To what extent can the strength of a local urban community impact neighborhood safety? We construct measures of community vibrancy based on a unique dataset of block party permit approvals from the ...City of Philadelphia. Our first measure captures the overall volume of block party events in a neighborhood whereas our second measure captures differences in the type (regular versus spontaneous) of block party activities. We use both regression modeling and propensity score matching to control for the economic, demographic and land use characteristics of the surrounding neighborhood when examining the relationship between crime and our two measures of community vibrancy. We conduct our analysis on aggregate levels of crime and community vibrancy from 2006 to 2015 as well as the trends in community vibrancy and crime over this time period. We find that neighborhoods with a higher number of block parties have a significantly higher crime rate, while those holding a greater proportion of spontaneous block party events have a significantly lower crime rate. We also find that neighborhoods which have an increase in the proportion of spontaneous block parties over time are significantly more likely to have a decreasing trend in total crime incidence over that same time period.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE: To identify mechanisms for cancer resistance in elephants and ...compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS: A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES: Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES: Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS: Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% 95% CI, 0%-5%; African wild dog, 8% 95% CI, 0%-16%; lion, 2% 95% CI, 0%-7%). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% 95% CI, 1.93%-3.48% vs human controls, 7.17% 95% CI, 5.91%-8.44% vs elephants, 14.64% 95% CI, 10.91%-18.37%; P < .001; doxorubicin exposure: human controls, 8.10% 95% CI, 6.55%-9.66% vs elephants, 24.77% 95% CI, 23.0%-26.53%; P < .001). CONCLUSIONS AND RELEVANCE: Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.
Accurate estimation of the change in crime over time is a critical first step toward better understanding of public safety in large urban environments. Bayesian hierarchical modeling is a natural way ...to study spatial variation in urban crime dynamics at the neighborhood level, since it facilitates principled "sharing of information" between spatially adjacent neighborhoods. Typically, however, cities contain many physical and social boundaries that may manifest as spatial discontinuities in crime patterns. In this situation, standard prior choices often yield overly smooth parameter estimates, which can ultimately produce mis-calibrated forecasts. To prevent potential over-smoothing, we introduce a prior that partitions the set of neighborhoods into several clusters and encourages spatial smoothness within each cluster. In terms of model implementation, conventional stochastic search techniques are computationally prohibitive, as they must traverse a combinatorially vast space of partitions. We introduce an ensemble optimization procedure that simultaneously identifies several high probability partitions by solving one optimization problem using a new local search strategy. We then use the identified partitions to estimate crime trends in Philadelphia between 2006 and 2017. On simulated and real data, our proposed method demonstrates good estimation and partition selection performance.
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Abstract Background & Aims Intestinal homeostasis and regeneration after injury is controlled by 2 different types of cells–slow cycling, injury-resistant reserve intestinal stem cells (ISC) and ...actively proliferative ISC. Putative reserve ISCs have been identified using a variety of methods, including CreER insertions at Hopx or Bmi1 loci in mice and DNA label retention. Label-retaining cells (LRCs) include dormant stem cells in several tissues; in the intestine, LRCs appear to share some properties with reserve ISCs, which can be marked by reporter alleles. We investigated the relationships between these populations. Methods Studies were performed in Lgr5−EGFP-IRES-creERT2 , Bmi1-CreERT2 , Hopx-CreERT2 , and TRE-H2BGFP::Hopx-CreERT2::lox-stop-lox-tdTomato mice . Intestinal epithelial cell populations were purified; we compared reporter allele-marked reserve ISCs and several LRC populations (marked by H2B-GFP retention) using histologic, flow cytometry and functional and single-cell gene expression assays. Results LRCs were dynamic and their cellular composition changed with time. Short-term LRCs had properties of secretory progenitor cells undergoing commitment to the Paneth or enteroendocrine lineages while retaining some stem cell activity. Long-term LRCs lost stem cell activity and were a homogenous population of terminally differentiated Paneth cells. Reserve ISCs marked with HopxCreER were primarily quiescent (in G0), with inactive Wnt signaling and robust stem cell activity. In contrast, most LRCs were in G1 arrest and expressed genes that are regulated by the Wnt pathway or are in the secretory lineage. Conclusions LRCs are molecularly and functionally distinct from reporter-marked reserve intestinal stem cells. This information provides an important basis for future studies of relationships among intestinal stem cell populations.
