Engineering vascularised tissues in vitro

Tissue engineering aims at replacing or regenerating tissues lost due to diseases or traumas (Langer and Vacanti, 1993). However, mimicking in vitro the physiological complexity of vascularized tissue is a major obstacle, which possibly contributes to impaired healing in vivo. In higher organisms, native features including the vascular network, the lymphatic networks and interstitial flow promote both mass transport and organ development. Attempts to mimic those features in engineered tissues will lead to more clinically relevant cell-based therapies. Aside from current strategies promoting angiogenesis from the host, an alternative concept termed prevascularization is emerging. It aims at creating a biological vasculature inside an engineered tissue prior to implantation. This vasculature can rapidly anastamose with the host and enhances tissue survival and differentiation. Interestingly, growing evidence supports a role of the vasculature in regulating pattern formation and tissue differentiation. Thus, prevascularized tissues also benefit from an intrinsic contribution of their vascular system to their development. From those early attempts are emerging a body of principles and strategies to grow and maintain, in vitro, those self-assembled biological vascular networks. This could lead to the generation of engineered tissues of more physiologically relevant complexity and improved regenerative potential

A Mouse Model for Trichothiodystrophy

Nucleotide excision repair (NER) is a versatile DNA repair mechanism that safeguards the genome from many types of DNA damages. The importance ofNER is highlighted by three inherited human disorders with defective NER: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). XP patients display enhanced susceptibility to sunlight-induced skin cancer, but CS and TTD are not associated with increased cancer susceptibility despite an NER defect. Moreover, CS and TID patients are characterized by a broad range of neurodevelopmental abnormalities, which al:e difficult to rationalise as a consequence of a defect in NER. One of the NER genes, XPD, is implicated in XP, XP with combined features of CS, and TTD. XPD is a subunit of the dually functional transcription factor IIH (TFIIH) complex, involved in NER and basal transcription initiation. It was hypothesized that mutations in XPD may not only affect NER, causing XP and photosensitivity in TID, but may also impair the tTanscription function of TFIIH accounting for the neurodevelopmental abnormalities in CS and TID. The aim of the work outlined in this thesis is to gain insight into the molecular basis of the clinical symptoms associated with defects in the XPD gene, and into t

Thermodynamics of Higher Spin Black Holes in AdS3_3

We discuss the thermodynamics of recently constructed three-dimensional higher spin black holes in SL(N,R)\times SL(N,R) Chern-Simons theory with generalized asymptotically-anti-de Sitter boundary conditions. From a holographic perspective, these bulk theories are dual to two-dimensional CFTs with W_N symmetry algebras, and the black hole solutions are dual to thermal states with higher spin chemical potentials and charges turned on. Because the notion of horizon area is not gauge-invariant in the higher spin theory, the traditional approaches to the computation of black hole entropy must be reconsidered. One possibility, explored in the recent literature, involves demanding the existence of a partition function in the CFT, and consistency with the first law of thermodynamics. This approach is not free from ambiguities, however, and in particular different definitions of energy result in different expressions for the entropy. In the present work we show that there are natural definitions of the thermodynamically conjugate variables that follow from careful examination of the variational principle, and moreover agree with those obtained via canonical methods. Building on this intuition, we derive general expressions for the higher spin black hole entropy and free energy which are written entirely in terms of the Chern-Simons connections, and are valid for both static and rotating solutions. We compare our results to other proposals in the literature, and provide a new and efficient way to determine the generalization of the Cardy formula to a situation with higher spin charges.Comment: 30 pages, PDFLaTeX; v2: typos corrected, explicit expressions for the free energy adde

AdS_3 Partition Functions Reconstructed

For pure gravity in AdS_3, Witten has given a recipe for the construction of holomorphically factorizable partition functions of pure gravity theories with central charge c=24k. The partition function was found to be a polynomial in the modular invariant j-function. We show that the partition function can be obtained instead as a modular sum which has a more physical interpretation as a sum over geometries. We express both the j-function and its derivative in terms of such a sum.Comment: 9 page

