Letter from Maures Horner to Joseph Le Conte, 1890 Sep 18.

[letterhead]Sep. 18. 1890.SirI take the liberty of enclosing Mr. Bryce\u27s letter of introduction and hope to do myself the pleasure of calling upon you tomorrow.I amYrs SincerlyMaures HornerProf. Joseph Le ConteUniversity of CaliforniaBerkeley06163 Boston, Aug. 21Dear Professor LeconteLet me introduce to your my friend Mr. Maures Horner of London, who proposes to visit San Francisco and will be much interested in seeing your State University and hearing of what is being done among you in the 06163 way of scientific research, this being a subject in which he is earnestly concerned. Believe me, with hopes of myself coming to see you in I am able to reach California this fall.Very truly yours,J. Bryce

Molecular Mechanisms by Which Adapter Protein SH2B1(beta) Facilitates NGF-Dependent Neuronal Differentiation.

Nerve Growth Factor (NGF) has long been recognized as a critical factor in the survival and maintenance of sympathetic neurons. Recent findings have shown that NGF is also required for the sympathetic neuron’s axonal growth and appropriate target organ innervation during development. However, the molecular mechanisms by which NGF elicits these effects are largely unknown. The ubiquitously expressed adapter protein SH2B1 binds to active NGF receptor TrkA and has been implicated in NGF-mediated differentiation and survival of sympathetic neurons. This work provides evidence that SH2B1β facilitates the NGF-dependent nuclear export of FoxO1, a pro-apoptotic transcription factor. While SH2B1 was originally thought to localize and function only at the cell membrane, more recent studies indicated that SH2B1β undergoes nucleocytoplasmic shuttling. The work described in this thesis identifies a functional nuclear localization sequence and provides evidence that nuclear cycling of SH2B1β is critical to promote NGF-mediated differentiation of the preneuronal PC12 cell line. SH2B1β was found to specifically enhance the NGF-induced transcription of a primary response gene required for neuronal differentiation, urokinase plasminogen activator receptor (uPAR). Preventing translocation either into or out of the nucleus abolished the ability of SH2B1β to enhance the transcription of uPAR in response to NGF. Similarly, NGF-dependent neurite outgrowth was inhibited in PC12 cells stably expressing a nuclear import defective SH2B1β. Knocking down endogenous levels of SH2B1 inhibited the NGF-induced transcription of uPAR as well as NGF-dependent neurite outgrowth, suggesting that endogenous SH2B1 is required for both NGF-dependent gene expression and neurite outgrowth. TAP tagged-SH2B1β was used to identify nuclear binding partners of SH2B1, including a putative transcription factor that inhibits NGF-dependent neurite outgrowth. Taken together, these results suggest a nuclear role for SH2B1β during NGF-dependent differentiation and survival. The ability of SH2B1β to influence the subcellular localization of FoxO1 and bind to and counteract the function of a novel transcription factor raises the possibility SH2B1β cycling between the nucleus and cytoplasm is required to shuttle transcription factors into or out of the nucleus.Ph.D.Cellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/60645/1/maurest_1.pd

Lithium-ion battery SoH estimation based on incremental capacity peak tracking at several current levels for online application

In this paper, an extension to high C-rates of State of Health (SoH) diagnostic methods based on Incremental Capacity (IC) peak tracking is proposed. A set of eleven NCA Lithium-ion batteries who went under different ageing protocol is used. Charge and discharge cycles are performed at C/20, C/10, C/5 and C/2, and then used for IC analysis. Correlations between the variations of IC peaks and SoH are presented and modelized, and shown to be accurate estimators for all tested C-rates

An Incremental Capacity Parametric Model Based on Logistic Equations for Battery State Estimation and Monitoring

An incremental capacity parametric model for batteries is proposed. The model is based on Verhulst’s logistic equations and distributions in order to describe incremental capacity peaks. The model performance is compared with polynomial models and is demonstrated on a commercial lithium-ion cell. Experimental data features low-current discharges performed at temperatures ranging from −20 °C to 55 °C. The results demonstrate several advantages of the model compared to empirical models. The proposed model enables a clear description of the geometric features of incremental capacity peaks. It also doubles as an open circuit voltage model as the voltage curve can be fully recovered from parameterization on incremental capacity curves. The study of temperature sensitivity show that peak geometric parameters can be modelled as a function of temperature. An example of practical application is then displayed by using the model to estimate battery state-of-charge from voltage and temperature measurements. This example can expand to other practical applications for battery management systems such as state-of-health monitoring

Lysosome-mediated processing of chromatin in senescence

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression

Studies of Metabolic Phenotypic Correlates of 15 Obesity Associated Gene Variants

