Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks

White matter differences between healthy young ApoE4 carriers and non-carriers identified with tractography and support vector machines.

The apolipoprotein E4 (ApoE4) is an established risk factor for Alzheimer's disease (AD). Previous work has shown that this allele is associated with functional (fMRI) changes as well structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess the diffusion characteristics and the white matter (WM) tracts of healthy young (20-38 years) ApoE4 carriers and non-carriers. No significant differences in diffusion indices were found between young carriers (ApoE4+) and non-carriers (ApoE4-). There were also no significant differences between the groups in terms of normalised GM or WM volume. A feature selection algorithm (ReliefF) was used to select the most salient voxels from the diffusion data for subsequent classification with support vector machines (SVMs). SVMs were capable of classifying ApoE4 carrier and non-carrier groups with an extremely high level of accuracy. The top 500 voxels selected by ReliefF were then used as seeds for tractography which identified a WM network that included regions of the parietal lobe, the cingulum bundle and the dorsolateral frontal lobe. There was a non-significant decrease in volume of this WM network in the ApoE4 carrier group. Our results indicate that there are subtle WM differences between healthy young ApoE4 carriers and non-carriers and that the WM network identified may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age

Molecular mechanisms of protein sorting in the synaptic vesicle life cycle.

Synaptic vesicle (SV) proteins are synthesized at the level of the cell body and transported along the axons in precursor vesicles which undergo cycles of exo-endocytosis in transit to either the distal growth cone or the nerve terminal. I sought to investigate the mechanisms underlying the sorting of SV components and to determine whether and how SV exocytosis is regulated prior to synaptogenesis. SV fusion is underlain by the interaction of vesicle-associated membrane protein (VAMP) 2 with plasma membrane partners. Fluorescence resonance energy transfer analysis reveals that VAMP2 interacts with Synaptophysin I (SypI), a major resident of SVs, on the SV membrane and that exocytotic stimuli cause dissociation of this complex at a stage preceding SV fusion. This observation is consistent with the idea that SypI limits VAMP2 availability for fusogenic complexes. The interaction between SypI and VAMP2 occurs early along the exocytotic pathway and is required in order for SypI to govern the sorting of VAMP2 to SVs. The control of VAMP2 sorting by its negative regulator SypI establishes a mechanism which prevents the fusion at inappropriate sites of SVs directed to the nerve terminal. The study of SV dynamics in developing hippocampal neurons reveals that cAMP-dependent pathways affect SV distribution and recycling in the axonal growth cone and that these effects are mediated by the SV-associated phosphoprotein synapsin I. Synapsin I and its phosphorylation by cAMP-dependent protein kinase A play a pivotal role in regulating SV organization and dynamics in neuronal growth cones and in determining the formation of synaptic contacts. These results provide new clues as to the bases of the well known activity of synapsin I in synapse maturation and indicate that molecular mechanisms similar to those operating at mature nerve terminals are active in developing neurons to regulate the SV life cycle prior to synaptogenesis

Simulating cosmic metal enrichment by the first galaxies

We study cosmic metal enrichment via AMR hydrodynamical simulations in a (10 Mpc/h)$^3$ volume following the Pop III-Pop II transition and for different Pop III IMFs. We have analyzed the joint evolution of metal enrichment on galactic and intergalactic scales at z=6 and z=4. Galaxies account for <9% of the baryonic mass; the remaining gas resides in the diffuse phases: (a) voids, i.e. regions with extremely low density ($\Delta$<1), (b) the true intergalactic medium (IGM, 1<$\Delta$<10) and (c) the circumgalactic medium (CGM, 10<$\Delta<10^{2.5}$), the interface between the IGM and galaxies. By z=6 a galactic mass-metallicity relation is established. At z=4, galaxies with a stellar mass $M_*=10^{8.5}M_\odot$ show log(O/H)+12=8.19, consistent with observations. The total amount of heavy elements rises from $\Omega^{SFH}_Z=1.52\, 10^{-6}$ at z=6 to 8.05 $10^{-6}$ at z=4. Metals in galaxies make up to ~0.89 of such budget at z=6; this fraction increases to ~0.95 at z=4. At z=6 (z=4) the remaining metals are distributed in CGM/IGM/voids with the following mass fractions: 0.06/0.04/0.01 (0.03/0.02/0.01). Analogously to galaxies, at z=4 a density-metallicity ($\Delta$-Z) relation is in place for the diffuse phases: the IGM/voids have a spatially uniform metallicity, Z~$10^{-3.5}$Zsun; in the CGM Z steeply rises with density up to ~$10^{-2}$Zsun. In all diffuse phases a considerable fraction of metals is in a warm/hot (T>$10^{4.5}$K) state. Due to these physical conditions, CIV absorption line experiments can probe only ~2% of the total carbon present in the IGM/CGM; however, metal absorption line spectra are very effective tools to study reionization. Finally, the Pop III star formation history is almost insensitive to the chosen Pop III IMF. Pop III stars are preferentially formed in truly pristine (Z=0) gas pockets, well outside polluted regions created by previous star formation episodes.Comment: 23 pages, 18 figures, 3 tables, Accepted for publication in MNRA

Understanding How Stochasticity Impacts Reconstructions of Recent Species Divergent History.

Molecular phylogenetic studies are complicated by the fact that differentiation between orthologous gene copies is determined by two stochastic process–lineage sorting (coalescent) and mutational processes. The former could lead to discrepancies between the species divergent history and genealogies, while the later could result in differences between genealogies and estimated gene trees. Only recently has the idea of incorporating the coalescent process into species-tree estimation been applied in empirical phylogenetics. My thesis focuses on examining the impacts of these two stochasticities on reconstructing recent species divergent histories where incomplete lineage sorting is prevalent. Using simulated data, the effect of mutation variance is re-evaluated on accuracy of species-tree estimates with different methods, ranging from the simplest “democratic voting”, to the Maximum-likelihood method includes the branch length information, and the implications in terms of sampling design, methods for gene-tree and species-tree estimation, are discussed in Chapter II&III. While future phylogenetic studies will benefit from the new species-tree estimation methods, it is not clear is the extent to which species relationships estimated with data and methods that predate these developments are robust. I proposed a parametric bootstrap species tree (PBST) approach to assess the reliability of past phylogenetic studies in which the stochastic lineage sorting processes were overlooked, and applied the approach as a meta-analysis of east African cichlid phylogenies in Chapter IV. Another problem for empirical phylogenetic studies to applying species-tree estimation is to having a multi-locus sequencing dataset, Next-generation sequencing (NGS) combined with Reduce Representation Library technique has the premise but concerns exist about whether the high NGS error rates are amenable for directly use for phylogenetic analysis. The use of NGS as primary data for reconstructing the divergent history was explored of four montane grasshopper species in Chapter IV, and parametric simulation was used to three possible sources of uncertainty in the estimated species tree: the true species divergent history, sequencing errors and error correction method. Possible improvement on sampling design and the methodological developments needed for future studies are discussed. The last chapter explored the use of gene divergent history combined with geographic information to infer speciation models.Ph.D.Ecology and Evolutionary BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91486/1/huatengh_1.pd