The chiral ring of AdS3/CFT2 and the attractor mechanism

We study the moduli dependence of the chiral ring in N = (4,4) superconformal field theories, with special emphasis on those CFTs that are dual to type IIB string theory on AdS3xS3xX4. The chiral primary operators are sections of vector bundles, whose connection describes the operator mixing under motion on the moduli space. This connection can be exactly computed using the constraints from N = (4,4) supersymmetry. Its curvature can be determined using the tt* equations, for which we give a derivation in the physical theory which does not rely on the topological twisting. We show that for N = (4,4) theories the chiral ring is covariantly constant over the moduli space, a fact which can be seen as a non-renormalization theorem for the three-point functions of chiral primaries in AdS3/CFT2. From the spacetime point of view our analysis has the following applications. First, in the case of a D1/D5 black string, we can see the matching of the attractor flow in supergravity to RG-flow in the boundary field theory perturbed by irrelevant operators, to first order away from the fixed point. Second, under spectral flow the chiral primaries become the Ramond ground states of the CFT. These ground states represent the microstates of a small black hole in five dimensions consisting of a D1/D5 bound state. The connection that we compute can be considered as an example of Berry's phase for the internal microstates of a supersymmetric black hole.Comment: 72 pages (60 + appendices

Semiclassical Analysis of String/Gauge Duality on Non-commutative Space

We use semiclassical method to study closed strings in the modified AdS_5*S^5 background with constant B-fields. The point-like closed strings and the streched closed strings rotating around the big circle of S^5 are considered. Quantization of these closed string leads to a time-dependent string spectrum, which we argue to correspond to the RG-flow of the dual noncommutative Yang Mills theory.Comment: 19 pages, 1 figure, revtex4. minor corrections. references adde

Near Horizon Limits of Massless BTZ and Their CFT Duals

We consider the massless BTZ black hole and show that it is possible to take its "near horizon" limit in two distinct ways. The first one leads to a null self-dual orbifold of AdS3 and the second to a spacelike singular AdS3/Z_K orbifold in the large K limit, the "pinching orbifold". We show that from the dual 2d CFT viewpoint, the null orbifold corresponds to the p^+=0 sector of the Discrete Light-Cone Quantisation (DLCQ) of the 2d CFT where a chiral sector of the CFT is decoupled, while the pinching orbifold corresponds to taking an infinite mass gap limit in both the right and left sectors of the 2d CFT, essentially leaving us with the states L_0=\bar L_0=c/24 only. In the latter case, one can combine the near horizon limit with sending the 3d Planck length l_P to zero, or equivalently the dual CFT central charge c to infinity. We provide preliminary evidence that in that case some nontrivial dynamics may survive the limit.Comment: 22 pages, no figures, v2: minor improvements, references adde

High-Throughput Assay for the Identification of Compounds Regulating Osteogenic Differentiation of Human Mesenchymal Stromal Cells

Human mesenchymal stromal cells are regarded as the golden standard for cell-based therapies. They present multilineage differentiation potential and trophic and immunosuppressive abilities, making them the best candidate for clinical applications. Several molecules have been described to increase bone formation and were mainly discovered by candidate approaches towards known signaling pathways controlling osteogenesis. However, their bone forming potential is still limited, making the search for novel molecules a necessity. High-throughput screening (HTS) not only allows the screening of a large number of diverse chemical compounds, but also allows the discovery of unexpected signaling pathways and molecular mechanisms for a certain application, even without the prior knowledge of the full molecular pathway. Typically HTS is performed in cell lines, however, in this manuscript we have performed a phenotypical screen on more clinically relevant human mesenchymal stromal cells, as a proof of principle that HTS can be performed in those cells and can be used to find small molecules that impact stem cell fate. From a library of pharmacologically active small molecules, we were able to identify novel compounds with increased osteogenic activity. These compounds allowed achieving levels of bone-specific alkaline phosphatase higher than any other combination previously known. By combining biochemical techniques, we were able to demonstrate that a medium to high-throughput phenotypic assay can be performed in academic research laboratories allowing the discovery of novel molecules able to enhance stem cell differentiation

Exact ground states of generalized Hubbard models

We present a simple method for the construction of exact ground states of generalized Hubbard models in arbitrary dimensions. This method is used to derive rigorous criteria for the stability of various ground state types, like the $\eta$-pairing state, or N\'eel and ferromagnetic states. Although the approach presented here is much simpler than the ones commonly used, it yields better bounds for the region of stability.Comment: Revtex, 8 page