bulunmuştur. Öğrencilerin sınıf düzeyi yükseldikçe problem çözmebeceri puanlarının istatistiksel olarak anlamlı düzeyde artış gösterdiği belirlenmiştir. Birinci sınıfların, ikinci ve dördüncü sınıflara göre dahaçok dış kontrol odaklı oldukları belirlenmiştir. Üçüncü sınıfla birinci sınıf öğrencileri arasında istatistiksel olarak anlamlı bir farkbulunmamıştır. Sonuç: Son sınıf hemşirelik öğrencilerinin problem çözme becerilerin diğer sınıflara göre yüksek olması ve iç kontrol odaklıgrup olması hemşirelik eğitimi boyunca beklenen gelişime ulaşılmış olmasını göstermesi bakımından önemli bir sonuçtur. Background: Problem solving and internal locus of control are features aimed to be developed in students throughout the nursing education.Objectives: To identify the relationship between level of problem solving skills and locus of control scores in nursing students'. Methods:The study was planned in descriptive and correlational design. The sample comprised 289 students studying in school of nursing. that Thereliability and validity tested by Şahin, Şahin ve Heppner (1993) which that Problem Solving Inventory and improved by Dağ (2002) whichthat Locus of Control Scale were used in data collection. Results: As nursing students' grade level increased, the problem solving scoresincreased significantly, too. It was determined that the freshmen were more external locus oriented than second and fourth year students. Nosignificant statistical relationship was found between first-year and the third-year students. A medium-level significant relationship (in thepositive direction) was found between locus of control scores and problem solving skills. Conclusion: The finding that senior nursingstudents formed the group with highest-level problem solving skills and the greatest internal locus of control is an important result in termsof showing that the expected development progress is reache

Mice with a Targeted Deletion of the Type 2 Deiodinase Are Insulin Resistant and Susceptible to Diet Induced Obesity

The type 2 iodothyronine deiodinase (D2) converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT), and mice with a disrupted Dio2 gene (D2KO) have an impaired response to cold. BAT is also activated by overfeeding.After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V0(2)) was not different between genotypes, but D2KO mice had an increased respiratory exchange ratio (RER), suggesting preferential use of carbohydrates. Consistent with this, serum free fatty acids and β-hydroxybutyrate were lower in D2KO mice on a HFD, while hepatic triglycerides were increased and glycogen content decreased. Neither genotype showed glucose intolerance, but D2KO mice had significantly higher insulin levels during GTT independent of diet. Accordingly, during ITT testing D2KO mice had a significantly reduced glucose uptake, consistent with insulin resistance. Gene expression levels in liver, muscle, and brown and white adipose tissue showed no differences that could account for the increased weight gain in D2KO mice. However, D2KO mice have higher PEPCK mRNA in liver suggesting increased gluconeogenesis, which could also contribute to their apparent insulin resistance.We conclude that the loss of the Dio2 gene has significant metabolic consequences. D2KO mice gain more weight on a HFD, suggesting a role for D2 in protection from diet-induced obesity. Further, D2KO mice appear to have a greater reliance on carbohydrates as a fuel source, and limited ability to mobilize and to burn fat. This results in increased fat storage in adipose tissue, hepatic steatosis, and depletion of liver glycogen in spite of increased gluconeogenesis. D2KO mice are also less responsive to insulin, independent of diet-induced obesity

Human-specific histone methylation signatures at transcription start sites in prefrontal neurons

Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex the genome-wide distribution of histone H3 trimethylated at lysine 4 (H3K4me3), an epigenetic mark sharply regulated at TSS, and identified 471 sequences with human-specific enrichment or depletion. Among these were 33 loci selectively methylated in neuronal but not non-neuronal chromatin from children and adults, including TSS at DPP10 (2q14.1), CNTN4 and CHL1 (3p26.3), and other neuropsychiatric susceptibility genes. Regulatory sequences at DPP10 and additional loci carried a strong footprint of hominid adaptation, including elevated nucleotide substitution rates and regulatory motifs absent in other primates (including archaic hominins), with evidence for selective pressures during more recent evolution and adaptive fixations in modern populations. Chromosome conformation capture at two neurodevelopmental disease loci, 2q14.1 and 16p11.2, revealed higher order chromatin structures resulting in physical contact of multiple human-specific H3K4me3 peaks spaced 0.5-1 Mb apart, in conjunction with a novel cis-bound antisense RNA linked to Polycomb repressor proteins and downregulated DPP10 expression. Therefore, coordinated epigenetic regulation via newly derived TSS chromatin could play an important role in the emergence of human-specific gene expression networks in brain that contribute to cognitive functions and neurological disease susceptibility in modern day humans

