Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches

Xenotransplantation of patient-derived samples in mouse models has been instrumental in depicting the role of hematopoietic stem and progenitor cells in the establishment as well as progression of hematological malignancies. The foundations for this field of research have been based on the development of immunodeficient mouse models, which provide normal and malignant human hematopoietic cells with a supportive microenvironment. Immunosuppressed and genetically modified mice expressing human growth factors were key milestones in patient-derived xenograft (PDX) models, highlighting the importance of developing humanized microenvironments. The latest major improvement has been the use of human bone marrow (BM) niche-forming cells to generate human-mouse chimeric BM tissues in PDXs, which can shed light on the interactions between human stroma and hematopoietic cells. Here, we summarize the methods used for human hematopoietic cell xenotransplantation and their milestones and review the latest approaches in generating humanized BM tissues in mice to study human normal and malignant hematopoiesis

Finite size effects on the phase diagram of a binary mixture confined between competing walls

A symmetrical binary mixture AB that exhibits a critical temperature T_{cb} of phase separation into an A-rich and a B-rich phase in the bulk is considered in a geometry confined between two parallel plates a distance D apart. It is assumed that one wall preferentially attracts A while the other wall preferentially attracts B with the same strength (''competing walls''). In the limit $D\to \infty$, one then may have a wetting transition of first order at a temperature T_{w}, from which prewetting lines extend into the one phase region both of the A-rich and the B-rich phase. It is discussed how this phase diagram gets distorted due to the finiteness of D% : the phase transition at T_{cb} immediately disappears for D<\infty due to finite size rounding, and the phase diagram instead exhibit two two-phase coexistence regions in a temperature range T_{trip}<T<T_{c1}=T_{c2}. In the limit D\to \infty T_{c1},T_{c2} become the prewetting critical points and T_{trip}\to T_{w}. For small enough D it may occur that at a tricritical value D_{t} the temperatures T_{c1}=T_{c2} and T_{trip} merge, and then for D<D_{t} there is a single unmixing critical point as in the bulk but with T_{c}(D) near T_{w}. As an example, for the experimentally relevant case of a polymer mixture a phase diagram with two unmixing critical points is calculated explicitly from self-consistent field methods

Climate change is catchy – but when will it really hurt?

Concern and general awareness about the impacts of climate change in all sectors of the social- ecological-economic system is growing as a result of improved climate science products and information, as well as increased media coverage of the apparent manifestations of the phenomenon in our society. However, scales of climate variability and change, in space and time, are often confused and so  attribution of impacts on various sectors, including the health sector, can be misunderstood and  misrepresented. In this review, we assess the mechanistic links between climate and infectious  diseases in particular, and consider how this relationship varies, and may vary according to different time scales, especially for aetiologically climate-linked diseases. While climate varies in the medium (inter- annual) time frame, this variability itself may be oscillating and/or trending on cyclical and long-term (climate change) scales because of regional and global scale climate phenomena such as the El-Niño southern oscillation coupled with global-warming drivers of  climate change. As several studies have shown, quantifying and modelling these linkages and associations at appropriate time and space scales is both necessary and increasingly feasible with improved climate science products and better epidemiological data. The application of this approach is considered for South Africa, and the need for a more concerted effort in this regard is supported

Interface localisation-delocalisation transition in a symmetric polymer blend: a finite-size scaling Monte Carlo study

Using extensive Monte Carlo simulations we study the phase diagram of a symmetric binary (AB) polymer blend confined into a thin film as a function of the film thickness D. The monomer-wall interactions are short ranged and antisymmetric, i.e, the left wall attracts the A-component of the mixture with the same strength as the right wall the B-component, and give rise to a first order wetting transition in a semi-infinite geometry. The phase diagram and the crossover between different critical behaviors is explored. For large film thicknesses we find a first order interface localisation/delocalisation transition and the phase diagram comprises two critical points, which are the finite film width analogies of the prewetting critical point. Using finite size scaling techniques we locate these critical points and present evidence of 2D Ising critical behavior. When we reduce the film width the two critical points approach the symmetry axis $\phi=1/2$ of the phase diagram and for $D \approx 2 R_g$ we encounter a tricritical point. For even smaller film thickness the interface localisation/delocalisation transition is second order and we find a single critical point at $\phi=1/2$. Measuring the probability distribution of the interface position we determine the effective interaction between the wall and the interface. This effective interface potential depends on the lateral system size even away from the critical points. Its system size dependence stems from the large but finite correlation length of capillary waves. This finding gives direct evidence for a renormalization of the interface potential by capillary waves in the framework of a microscopic model.Comment: Phys.Rev.

Critical dynamics in thin films

Critical dynamics in film geometry is analyzed within the field-theoretical approach. In particular we consider the case of purely relaxational dynamics (Model A) and Dirichlet boundary conditions, corresponding to the so-called ordinary surface universality class on both confining boundaries. The general scaling properties for the linear response and correlation functions and for dynamic Casimir forces are discussed. Within the Gaussian approximation we determine the analytic expressions for the associated universal scaling functions and study quantitatively in detail their qualitative features as well as their various limiting behaviors close to the bulk critical point. In addition we consider the effects of time-dependent fields on the fluctuation-induced dynamic Casimir force and determine analytically the corresponding universal scaling functions and their asymptotic behaviors for two specific instances of instantaneous perturbations. The universal aspects of nonlinear relaxation from an initially ordered state are also discussed emphasizing the different crossovers that occur during this evolution. The model considered is relevant to the critical dynamics of actual uniaxial ferromagnetic films with symmetry-preserving conditions at the confining surfaces and for Monte Carlo simulations of spin system with Glauber dynamics and free boundary conditions.Comment: 64 pages, 21 figure

Escherichia coli Frameshift Mutation Rate Depends on the Chromosomal Context but Not on the GATC Content Near the Mutation Site

Different studies have suggested that mutation rate varies at different positions in the genome. In this work we analyzed if the chromosomal context and/or the presence of GATC sites can affect the frameshift mutation rate in the Escherichia coli genome. We show that in a mismatch repair deficient background, a condition where the mutation rate reflects the fidelity of the DNA polymerization process, the frameshift mutation rate could vary up to four times among different chromosomal contexts. Furthermore, the mismatch repair efficiency could vary up to eight times when compared at different chromosomal locations, indicating that detection and/or repair of frameshift events also depends on the chromosomal context. Also, GATC sequences have been proved to be essential for the correct functioning of the E. coli mismatch repair system. Using bacteriophage heteroduplexes molecules it has been shown that GATC influence the mismatch repair efficiency in a distance- and number-dependent manner, being almost nonfunctional when GATC sequences are located at 1 kb or more from the mutation site. Interestingly, we found that in E. coli genomic DNA the mismatch repair system can efficiently function even if the nearest GATC sequence is located more than 2 kb away from the mutation site. The results presented in this work show that even though frameshift mutations can be efficiently generated and/or repaired anywhere in the genome, these processes can be modulated by the chromosomal context that surrounds the mutation site