PPARγ2 Regulates a Molecular Signature of Marrow Mesenchymal Stem Cells

Bone formation and hematopoiesis are anatomically juxtaposed and share common regulatory mechanisms. Bone marrow mesenchymal stromal/stem cells (MSC) contain a compartment that provides progeny with bone forming osteoblasts and fat laden adipocytes as well as fibroblasts, chondrocytes, and muscle cells. In addition, marrow MSC provide an environment for support of hematopoiesis, including the development of bone resorbing osteoclasts. The PPARγ2 nuclear receptor is an adipocyte-specific transcription factor that controls marrow MSC lineage allocation toward adipocytes and osteoblasts. Increased expression of PPARγ2 with aging correlates with changes in the MSC status in respect to both their intrinsic differentiation potential and production of signaling molecules that contribute to the formation of a specific marrow micro-environment. Here, we investigated the effect of PPARγ2 on MSC molecular signature in respect to the expression of gene markers associated exclusively with stem cell phenotype, as well as genes involved in the formation of a stem cell supporting marrow environment. We found that PPARγ2 is a powerful modulator of stem cell-related gene expression. In general, PPARγ2 affects the expression of genes specific for the maintenance of stem cell phenotype, including LIF, LIF receptor, Kit ligand, SDF-1, Rex-1/Zfp42, and Oct-4. Moreover, the antidiabetic PPARγ agonist TZD rosiglitazone specifically affects the expression of “stemness” genes, including ABCG2, Egfr, and CD44. Our data indicate that aging and anti-diabetic TZD therapy may affect mesenchymal stem cell phenotype through modulation of PPARγ2 activity. These observations may have important therapeutic consequences and indicate a need for more detailed studies of PPARγ2 role in stem cell biology

Fermentative Approaches to Hydrogen Production

A PowerPoint presentation given as part of the 2005 Hydrogen Program Review, May 23-26, 2005, in Washington, D.C

An Integrated Approach to the Recovery of Fiber, Chemicals and Energy from Fibrous Textile and Carpet Waste

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Structural domains involved in the regulation of transmitter release by synapsins

Author Posting. © Society for Neuroscience, 2005. This article is posted here by permission of Society for Neuroscience for personal use, not for redistribution. The definitive version was published in Journal of Neuroscience 25 (2005): 2658-2669, doi:10.1523/JNEUROSCI.4278-04.2005.Synapsins are a family of neuron-specific phosphoproteins that regulate neurotransmitter release by associating with synaptic vesicles. Synapsins consist of a series of conserved and variable structural domains of unknown function. We performed a systematic structure-function analysis of the various domains of synapsin by assessing the actions of synapsin fragments on neurotransmitter release, presynaptic ultrastructure, and the biochemical interactions of synapsin. Injecting a peptide derived from domain A into the squid giant presynaptic terminal inhibited neurotransmitter release in a phosphorylation-dependent manner. This peptide had no effect on vesicle pool size, synaptic depression, or transmitter release kinetics. In contrast, a peptide fragment from domain C reduced the number of synaptic vesicles in the periphery of the active zone and increased the rate and extent of synaptic depression. This peptide also slowed the kinetics of neurotransmitter release without affecting the number of docked vesicles. The domain C peptide, as well as another peptide from domain E that is known to have identical effects on vesicle pool size and release kinetics, both specifically interfered with the binding of synapsins to actin but not with the binding of synapsins to synaptic vesicles. This suggests that both peptides interfere with release by preventing interactions of synapsins with actin. Thus, interactions of domains C and E with the actin cytoskeleton may allow synapsins to perform two roles in regulating release, whereas domain A has an actin-independent function that regulates transmitter release in a phosphorylation-sensitive manner.This work was supported by grants from The Fisher Center for Alzheimer’s Disease Research (P.G., F.B.), National Institutes of Health Grants NS-21624 (G.J.A.) and MH39327 (P.G.), the Italian Ministry of Education (F.B.), Consorzio Italiano Biotecnologie (F.B.), and a Ramon y Cajal fellowship (S.H.)

Programming of embryonic development

Assisted reproductive techniques (ART) and parental nutritional status have profound effects on embryonic/fetal and placental development, which are probably mediated via “programming” of gene expression, as reflected by changes in their epigenetic landscape. Such epigenetic changes may underlie programming of growth, development, and function of fetal organs later in pregnancy and the offspring postnatally, and potentially lead to long-term changes in organ structure and function in the offspring as adults. This latter concept has been termed developmental origins of health and disease (DOHaD), or simply developmental programming, which has emerged as a major health issue in animals and humans because it is associated with an increased risk of non-communicable diseases in the offspring, including metabolic, behavioral, and reproductive dysfunction. In this review, we will briefly introduce the concept of developmental programming and its relationship to epigenetics. We will then discuss evidence that ART and periconceptual maternal and paternal nutrition may lead to epigenetic alterations very early in pregnancy, and how each pregnancy experiences developmental programming based on signals received by and from the dam. Lastly, we will discuss current research on strategies designed to overcome or minimize the negative consequences or, conversely, to maximize the positive aspects of developmental programming

