Distinguishing the rates of gene activation from phenotypic variations

Background: Stochastic genetic switching driven by intrinsic noise is an important process in gene expression. When the rates of gene activation/inactivation are relatively slow, fast, or medium compared with the synthesis/degradation rates of mRNAs and proteins, the variability of protein and mRNA levels may exhibit very different dynamical patterns. It is desirable to provide a systematic approach to identify their key dynamical features in different regimes, aiming at distinguishing which regime a considered gene regulatory network is in from their phenotypic variations. Results: We studied a gene expression model with positive feedbacks when genetic switching rates vary over a wide range. With the goal of providing a method to distinguish the regime of the switching rates, we first focus on understanding the essential dynamics of gene expression system in different cases. In the regime of slow switching rates, we found that the effective dynamics can be reduced to independent evolutions on two separate layers corresponding to gene activation and inactivation states, and the transitions between two layers are rare events, after which the system goes mainly along deterministic ODE trajectories on a particular layer to reach new steady states. The energy landscape in this regime can be well approximated by using Gaussian mixture model. In the regime of intermediate switching rates, we analyzed the mean switching time to investigate the stability of the system in different parameter ranges. We also discussed the case of fast switching rates from the viewpoint of transition state theory. Based on the obtained results, we made a proposal to distinguish these three regimes in a simulation experiment. We identified the intermediate regime from the fact that the strength of cellular memory is lower than the other two cases, and the fast and slow regimes can be distinguished by their different perturbation-response behavior with respect to the switching rates perturbations. Conclusions: We proposed a simulation experiment to distinguish the slow, intermediate and fast regimes, which is the main point of our paper. In order to achieve this goal, we systematically studied the essential dynamics of gene expression system when the switching rates are in different regimes. Our theoretical understanding provides new insights on the gene expression experiments.NSFC [11174011, 11021463, 11171009, 11421101, 91130005]; National Science Foundation for Excellent Young Scholars [11222114]SCI(E)[email protected]

Cotransplantation of Mesenchymal Stem Cells and Immature Dendritic Cells Potentiates the Blood Glucose Control of Islet Allografts

Background. Transplantation of islets is a promising alternative to treat type 1 diabetes (T1D), but graft rejection is the major obstacle to its application in clinical practice. We evaluated the effects of mesenchymal stem cells (MSCs) and immature dendritic cells (imDCs) on islet transplantation in diabetic model. Methods. The streptozotocin T1D model was established in BABL/c mice. Rat islets were isolated and identified with dithizone (DTZ) staining. MSCs and imDCs were isolated from bone marrow of syngenic mice. Islets, alone or along with MSCs and/or imDCs, were transplanted to the left kidney capsule of diabetic mice. The blood glucose levels and glycosylated hemoglobin levels after transplantation were monitored. Results. Cotransplantation significantly decreased blood glucose and glycosylated hemoglobin levels in the diabetes mice. Transplantation of 200 islets + 2 × 105 MSCs + 2 × 105 imDCs could not only restore normal blood glucose levels, but also significantly prolong graft survival for 12.6±3.48 days. Conclusions. Cotransplantation of allogenic islets with imDCs and/or MSCs can significantly promote graft survival, reverse hyperglycemia, and effectively control the glycosylated hemoglobin levels

Bioactive phytochemicals and their potential roles in modulating gut microbiota

Dietary phytochemicals, including polyphenols, sulfur-containing compounds, terpenoids, polysaccharides, saponins, pigments, and phytohaemagglutinins, have antioxidant, anti-inflammatory, antiviral, and cancer-preventive or therapeutic properties. Upon entering the body, these compounds pass through the stomach, liver, small intestine, and colon in that order. Bacteria play an important role in the absorption and processing of dietary phytochemicals in the small intestine and in the large intestine. However, the specific processes by which dietary phytochemicals are absorbed and metabolized in the host colon have not been elucidated. This paper describes the metabolism of phytochemicals (including polyphenols, terpenoids, and plant organosulfides) in the colon and describes the roles played by these dietary phytochemicals in the colon, with emphasis on their effects on the gut microbiota. Upon entry into the host, phytochemicals are absorbed and metabolized mainly in the colon, and the differences in their absorption and metabolism are largely due to differences in the colonic microbiota. Moreover, phytochemicals can be absorbed in the intestine by acting on them through enzymes produced by intestinal cells and stem cells, or by interacting with the intestinal flora, thus ameliorating the associated diseases

Protein Design: Toward Functional Metalloenzymes

The scope of this Review is to discuss the construction of metal sites in designed protein scaffolds. We categorize the effort of designing proteins into redesign, which is to rationally engineer desired functionality into an existing protein scaffold,(1-9) and de novo design, which is to build a peptidic or protein system that is not directly related to any sequence found in nature yet folds into a predicted structure and/or carries out desired reactions.(10-12) We will analyze and interpret the significance of designed protein systems from a coordination chemistry and biochemistry perspective, with an emphasis on those containing constructed metal sites as mimics for metalloenzymes