We consider the task of discovering gene regulatory networks, which are defined as sets of genes and the corresponding transcription factors which regulate their expression levels. This can be viewed ...as a variable selection problem, potentially with high dimensionality. Variable selection is especially challenging in high-dimensional settings, where it is difficult to detect subtle individual effects and interactions between predictors. Bayesian Additive Regression Trees BART, Ann. Appl. Stat. 4 (2010) 266–298 provides a novel nonparametric alternative to parametric regression approaches, such as the lasso or stepwise regression, especially when the number of relevant predictors is sparse relative to the total number of available predictors and the fundamental relationships are nonlinear. We develop a principled permutation-based inferential approach for determining when the effect of a selected predictor is likely to be real. Going further, we adapt the BART procedure to incorporate informed prior information about variable importance. We present simulations demonstrating that our method compares favorably to existing parametric and nonparametric procedures in a variety of data settings. To demonstrate the potential of our approach in a biological context, we apply it to the task of inferring the gene regulatory network in yeast (Saccharomyces cerevisiae). We find that our BART-based procedure is best able to recover the subset of covariates with the largest signal compared to other variable selection methods. The methods developed in this work are readily available in the R package bartMachine.
The recent development of targeted murine reporter alleles as proxies for intestinal stem cell activity has led to significant advances in our understanding of somatic stem cell hierarchies and ...dynamics. Analysis of these reporters has led to a model in which an indispensable reserve stem cell at the top of the hierarchy (marked by Bmi1 and Hopx reporters) gives rise to active intestinal stem cells (marked by an Lgr5 reporter). Despite these advances, controversy exists regarding the specificity and fidelity with which these alleles distinguish intestinal stem cell populations. Here, we undertake a comprehensive comparison of widely used proxy reporters including both CreERT2 and EGFP cassettes targeted to the Lgr5, Bmi1, and Hopx loci. Single-cell transcriptional profiling of these populations and their progeny reveals that reserve and active intestinal stem cells are molecularly and functionally distinct, supporting a two-stem-cell model for intestinal self-renewal.
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•Proxy intestinal stem cell reporter alleles often mark heterogeneous populations•Discrepancies exist between proxy reporter activity and endogenous transcripts•Reserve and active intestinal stem cells are molecularly distinct•Reserve intestinal stem cells give rise to active stem cells during homeostasis
In this study, Lengner and colleagues utilize single-cell profiling to provide a comparative analysis of epithelial cells marked by a number of putative intestinal stem cell proxy reporter alleles. They confirm the existence of two molecularly distinct stem cell populations governing homeostasis, with a long-term reserve stem cell giving rise to a short-term active stem cell.
The transition from vegetative growth to flower formation is critical for the survival of flowering plants. The plant-specific transcription factor LEAFY (LFY) has central, evolutionarily conserved ...roles in this process, both in the formation of the first flower and later in floral patterning. We performed genome-wide binding and expression studies to elucidate the molecular mechanisms by which LFY executes these roles. Our study reveals that LFY directs an elaborate regulatory network in control of floral homeotic gene expression. LFY also controls the expression of genes that regulate the response to external stimuli in Arabidopsis. Thus, our findings support a key role for LFY in the coordination of reproductive stage development and disease response programs in plants that may ensure optimal allocation of plant resources for reproductive fitness. Finally, motif analyses reveal a possible mechanism for stage-specific LFY recruitment and suggest a role for LFY in overcoming polycomb repression.
