The Effects of Different Intensities on Eccentric Cycling Blood Flow Patterns at a Concentric Cycling Workload Match

Decrease of blood flow to tissues, due to plaque built by atherosclerosis, increases mortality and morbidity. Homeostatic balance in the vascular system depends directly on endothelial cells, and blood flow, better known as endothelial sheer stress (ESS). Different types of blood flow patterns have been established measured by Reynolds number (Re), and turbulent flow has been associated with the decrease of ESS. Eccentric exercise (ECC) has gained attention as a novel exercise modality that increases muscle performance without increasing metabolic demands; however, little is known about ESS during ECC. PURPOSE: To determine the effects of ECC cycling in blood flow patterns in young, apparently healthy individuals. METHODS: 18 apparently healthy participants, were recruited for two laboratory visits. First visit served to obtain maximum oxygen consumption and peak power (PP), to determine workload intensities, followed by a 5-min familiarization on eccentric ergometer. Second visit on eccentric ergometer assessed blood flow patterns (i.e. ESS and Re measured via imaging ultrasound and Doppler) during a 3-workload steady exercise test at low, moderate, and high intensities. RESULTS: There was an interaction of exercise intensity on antegrade ESS (F(3,53.7)=26.90, p\u3c0.001), but not Sex (p\u3e0.05), and a random effect of participant (p\u3c0.001) and Re anterograde (F(3,53.6)=25.03, p\u3c0.001), but not Sex or random effect of participant (p\u3e0.05). There was an interaction of condition on retrograde ESS (F(3,53.4)=11.21, p\u3c0.001), but not Sex (p\u3e0.05), and a random effect of participant (p\u3c0.001). and Re retrograde (F(3,54.3)=12.34, p\u3c0.001), Sex (F(1,18.5)=4.41, p=0.05), and random effect of participant (p\u3e0.05). CONCLUSION: Eccentric cycling exercise produces exercise-induced blood flow patterns that are intensity-dependent in males and females and these patterns are similar to traditional concentric cycling

ABJM Baryon Stability and Myers effect

We consider magnetically charged baryon vertex like configurations in AdS^4 X CP^3 with a reduced number of quarks l. We show that these configurations are solutions to the classical equations of motion and are stable beyond a critical value of l. Given that the magnetic flux dissolves D0-brane charge it is possible to give a microscopical description in terms of D0-branes expanding into fuzzy CP^n spaces by Myers dielectric effect. Using this description we are able to explore the region of finite 't Hooft coupling.Comment: 29 pages, Latex; minor changes; version to appear in JHE

Bivalent therapeutic vaccine against HPV16/18 genotypes consisting of a fusion protein between the extra domain A from human fibronectin and HPV16/18 E7 viral antigens.

In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer. Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic-polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors. hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocyte-derived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDA-HPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors. Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

Different Patterns of Evolution in the Centromeric and Telomeric Regions of Group A and B Haplotypes of the Human Killer Cell Ig-Like Receptor Locus

The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ∼6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ∼1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region

Present Status and Future Programs of the n_TOF Experiment

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial License 3.0, which permits unrestricted use, distribution, and reproduction in any noncommercial medium, provided the original work is properly citedThe neutron time-of-flight facility n_TOF at CERN, Switzerland, operational since 2001, delivers neutrons using the Proton Synchrotron (PS) 20 GeV/c proton beam impinging on a lead spallation target. The facility combines a very high instantaneous neutron flux, an excellent time of flight resolution due to the distance between the experimental area and the production target (185 meters), a low intrinsic background and a wide range of neutron energies, from thermal to GeV neutrons. These characteristics provide a unique possibility to perform neutron-induced capture and fission cross-section measurements for applications in nuclear astrophysics and in nuclear reactor technology.The most relevant measurements performed up to now and foreseen for the future will be presented in this contribution. The overall efficiency of the experimental program and the range of possible measurements achievable with the construction of a second experimental area (EAR-2), vertically located 20 m on top of the n_TOF spallation target, might offer a substantial improvement in measurement sensitivities. A feasibility study of the possible realisation of the installation extension will be also presented

The mosaic of KIR haplotypes in rhesus macaques

To further refine and improve biomedical research in rhesus macaques, it is necessary to increase our knowledge concerning both the degree of allelic variation (polymorphism) and diversity (gene copy number variation) in the killer cell immunoglobulin-like receptor (KIR) gene cluster. Pedigreed animals in particular should be studied, as segregation data will provide clues to the linkage of particular KIR genes/alleles segregating on a haplotype and to its gene content as well. A dual strategy allowed us to screen the presence and absence of genes and the corresponding transcripts, as well as to track differences in transcription levels. On the basis of this approach, 14 diverse KIR haplotypes have been described. These haplotypes consist of multiple inhibitory and activating Mamu-KIR genes, and any gene present on one haplotype may be absent on another. This suggests that the cost of accelerated evolution by recombination may be the loss of certain framework genes on a haplotype

Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses

Plant plasma membrane localized pattern recognition receptors (PRRs) detect extracellular pathogen-associated molecules. PRRs such as Arabidopsis EFR and rice XA21 are taxonomically restricted and are absent from most plant genomes. Here we show that rice plants expressing EFR or the chimeric receptor EFR::XA21, containing the EFR ectodomain and the XA21 intracellular domain, sense both Escherichia coli- and Xanthomonas oryzae pv. oryzae (Xoo)-derived elf18 peptides at sub-nanomolar concentrations. Treatment of EFR and EFR::XA21 rice leaf tissue with elf18 leads to MAP kinase activation, reactive oxygen production and defense gene expression. Although expression of EFR does not lead to robust enhanced resistance to fully virulent Xoo isolates, it does lead to quantitatively enhanced resistance to weakly virulent Xoo isolates. EFR interacts with OsSERK2 and the XA21 binding protein 24 (XB24), two key components of the rice XA21-mediated immune response. Rice-EFR plants silenced for OsSERK2, or overexpressing rice XB24 are compromised in elf18-induced reactive oxygen production and defense gene expression indicating that these proteins are also important for EFR-mediated signaling in transgenic rice. Taken together, our results demonstrate the potential feasibility of enhancing disease resistance in rice and possibly other monocotyledonous crop species by expression of dicotyledonous PRRs. Our results also suggest that Arabidopsis EFR utilizes at least a subset of the known endogenous rice XA21 signaling components