4,636 research outputs found
TAT-BH4 counteracts A beta toxicity on capillary endothelium
No full textOxidative stress is one of the factor contributing to blood brain barrier degeneration. This phenomenon is observed during pathological conditions such as Alzheimer's disease or cerebral amyloid angiopathy in which brain haemorrhages are very frequent. Both diseases are characterized by beta amyloid peptide deposition either in neurons or in vessels. Oxidative stress leads to impairment of mitochondrial functions and apoptotic cell death subsequent to caspases activation. In this paper we demonstrate that BH4 domain of Bcl-xl administrated to endothelial cells as the conjugated form with TAT peptide, reverts Abeta-induced apoptotic cell death by activating a survival programme which is Akt/endothelial nitric oxide synthase dependent
Comparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and an apparent absence of selective constraints.
No full textContains fulltext :
110619.pdf (Publisher’s version ) (Open Access)Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non-pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of "classical" antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design
A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma
No full textAngiogenesis and vasculogenesis are regulated in large
part by several different growth factors and their
associated receptor tyrosine kinases (RTKs). Foremost
among these is the vascular endothelial growth factor
(VEGF) family including VEGF receptor (VEGFR)-2
and -1. VEGFR ligand binding and biological activity are
regulated at many levels, one of which is by a soluble,
circulating form of VEGFR-1 (sVEGFR-1). This sVEGFR-1
can act as a competitive inhibitor of its ligand, serve
as a possible biomarker, and play important roles in
cancer and other diseases such as preeclampsia.
Recombinant forms of sVEGFR-2 have been shown to
have antiangiogenic activity, but a naturally occurring
sVEGFR-2 has not been described previously. Here,
we report such an entity. Having a molecular weight
of f160 kDa, sVEGFR-2 can be detected in mouse and
human plasma with several different monoclonal and
polyclonal anti-VEGFR-2 antibodies using both ELISA
and immunoprecipitation techniques. In vitro studies
have determined that the sVEGFR-2 fragment can
be found in the conditioned media of mouse and
human endothelial cells, thus suggesting that it may
be secreted, similar to sVEGFR-1, or proteolytically
cleaved from the cell. Potential biological activity of this
protein was inferred from experiments in which mouse
sVEGFR-2 could bind to VEGF-coated plates. Similar
to sVEGFR-1 and other soluble circulating RTKs,
sVEGFR-2 may have regulatory consequences with
respect to VEGF-mediated angiogenesis as well
as potential to serve as a quantitative biomarker of
angiogenesis and antiangiogenic drug activity,
particularly for drugs that target VEGF or VEGFR-2
On minimal non-PE-groups
No full textAbstractIf H is a subgroup of a finite group G, by HG denote the normal closure of H in G. G is called a PE-group if every minimal subgroup X of G satisfies NG(X) ∩ XG = X. The author proves that all PE-groups are solvable with the Fitting height at most 3 and classifies the minimal non-PE-groups
[[alternative]]The Study of Acknowledgement of Risk Management on Perception of PE Teachers in Taoyuan Junior High Schools
No full text[[abstract]]The purpose of this study was to (1) explore the acknowledgement about physical activity risk management of junior high school PE teachers in Taoyuan, (2) compare PE teachers’ perception difference about risk management with different background (3) realize the strategy of risk management plan of PE teachers in junior high school. (4) finally build effective risk management plan for all PE teachers in junior high school.
One hundred and ninety two Taoyuan PE teachers served as the subjects of this study with the questionnaire of ” PE Teacher’s Perception of The Risk Management”. This study used descriptive statistics, t-test, and one-way ANOVA to analyze data. Besides, the research also chose seven PE teachers to do semi-structured interview, trying to understand risk management strategy of PE teachers. The results were listed as below:
1.The perception of risk management of physical teachers in junior high school, based on the importance, was: theory layer, practical layer, law layer, entity and application layer.
2.Significant difference was found in gender, practical layer, law layer and entity; while other factors showed no significant difference.
3.All the interviewees didn’t take action about risk management , but all of them agreed that risk management plan of physical activity is necessary. They suggested higher authorities ask junior high school to set risk management plan for physical activity, and become an evaluated item.
