16 PhD Fellowships in Life Sciences: Muenster, Germany

The International Max Planck Research School – Molecular Biomedicine (IMPRS-MBM) and the Graduate Program Cell Dynamics and Disease (CEDAD) offer 16 PhD Fellowships in Life Sciences. CEDAD and IMPRS-MBM - jointly run by the University of Münster and the Max Planck Institute for Molecular Biomedicine - offer integrative approaches to biomedical research with a strong emphasis on imaging.

Research areas: Cell and Molecular Biology Stem Cell Biology Developmental Biology Neurobiology Vascular Biology Immunology Microbiology and more.

The application period for the 3-year PhD program is 7 March 2010 - 20 May 2010.
Projects start in October 2010.
For online application and further information go to
WWW.CEDAD.UNI-MUENSTER.DE.

The program offers excellent scientific and transferable skills training. The program language is English. There are no tuition fees. Successful candidates will receive a competitive tax-free fellowship as well as support with administrative matters, accomodation, visas etc. We invite applications from highly qualified and motivated students of any nationality. We are looking forward to your application for a PhD fellowship in Münster, "the world’s most liveable city" (LivCom Award 2004). 

Date of fist online : 2010/02/12
Fist online date : 2010/02/12
Expected end of parution : 2010/05/14

Type of funding: Public sector funding (Grant)
Precision on the financing: Fellowship of 1365-1400 Euro per month
Wage: Fellowship of 1365-1400 Euro per month, tax-free

Source: www.abg.asso.fr

 

Catalytic antibodies in hemophilia patients

This is the PhD project of my friend Bharath Wootla. It's interesting how his mentor Sébastien Lacroix-Desmazes guided by Srinivas Kaveri got this idea, and published in Nature Medicine, and a much bigger study later on in the New England Journal of Medicine. The idea is simple: congenital hemophilia patients lack the gene for factor VIII, a protein that is pivotal in blood coagulation pathway. When patients suffering from hemophilia undergo an injury, their blood does not clot and can lead to death due to bleeding. One way of treating these people is to administer exogenous FVIII. However, the immune system of some patients consider the exogenous FVIII as foreign and develop anti-FVIII antibodies. These antibodies inhibit the procoagulant activity of FVIII and hence are also known as FVIII inhibitors. Sébastien in 1999 showed that these antibodies possess catalytic activity and Bharath later on from 2004-2009 studied the mechanisms by which these antibodies inactivate FVIII. The enzymatic activities were studied by incubating the patient's IgG with FVIII. The resultant mixture was analyzed using SDS-PAGE gels for the hydrolysis of FVIII. They have used intravenous immunoglobulin, a pool of IgG from 1000's of healthy blood donors as a control along with the molecules incubated alone in the buffer to check for auto-degradation of proteins. Due to my limited knowledge of enzyme kinetics, I would suggest the readers to refer the publications listed below for more information.

Suggested Reading:
1. Lacroix-Desmazes S, Moreau A, Sooryanarayana, Bonnemain C, Stieltjes N, Pashov A, Sultan Y, Hoebeke J, Kazatchkine MD, Kaveri SV. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med. 1999 Sep;5(9):1044-7.
2. Lacroix-Desmazes S, Wootla B, Dasgupta S, Delignat S, Bayry J, Reinbolt J, Hoebeke J, Saenko E, Kazatchkine MD, Friboulet A, Christophe O, Nagaraja V, Kaveri SV. Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII. J Immunol. 2006 Jul 15;177(2):1355-63.
3. Wootla B, Mahendra A, Dimitrov JD, Friboulet A, Borel-Derlon A, Rao DN, Uda T, Borg JY, Bayry J, Kaveri SV, Lacroix-Desmazes S. Factor VIII-hydrolyzing IgG in acquired and congenital hemophilia. FEBS Lett. 2009 Aug 6;583(15):2565-72.

The orign of IKDC (Interferon producing killer dendritic cells)

The discovery of IKDC or Interferon producing Dendritic Cells in 2006 created enthusiasm in the immunology research (refrences 1 and 2). The DCs that can kill! what a link between innate and adaptive immunity. Interferons are involved in elimination of  viruses etc that are engulfed in the phagocytes. These interferons are secreted by NK or natural killer cells. The IKDCs were put along with other "hybrid cells" such as NKT cells, which share features with natural killer (NK) cells and T lymphocytes, and plasmacytoid dendritic cells (DCs), which combine the qualities of B cells and conventional DCs. IKDCs can function as NK cells by killing the cells lacking MHC molecules, like plasmacytoid DCs that produce interferon and like DCs that present antigen to conventional T cells. IKDCs not only secret type I and type II interferons to recognize and kill tumor cells effectively, but also express MHC-II molecules to present antigens. Thus, IKDCs are considered as important immunosurveilance cells for tumors, providing a link between innate and adaptive immunity. However, the developmental pathways of these cells were not fully understood.
However, Di Santos group from Pasteur Institute, Paris and Caminschi group from Australia studied the development of IKDCs and proved that these are not DCs but actually a subset of NK cells (Refrence 3 and 4). Generally mature NK cells in humans or mice express NK group 2, member D (NKG2D), CD161, NK-cell protein 46 (NKp46) and CD122. However, the expression of Ly49 family members, CD127, CD27 and KLRG1 (killer-cell lectin-like receptor subfamily G, member 1) in mice, and of KIRs (killer-cell immunoglobulin-like receptors), CD56 and CD16 in humans suggests heterogeneity within the mature NK-cell pool.