A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines

Background: The outstanding performance of an elite athlete might be associated with changes in their blood metabolic profile. The aims of this study were to compare the blood metabolic profiles between moderate- and high-power and endurance elite athletes and to identify the potential metabolic pathways underlying these differences. Methods: Metabolic profiling of serum samples from 191 elite athletes from different sports disciplines (121 high- and 70 moderate-endurance athletes, including 44 high- and 144 moderate-power athletes), who participated in national or international sports events and tested negative for doping abuse at anti-doping laboratories, was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was conducted using orthogonal partial least squares discriminant analysis. Differences in metabolic levels between high- and moderate-power and endurance sports were assessed by univariate linear models. Results: Out of 743 analyzed metabolites, gamma-glutamyl amino acids were significantly reduced in both high-power and high-endurance athletes compared to moderate counterparts, indicating active glutathione cycle. High-endurance athletes exhibited significant increases in the levels of several sex hormone steroids involved in testosterone and progesterone synthesis, but decreases in diacylglycerols and ecosanoids. High-power athletes had increased levels of phospholipids and xanthine metabolites compared to moderate-power counterparts. Conclusions: This pilot data provides evidence that high-power and high-endurance athletes exhibit a distinct metabolic profile that reflects steroid biosynthesis, fatty acid metabolism, oxidative stress, and energy-related metabolites. Replication studies are warranted to confirm differences in the metabolic profiles associated with athletes’ elite performance in independent data sets, aiming ultimately for deeper understanding of the underlying biochemical processes that could be utilized as biomarkers with potential therapeutic implications

Bone Loss in Diabetes: Use of Antidiabetic Thiazolidinediones and Secondary Osteoporosis

Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy

The old Galactic open clusters FSR1716 and Czernik23

Open clusters older than $\sim4$ Gyr are rare in the Galaxy. Affected by a series of mass-decreasing processes, the stellar content of most open clusters dissolves into the field in a time-scale shorter than $\sim1$ Gyr. In this sense, improving the statistics of old objects may provide constraints for a better understanding of the dynamical dissolution of open clusters. Isochrone fits indicate that FSR 1716 is more probably an old ($\sim7$ Gyr) and absorbed (\aV=6.3\pm0.2) open cluster, located $\approx0.6$ kpc inside the Solar circle in a contaminated central field. However, we cannot rule out the possibility of a low-mass, loose globular cluster. Czernik 23 is shown to be an almost absorption-free open cluster, $\sim5$ Gyr old, located about 2.5 kpc towards the anti-centre. In both cases, Solar and sub-Solar ($[Fe/H]\sim-0.5$) metallicity isochrones represent equally well the stellar sequences. Both star clusters have a low mass content (\la200 \ms) presently stored in stars. Their relatively small core and cluster radii are comparable to those of other open clusters of similar age. These structural parameters are probably consequence of the several Gyrs of mass loss due to stellar evolution, tidal interactions with the disk (and bulge in the case of FSR 1716), and possibly giant molecular clouds. Czernik 23, and especially FSR 1716, are rare examples of extreme dynamical survivors. The identification of both as such represents an increase of $\approx10$ to the known population of open clusters older than $\sim4$ Gyr in the Galaxy.Comment: 15 pages and 13 figures. Accepted by A&

Two refreshing views of Fluctuation Theorems through Kinematics Elements and Exponential Martingale

In the context of Markov evolution, we present two original approaches to obtain Generalized Fluctuation-Dissipation Theorems (GFDT), by using the language of stochastic derivatives and by using a family of exponential martingales functionals. We show that GFDT are perturbative versions of relations verified by these exponential martingales. Along the way, we prove GFDT and Fluctuation Relations (FR) for general Markov processes, beyond the usual proof for diffusion and pure jump processes. Finally, we relate the FR to a family of backward and forward exponential martingales.Comment: 41 pages, 7 figures; version2: 45 pages, 7 figures, minor revisions, new results in Section

Exploration of Burnout, Emotional Thriving, and Emotional Recovery in an Academic Medical Center: a Mixed Methods Quality Improvement Project

Introduction: Healthcare provider burnout, an indicator of wellbeing, impacts patient safety, provider distress, and employee turnover. In this mixed methods, multi-site quality improvement study conducted \u3c6 months prior to the start of the COVID-19 pandemic, we assessed employee wellbeing in a large clinical department. Methods: Wellbeing surveys were sent electronically to Department of Medicine clinicians, researchers, administrators, and staff from August-September 2019 assessing perceptions of Burnout, Emotional Thriving (ET), and Emotional Recovery (ER). Qualitative responses were reviewed for themes using mixed inductive-deductive analysis. The initial coding was done by small teams with consensus obtained through large group discussions. This study was IRB-approved as non-human subjects research. Results: Of the 671 respondents, 54% met criteria for burnout (Burnout+), 65% for ER (ER+), and 61% for ET (ET+). ER+ and ET+ were present in nearly half of Burnout+ respondents (53% and 43% respectively). Several themes emerged in the qualitative analysis: workload and expectations; tangible resources; work culture; and salary/benefits, with leadership influencing each of the domains. Conclusion: Burnout, ET, and ER can co-exist within the same individual. Employee wellbeing is not adequately reflected by the binary of whether or not an individual is experiencing burnout. All employees at academic medical centers, including staff, researchers, and clinicians, are vulnerable to the same workplace factors driving burnout. Our findings have been used to target areas of intervention during the COVID-19 pandemic at our institution. We propose that other academic medical centers may have similar workplace stressors that they could assess and target for improvement