4G antennas for wireless eyewear devices and related SAR

This article was published in Comptes Rendus Physique [© Elsevier France] and the definitive version is available at: http://dx.doi.org/10.1016/j.crhy.2015.10.009In this paper, we first present a feasibility study to design 4G antennas (700–960 MHz and 1.7–2.7 GHz) for eyewear devices. Those eyewear devices should be connected to the last generation cellular networks, Wireless Local Area Networks or wireless hotspots. Three coupling element type antennas with their matching networks are evaluated in terms of reflection coefficient and total radiation efficiency when the eyewear is placed on the user's head. We also present Specific Absorption Rate (SAR) simulations when the eyewear is positioned over a homogeneous SAM phantom and over a heterogeneous VH (Visible Human) phantom: the SAR levels are compared to international limit values. In a second step, we present experimental results obtained with 3D printed eyewear and coupling elements etched on a classical PCB substrate where the matching circuits are optimized close to the feeding point of the coupling element. Simulated and measured values are in very good agreement: 7 to 16% and 9 to 35% total efficiency are respectively obtained for the low- and high-frequency bands. However, simulated SAR values are somewhat higher than authorized levels with preoccupant high electromagnetic field distribution close to the eye of the user

Impaired Embryonic Development in Mice Overexpressing the RNA-Binding Protein TIAR

TIA-1-related (TIAR) protein is a shuttling RNA-binding protein involved in several steps of RNA metabolism. While in the nucleus TIAR participates to alternative splicing events, in the cytoplasm TIAR acts as a translational repressor on specific transcripts such as those containing AU-Rich Elements (AREs). Due to its ability to assemble abortive pre-initiation complexes coalescing into cytoplasmic granules called stress granules, TIAR is also involved in the general translational arrest observed in cells exposed to environmental stress. However, the in vivo role of this protein has not been studied so far mainly due to severe embryonic lethality upon tiar invalidation.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73.

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers

The role of atmospheric deposition in the biogeochemistry of the Mediterranean Sea

Estimates of atmospheric inputs to the Mediterranean (MED) and some coastal areas are reviewed, and uncertainities in these estimates considered. Both the magnitude and the mineralogical composition of atmospheric dust inputs indicate that eolian deposition is an important (50%) or prevailing (>80%) contribution to sediments in the offshore waters of the entire Mediterranean (MED) basin. Model data for trace metals and nutrients indicate that the atmosphere delivers more than half the lead and nitrogen, one-third of total phosphorus, and 10% of the zinc entering the entire basin. Measured data in sub-basins, such as the north-western MED and northern Adriatic indicate an even greater proportion of atmospheric versus riverine inputs. When dissolved fluxes are compared (the form most likely to impinge on surface water biogeochemical cycles), the atmosphere is found to be 5 to 50 times more important than rivers for dissolved Zn and 15 to 30 times more important for Pb fluxes. Neglecting co-limitation by other nutrients, new production supported by atmospheric nitrogen deposition ranges from 2-4 g C m-2 yr-1, whereas atmospheric phosphorus deposition appears to support less than 1 g C m-2 yr-1. In spite of the apparently small contribution of atmospheric deposition to overall production in the basin it has been suggested that certain episodes of phytoplankton blooms are triggered by atmospheric deposition of N, P or Fe. Future studies are needed to clarify the extent and causal links between these episodic blooms and atmospheric/oceanographic forcing functions. A scientific program aimed at elucidating the possible biogeochemical effects of Saharan outbreaks in the MED through direct sampling of the ocean and atmosphere before and after such events is therefore highly recommended

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Uniform, Strain-Free, Large-Scale Graphene and h-BN Monolayers Enabled by Hydrogel Substrates

Translation of the unique properties of 2D monolayers from non-scalable micron-sized samples to macroscopic scale is a longstanding challenge obstructed by the substrate-induced strains, interface nonuniformities, and sample-to-sample variations inherent to the scalable fabrication methods. So far, the most successful strategies to reduce strain in graphene are the reduction of the interface roughness and lattice mismatch by using hexagonal boron nitride (h-BN), with the drawback of limited uniformity and applicability to other 2D monolayers, and liquid water, which is not compatible with electronic devices. This work demonstrates a new class of substrates based on hydrogels that overcome these limitations and excel h-BN and water substrates at strain relaxation enabling superiorly uniform and reproducible centimeter-sized sheets of unstrained monolayers. The ultimate strain relaxation and uniformity are rationalized by the extreme structural adaptability of the hydrogel surface owing to its high liquid content and low Young's modulus, and are universal to all 2D materials irrespective of their crystalline structure. Such platforms can be integrated into field effect transistors and demonstrate enhanced charge carrier mobilities in graphene. These results present a universal strategy for attaining uniform and strain-free sheets of 2D materials and underline the opportunities enabled by interfacing them with soft matter.ISSN:1613-6810ISSN:1613-682