Suggested reading:
1. Chan et al, Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity, Nature Medicine - 12, 207 - 213 (2006)
2. Taieb et al, A novel dendritic cell subset involved in tumor immunosurveillance, Nature Medicine - 12, 214 - 219 (2006)
3. Vosshenrich et al, CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells.J Exp Med. Oct 29;204(11):2569-78 (2007)
4. Caminschi et al, Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells.J Exp Med. Oct 29;204(11):2579-90 (2007)
5. Huntington et al, Developmental pathways that generate natural-killer-cell diversity in mice and humans, Nature Reviews Immunology 7, 703-714 (2007)

Antibiotic resistence in the natural environment

The discovery of penicillin in the petri dished that could not be washed in time revolutionized the health care during the 20th century. Unfortunately, it created a new problem:  the resistance of bacteria towards antibiotics.One of the reasons for this is the indiscriminate use of antibiotics for diseases where it is not "essential". In addition, the reference I suggested below elucidates the role of natural environment in spreading the antibiotic resistant bacteria. the micro-organisms themselves have antibiotic resistant genes under natural circumstances. These could be spread by wild animals and migratory birds compounding the effect.
The indiscriminate use of antibiotics for clinical and agricultural purposes will have a drastic impact of future human health. Sweden should be applauded for banning the use of antibiotics in cattle health. As a result, the chances of antibiotics resistant strains passing over to humans are minimized. However, there is a need for judicious use or alternative strategies for controlling infections.


Suggested reading:
Heather K. Allen, Justin Donato, Helena Huimi Wang, Karen A. Cloud-Hansen, Julian Davies & Jo Handelsman, Call of the wild: antibiotic resistance genes in natural environments, Nature Reviews Microbiology, 8, 251-259 (April 2010).

The lakshman rekha between science and business

Is science for betterment of humanity or for profits? No one has a better answer. When we see the breakthroughs in science over the past century, one feels that science has revolutionised the health and reduced mortality rate. Probably, 33% of present population are living due to timely intervention of science and health (for eg, vaccination, first aid etc). but, if we see the profits of the multinational pharmaceutical companies such as Pfizer, GSK, Astrazeneca, Monsanto etc, we feel that science is just a business.
The controversy over Bt brinjal is a good example where the MNCs are pushing their products over poor farmers. No one thinks whether the toxin towards pests is safe for humans or not. moreover, Bt cotton has increased burden on farmers rather than reducing them. the prices of seeds have increased enormously over the period when Bt cotton was introduced. Now, Monsanto claims that the old Bt cotton variety is vulnerable to pests and is planning to introduce new one. Imagine long terms effects if these are short term effects?
Latest article in science tells that a US judge rejects patent on breast cancer genes BRCA1 and BRCA2 by Myriad Genetics of Salt Lake City. The opposition groups claim that these genes are product of nature and thus can not be patented. Myriad, licensed the BRCA genes from the University of Utah and others who discovered them. In addition, it runs a testing service to check for mutations that convey a risk for breast cancer. Hope sense prevails on the scientists who discovered them and not become too capitalist.

Mystery mast cells under scanner again

Mast Cells are the most neglected immune cells to be studied yet are the most important amongst them. They are the classical mediators of allergic reactions. When the antigen-specific IgE binds to an antigen (usually allergen), it triggers mast cell activation by binding to high-affinity Fc epsilon receptor I. This leads to the release of mast cell mediators such as histamine, chymotryptase, tryptase, TNF etc. To protect the mast cells from activation induced death, the CD200R is induced. CD200R inhibits mast cell activation through ITIM (immunoreceptor tyrosine-based inhibition motif ).

Recent evidence shows that Mast cellos sense pathogens through toll-like receptor mediated pathways. In addition, the receptors for IgG2a and Ig light chains have been identified. However, the receptor for IgLC is yet to be characterised. Added to this is the concept of MCregs (regulatory mast cells). Mast cells are identified in the triumvirate along with Tregs and Th17. While the tregs inhibit mast cells, mast cells in turn activate the Th17 cells. The complete mechanisms underlying this three-way interactions is to be explore.