Genome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci associate with type 2 diabetes and to elucidate potential underlying metabolic mechanisms.15 gene variants in 14 loci including TMEM18 (rs7561317), SH2B1 (rs7498665), KCTD15 (rs29941), NEGR1 (rs2568958), ETV5 (rs7647305), BDNF (rs4923461, rs925946), SEC16B (rs10913469), FAIM2 (rs7138803), GNPDA2 (rs10938397), MTCH2 (rs10838738), BAT2 (rs2260000), NPC1 (rs1805081), MAF (rs1424233), and PTER (rs10508503) were genotyped in 18,014 middle-aged Danes.Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15-1.20 for overweight, 1.10-1.25 for obesity, and 1.41-1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78-0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07-1.27, p = 7.8×10(-4))).Associations with overweight and/or obesity and measures of obesity were confirmed for seven out of the 15 gene variants. The obesity risk allele of BDNF rs4923461 protected against type 2 diabetes, which could suggest neuronal and peripheral distinctive ways of actions for the protein. SH2B1 rs7498665 associated with type 2 diabetes independently of BMI

The C. elegans H3K27 Demethylase UTX-1 Is Essential for Normal Development, Independent of Its Enzymatic Activity

Epigenetic modifications influence gene expression and provide a unique mechanism for fine-tuning cellular differentiation and development in multicellular organisms. Here we report on the biological functions of UTX-1, the Caenorhabditis elegans homologue of mammalian UTX, a histone demethylase specific for H3K27me2/3. We demonstrate that utx-1 is an essential gene that is required for correct embryonic and postembryonic development. Consistent with its homology to UTX, UTX-1 regulates global levels of H3K27me2/3 in C. elegans. Surprisingly, we found that the catalytic activity is not required for the developmental function of this protein. Biochemical analysis identified UTX-1 as a component of a complex that includes SET-16(MLL), and genetic analysis indicates that the defects associated with loss of UTX-1 are likely mediated by compromised SET-16/UTX-1 complex activity. Taken together, these results demonstrate that UTX-1 is required for many aspects of nematode development; but, unexpectedly, this function is independent of its enzymatic activity

Duplication and Diversification of the Hypoxia-Inducible IGFBP-1 Gene in Zebrafish

Gene duplication is the primary force of new gene evolution. Deciphering whether a pair of duplicated genes has evolved divergent functions is often challenging. The zebrafish is uniquely positioned to provide insight into the process of functional gene evolution due to its amenability to genetic and experimental manipulation and because it possess a large number of duplicated genes.We report the identification and characterization of two hypoxia-inducible genes in zebrafish that are co-ortholgs of human IGF binding protein-1 (IGFBP-1). IGFBP-1 is a secreted protein that binds to IGF and modulates IGF actions in somatic growth, development, and aging. Like their human and mouse counterparts, in adult zebrafish igfbp-1a and igfbp-1b are exclusively expressed in the liver. During embryogenesis, the two genes are expressed in overlapping spatial domains but with distinct temporal patterns. While zebrafish IGFBP-1a mRNA was easily detected throughout embryogenesis, IGFBP-1b mRNA was detectable only in advanced stages. Hypoxia induces igfbp-1a expression in early embryogenesis, but induces the igfbp-1b expression later in embryogenesis. Both IGFBP-1a and -b are capable of IGF binding, but IGFBP-1b has much lower affinities for IGF-I and -II because of greater dissociation rates. Overexpression of IGFBP-1a and -1b in zebrafish embryos caused significant decreases in growth and developmental rates. When tested in cultured zebrafish embryonic cells, IGFBP-1a and -1b both inhibited IGF-1-induced cell proliferation but the activity of IGFBP-1b was significantly weaker.These results indicate subfunction partitioning of the duplicated IGFBP-1 genes at the levels of gene expression, physiological regulation, protein structure, and biological actions. The duplicated IGFBP-1 may provide additional flexibility in fine-tuning IGF signaling activities under hypoxia and other catabolic conditions

Hypoxia Impairs Primordial Germ Cell Migration in Zebrafish (Danio rerio) Embryos

Background: As a global environmental concern, hypoxia is known to be associated with many biological and physiological impairments in aquatic ecosystems. Previous studies have mainly focused on the effect of hypoxia in adult animals. However, the effect of hypoxia and the underlying mechanism of how hypoxia affects embryonic development of aquatic animals remain unclear. Methodology/Principal Findings: In the current study, the effect of hypoxia on primordial germ cell (PGC) migration in zebrafish embryos was investigated. Hypoxic embryos showed PGC migration defect as indicated by the presence of mis-migrated ectopic PGCs. Insulin-like growth factor (IGF) signaling is required for embryonic germ line development. Using real-time PCR, we found that the mRNA expression levels of insulin-like growth factor binding protein (IGFBP-1), an inhibitor of IGF bioactivity, were significantly increased in hypoxic embryos. Morpholino knockdown of IGFBP-1 rescued the PGC migration defect phenotype in hypoxic embryos, suggesting the role of IGFBP-1 in inducing PGC mis-migration. Conclusions/Significance: This study provides novel evidence that hypoxia disrupts PGC migration during embryonic development in fish. IGF signaling is shown to be one of the possible mechanisms for the causal link between hypoxia and PGC migration. We propose that hypoxia causes PGC migration defect by inhibiting IGF signaling through the induction of IGFBP-1