► Genome-wide analysis identifies direct LEAFY targets at two developmental stages ► LEAFY acts as a regulatory hub in the induction of floral homeotic gene expression ► LEAFY reduces defense against bacterial pathogens at the onset of reproduction ► Motif analysis reveals cis elements that may contribute to stage-specific LFY activity
Regeneration of the intestinal epithelium is driven by multiple intestinal stem cell (ISC) types, including an active, radiosensitive Wnt
ISC that fuels turnover during homeostasis and a reserve, ...radioresistant Wnt
ISC capable of generating active Wnt
ISCs. We examined the role of the Msi family of oncoproteins in the ISC compartment. We demonstrated that Msi proteins are dispensable for normal homeostasis and self-renewal of the active ISC, despite their being highly expressed in these cells. In contrast, Msi proteins are required specifically for activation of reserve ISCs, where Msi activity is both necessary and sufficient to drive exit from quiescence and entry into the cell cycle. Ablation of Msi activity in reserve ISCs rendered the epithelium unable to regenerate in response to injury that ablates the active stem cell compartment. These findings delineate a molecular mechanism governing reserve ISC quiescence and demonstrate a necessity for the activity of this rare stem cell population in intestinal regeneration.
Germline mutation is the mechanism by which genetic variation in a population is created. Inferences derived from mutation rate models are fundamental to many population genetics methods. Previous ...models have demonstrated that nucleotides flanking polymorphic sites-the local sequence context-explain variation in the probability that a site is polymorphic. However, limitations to these models exist as the size of the local sequence context window expands. These include a lack of robustness to data sparsity at typical sample sizes, lack of regularization to generate parsimonious models and lack of quantified uncertainty in estimated rates to facilitate comparison between models. To address these limitations, we developed Baymer, a regularized Bayesian hierarchical tree model that captures the heterogeneous effect of sequence contexts on polymorphism probabilities. Baymer implements an adaptive Metropolis-within-Gibbs Markov Chain Monte Carlo sampling scheme to estimate the posterior distributions of sequence-context based probabilities that a site is polymorphic. We show that Baymer accurately infers polymorphism probabilities and well-calibrated posterior distributions, robustly handles data sparsity, appropriately regularizes to return parsimonious models, and scales computationally at least up to 9-mer context windows. We demonstrate application of Baymer in three ways-first, identifying differences in polymorphism probabilities between continental populations in the 1000 Genomes Phase 3 dataset, second, in a sparse data setting to examine the use of polymorphism models as a proxy for de novo mutation probabilities as a function of variant age, sequence context window size, and demographic history, and third, comparing model concordance between different great ape species. We find a shared context-dependent mutation rate architecture underlying our models, enabling a transfer-learning inspired strategy for modeling germline mutations. In summary, Baymer is an accurate polymorphism probability estimation algorithm that automatically adapts to data sparsity at different sequence context levels, thereby making efficient use of the available data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Receptor engagement by HIV-1 during host cell entry activates signaling pathways that can reprogram the cell for optimal viral replication. To obtain a global view of the signaling events induced ...during HIV-1 entry, we conducted a quantitative phosphoproteomics screen of primary human CD4+ T cells after infection with an HIV-1 strain that engages the receptors CD4 and CXCR4. We quantified 1,757 phosphorylation sites with high stringency. The abundance of 239 phosphorylation sites from 175 genes, including several proteins in pathways known to be impacted by HIV-receptor binding, changed significantly within a minute after HIV-1 exposure. Several previously uncharacterized HIV-1 host factors were also identified and confirmed through RNAi depletion studies. Surprisingly, five serine/arginine-rich (SR) proteins involved in messenger RNA splicing, including the splicing factor SRm300 (SRRM2), were differentially phosophorylated. Mechanistic studies with SRRM2 suggest that HIV-1 modulates host cell alternative splicing machinery during entry in order to facilitate virus replication and release.
•A quantitative phosphoproteomics screen of HIV-1-infected primary human CD4+ T cells•The abundance of 239 phosphorylation sites from 175 genes changed after HIV-1 exposure•Previously uncharacterized HIV-1 host factors, including SR proteins, confirmed by RNAi•SRm300 and other SR proteins regulate alternative splicing of HIV-1 transcripts
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