Basophils: The neglected minority gains a new respect as antigen presenting cells

To function as an antigen-presenting cell, the cell must fulfill a number of criteria. Upon antigen exposure, the candidate cell must express MHC class II and co-stimulatory molecules. It must be able to take up and process antigen and localize to draining lymph nodes, where efficient T cell–antigen-presenting cell interactions take place. Ideally, the candidate cell would also express the relevant cytokines required for T cell differentiation, although other accessory cells may provide the required cytokines. Finally, the candidate cell must be able to induce CD4⁺ T cell proliferation and differentiation in in vitro and in vivo assays.
Differentiation of naïve CD4⁺ T cells into Th2 cells requires three signals: T cell receptor triggering through peptide antigen recognition in the context of MHC class II molecule, amplification of T cell receptor signaling via co-stimulatory molecules and the presence of appropriate cytokine. For Th2 cell differentiation, however, dendritic cells are not the one-stop shop for all three required signals since dendritic cells do not produce IL-4, the cytokine necessary for Th2 cell differentiation. This observation implies that other antigen-presenting cells, in addition to dendritic cells, may contribute to Th2 cell differentiation.
The studies by Artis and colleagues (Perrigoue et al, Nat Immunol 2009), Medzhitov and colleagues (Sokol al, Nat Immunol 2009), and Nakanishi and colleagues (Yoshimoto al, Nat Immunol 2009), use three different models and elegantly demonstrate that basophils meet the criteria for antigen-presenting cells for Th2 cell differentiation.
Artis and colleagues studied the intestinal helminth parasite Trichuris muris. They showed that CD11c-restricted expression of MHC class II was not sufficient to generate a Th2 inflammatory response. Medzhitov and colleagues investigated the role of basophils in Th2 response to protease antigen papain and OVA. They demonstrated that MHC expression on basophils was sufficient to drive Th2 cell differentiation. Nakanishi and colleagues focused on the role of basophils in augmentation of Th2 responses by antigen–IgE immune complexes.
With basophils added to the list of cells capable of antigen presentation to naïve CD4⁺ T cells, the question arises as to what is the dominant antigen-presenting cell in Th2 inflammatory responses. Four approaches were used to highlight the dominant role of basophils.
First, the authors showed that basophil depletion through treatment with a monoclonal antibody to FceRI significantly diminished Th2 cell differentiation. The second approach used diphtheria toxin in CD11c-DTR mice and demonstrated that depletion of dendritic cells did not alter Th2 cell differentiation in response to OVA plus papain Th2 immunity to T. muris. The third approach demonstrated that CD11c-restricted expression of MHC class II was not sufficient to induce Th2 cell differentiation in response to OVA plus papain or to protect against infection with T. muris. In the fourth approach, mice were immunized in the ear with papain and the ear was either left intact or removed after two hours in order to remove the source of tissue resident dendritic cells. The authors observed Th2 cell differentiation, albeit at lower levels, in the draining lymph node, despite removal of skin resident dendritic cells.
The idea that the basophil is the dominant antigen-presenting cell for Th2 cell differentiation is certainly intriguing, but its validation requires further investigation.

What discriminates danger signals from pathogens with that of damage to tissues

The immune system protects against infection by pathogenic microorganisms, but it also recognizes when the body has been injured. Burns, radiation exposure, and bruises all involve the immune system when responding to damaged tissue. Which signaling pathways recognize tissue damage and keep the resulting inflammatory response from getting out of hand? Patten recognition receptors, which recognize pathogens or components of injured cells (danger), trigger activation of the innate immune system. Whether and how the host distinguishes between danger- versus pathogen-associated molecular patterns remains unresolved. In seminal paper in Science (Vol. 323. no. 5922, pp. 1722 - 1725, March 2009), Chen and colleagues demonstrated an unique mechanisms by which the body differentiates between self- and non-self signals during danger.
They that CD24-deficient mice exhibit increased susceptibility to danger- (DAMPs) but not pathogen-associated molecular patterns (PAMPs). CD24 associates with high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), and heat shock protein 90 (HSP90), negatively regulates their stimulatory activity, and inhibits nuclear factor-kappa B (NF-B) activation. This occurs at least in part through CD24 association with Siglec-10 in humans or Siglec-G in mice. Our results reveal that the CD24-Siglec-G pathway protects the host against a lethal response to pathological cell death and discriminates danger- versus pathogen-associated molecular patterns. Through association with and inhibition of the molecules that are released after tissue damage, CD24 and Siglec-G protected mice from an otherwise lethal inflammatory response.

After a long time

Sorry friends for not being active in the previous months. Unfortunately, my India visit and subsequent work load contributed to the lack of time for the blog.
I request the contributors to keep posting messages not only about the opportunities but also about science.