In conclusion of the research, the PE teachers in junior high school think it is important to execute a better physical activity risk management. Author suggested junior high school should set risk management plan for physical activity to get “zero risk” in school.
Veterinary science : humans, animals and health
No full textThis living book is a collection of open access materials bringing scientific papers to a humanities audienc
AQA GCSE PE
No full textUnlock your full potential with this revision guide which focuses on the key content and skills you need to know. With My Revision Notes for AQA GCSE PE, which covers the Short Course, Full Course and Double Award, you can: - take control of your revision: plan and focus on the areas you need to revise with content summaries and commentary from an expert author - show you fully understand key topics by using specific examples to add depth to your knowledge of PE issues and processes - apply PE terms accurately with the help of key words and definitions on all topics - improve your skills to tackle exam questions with self-testing and exam-style questions and answers
Targeting Nanoparticles to Tumor Vasculature
No full textTargeting tumor vessels represents an indirect therapeutic approach in oncology by shifting the treatment away from the tumor cells themselves. Endothelial cells are generally considered genetically stable and do not use escape mechanisms against chemotherapeutic agents as frequently as tumor cells do. Also, a very large number of tumor cells can be killed by ischemia if a single vessel is occluded.
Tumor vascular markers have been identified and monoclonal antibodies targeting them have been constructed in my laboratory. There are numerous approaches to make antibodies more effective in cancer treatment. One option we have investigated is to use them for liposomal targeting to tumor vessels. Nanoparticles, and liposomes in particular, are extremely versatile because they can be adapted to carry drugs, imaging agents, or energy capture agents.
In my project, I have constructed liposomes targeted to three molecules identified as tumor vascular markers: VEGFR-2, phosphatidylserine (PS), and phosphatidylethanolamine (PE). To target VEGFR-2, I have used Fab' fragments derived from a series of rat monoclonal antibodies (RAFL) that bind to the extracellular domain of the receptor. For PS targeting, I used Fab' fragments derived from an anionic phospholipid binding antibody (bavituximab) and also a serum protein, beta-2-glycoprotein 1 (beta 2GP1). PE was targeted using a small antibiotic peptide, duramycin. All the liposome constructs bound to the purified target, as tested by solid phase assays. VEGFR-2 targeted liposomes bound to and were internalized by mouse endothelial cells expressing VEGFR-2. PS and PE targeted liposomes bound to endothelial cells that were subjected to stress factors that mimic the conditions encountered in the tumor environment. All the liposomes were also detected on the surface of endothelial cells inside tumors.
The tumor treatment potential was assessed by loading the liposomes with doxorubicin and treating mice in an orthotopic breast cancer model. The therapeutic benefit was also assessed for its ability to prolong survival in a lung pseudometastatic model. The tumor growth in the orthotopic model was not inhibited by any of the constructs compared with control liposomes, but VEGFR-2 targeted liposomes extended the survival in the pseudometastatic model. These data suggest that VEGFR-2 targeted liposomes could potentially be used as an antimetastatic agent in combination with treatments that would target the tumor of origin.
PS and PE binding liposomes were also used as probes for describing the membrane localization and exposure dynamics of PS and PE on the surface of irradiated cells. I have shown that PS and PE follow a similar exposure time course and they colocalize on the cell surface. PS and PE positive membrane patches appear to detach from the cytoskeleton and bud out from the cell surface. These findings suggest that PE and PS share common regulatory mechanisms of membrane translocation.
PS and PE binding liposomes were also used as probes for describing the membrane localization and exposure dynamics of PS and PE on the surface of irradiated cells. I have shown that PS and PE follow a similar exposure time course and they colocalize on the cell surface. PS and PE positive membrane patches appear to detach from the cytoskeleton and bud out from the cell surface. These findings suggest that PE and PS share common regulatory mechanisms of membrane translocation.
Long circulating liposomes provide benefit through passive targeting to the tumor environment. My findings imply that active targeting by adding a ligand should be done with care, so as not to impede the passive targeting effect. Compared to other vascular targeting agents, liposomes requir
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