Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes

Abstract Diabetic retinopathy (DR) is a major cause of blindness in working adults in the industrialized world. In addition to vision loss caused by macular edema and pathological angiogenesis, DR patients often exhibit neuronal dysfunction on electrophysiological testing, suggesting that there may be an independent neuronal phase of disease that precedes vascular disease. Given the tremendous metabolic requirements of the retina and photoreceptors in particular, we hypothesized that derangements in metabolic regulation may accelerate retinal dysfunction in diabetes. As such, we induced hyperglycemia with streptozotocin in mice with monoallelic Nampt deletion from rod photoreceptors, mice lacking SIRT3, and mice lacking SIRT5 and tested multiple components of retinal function with electroretinography. None of these mice exhibited accelerated retinal dysfunction after induction of hyperglycemia, consistent with normal-appearing retinal morphology in hyperglycemic Sirt3 −/− or Sirt5 −/− mice. However, mice lacking both SIRT3 and SIRT5 (Sirt3 −/− Sirt5 −/− mice) exhibited significant evidence of inner retinal dysfunction after induction of hyperglycemia compared to hyperglycemic littermate controls, although this dysfunction was not accompanied by gross morphological changes in the retina. These results suggest that SIRT3 and SIRT5 may be involved in regulating neuronal dysfunction in DR and provide a foundation for future studies investigating sirtuin-based therapies

Lookahead Strategies for Sequential Monte Carlo

Based on the principles of importance sampling and resampling, sequential Monte Carlo (SMC) encompasses a large set of powerful techniques dealing with complex stochastic dynamic systems. Many of these systems possess strong memory, with which future information can help sharpen the inference about the current state. By providing theoretical justification of several existing algorithms and introducing several new ones, we study systematically how to construct efficient SMC algorithms to take advantage of the "future" information without creating a substantially high computational burden. The main idea is to allow for lookahead in the Monte Carlo process so that future information can be utilized in weighting and generating Monte Carlo samples, or resampling from samples of the current state.Comment: Published in at http://dx.doi.org/10.1214/12-STS401 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Arithmetic Properties of Overpartition Pairs

Bringmann and Lovejoy introduced a rank for overpartition pairs and investigated its role in congruence properties of $\bar{pp}(n)$, the number of overpartition pairs of n. In particular, they applied the theory of Klein forms to show that there exist many Ramanujan-type congruences for the number $\bar{pp}(n)$. In this paper, we shall derive two Ramanujan-type identities and some explicit congruences for $\bar{pp}(n)$. Moreover, we find three ranks as combinatorial interpretations of the fact that $\bar{pp}(n)$ is divisible by three for any n. We also construct infinite families of congruences for $\bar{pp}(n)$ modulo 3, 5, and 9.Comment: 19 page

Adhesive and mechanical regulation of mesenchymal stem cell differentiation in human bone marrow and periosteum-derived progenitor cells

It has previously been demonstrated that cell shape can influence commitment of human bone marrow-derived mesenchymal stem cells (hBMCs) to adipogenic, osteogenic, chondrogenic, and other lineages. Human periosteum-derived cells (hPDCs) exhibit multipotency similar to hBMCs, but hPDCs may offer enhanced potential for osteogenesis and chondrogenesis given their apparent endogenous role in bone and cartilage repair in vivo. Here, we examined whether hPDC differentiation is regulated by adhesive and mechanical cues comparable to that reported for hBMC differentiation. When cultured in the appropriate induction media, hPDCs at high cell seeding density demonstrated enhanced levels of adipogenic or chondrogenic markers as compared with hPDCs at low cell seeding density. Cell seeding density correlated inversely with projected area of cell spreading, and directly limiting cell spreading with micropatterned substrates promoted adipogenesis or chondrogenesis while substrates promoting cell spreading supported osteogenesis. Interestingly, cell seeding density influenced differentiation through both changes in cell shape and non-shape-mediated effects: density-dependent adipogenesis and chondrogenesis were regulated primarily by cell shape whereas non-shape effects strongly influenced osteogenic potential. Inhibition of cytoskeletal contractility by adding the Rho kinase inhibitor Y27632 further enhanced adipogenic differentiation and discouraged osteogenic differentiation of hPDCs. Together, our results suggest that multipotent lineage decisions of hPDCs are impacted by cell adhesive and mechanical cues, though to different extents than hBMCs. Thus, future studies of hPDCs and other primary stem cell populations with clinical potential should consider varying biophysical metrics for more thorough optimization of stem cell differentiation.R01 EB000262 - NIBIB NIH HHS; R01 GM060692 - NIGMS NIH HHSPublished versio