In police reform circles, many scholars and policymakers diagnose the frayed relationship between police forces and the communities they serve as a problem of illegitimacy, or the idea that people ...lack confidence in the police and thus are unlikely to comply or cooperate with them. The core proposal emanating from this illegitimacy diagnosis is procedural justice, a concept that emphasizes police officers' obligation to treat people with dignity and respect, behave in a neutral, nonbiased way, exhibit an intention to help, and give them voice to express themselves and their needs, largely in the context of police stops. This Essay argues that legitimacy theory offers an incomplete diagnosis of the policing crisis, and thus de-emphasizes deeper structural, group-centered approaches to the problem of policing. The existing police regulatory regime encourages large swaths of American society to see themselves as existing within the law's aegis but outside its protection. This Essay critiques the reliance of police decision makers on a simplified version of legitimacy and procedural justice theory. It aims to expand the predominant understanding of police mistrust among African Americans and the poor, proposing that legal estrangement offers a better lens through which scholars and policymakers can understand and respond to the current problems of policing. Legal estrangement is a theory of detachment and eventual alienation from the law's enforcers, and it reflects the intuition among many people in poor communities of color that the law operates to exclude them from society. Building on the concepts of legal cynicism and anomie in sociology, the concept of legal estrangement provides a way of understanding the deep concerns that motivate today's police reform movement and points toward structural approaches to reforming policing.
Co-infection with Mycobacterium tuberculosis is the leading cause of death in individuals infected with HIV-1. It has long been known that HIV-1 infection alters the course of M. tuberculosis ...infection and substantially increases the risk of active tuberculosis (TB). It has also become clear that TB increases levels of HIV-1 replication, propagation and genetic diversity. Therefore, co-infection provides reciprocal advantages to both pathogens. In this Review, we describe the epidemiological associations between the two pathogens, selected interactions of each pathogen with the host and our current understanding of how they affect the pathogenesis of TB and HIV-1/AIDS in individuals with co-infections. We evaluate the mechanisms and consequences of HIV-1 depletion of T cells on immune responses to M. tuberculosis. We also discuss the effect of HIV-1 infection on the control of M. tuberculosis by macrophages through phagocytosis, autophagy and cell death, and we propose models by which dysregulated inflammatory responses drive the pathogenesis of TB and HIV-1/AIDS.
Homologous recombination maintains genomic integrity by repairing broken chromosomes. The broken chromosome is partially resected to produce single-stranded DNA (ssDNA) that is used to search for ...homologous double-stranded DNA (dsDNA). This homology driven ‘search and rescue’ is catalyzed by a class of DNA strand exchange proteins that are defined in relation to Escherichia coli RecA, which forms a filament on ssDNA. Here, we review the regulation of RecA filament assembly and the mechanism by which RecA quickly and efficiently searches for and identifies a unique homologous sequence among a vast excess of heterologous DNA. Given that RecA is the prototypic DNA strand exchange protein, its behavior affords insight into the actions of eukaryotic RAD51 orthologs and their regulators, BRCA2 and other tumor suppressors.
Single molecule methods have yielded new insight into how RecA filaments form and find homologous DNA.
RecA nucleation and growth on SSB-coated ssDNA is kinetically regulated by the RecFOR and RecOR complexes, which both microscopically and macroscopically alter the SSB–ssDNA nucleoprotein fiber.
RecA finds homology through many random, weak, and transient interactions made in parallel and ignores very short regions of microhomology resulting in a reduction of both dimensionality and complexity.
Abstract
The DECam Local Volume Exploration survey (DELVE) is a 126-night survey program on the 4 m Blanco Telescope at the Cerro Tololo Inter-American Observatory in Chile. DELVE seeks to understand ...the characteristics of faint satellite galaxies and other resolved stellar substructures over a range of environments in the Local Volume. DELVE will combine new DECam observations with archival DECam data to cover ∼15,000 deg
2
of high Galactic latitude (∣
b
∣ > 10°) southern sky to a 5
σ
depth of
g
,
r
,
i
,
z
∼ 23.5 mag. In addition, DELVE will cover a region of ∼2200 deg
2
around the Magellanic Clouds to a depth of
g
,
r
,
i
∼ 24.5 mag and an area of ∼135 deg
2
around four Magellanic analogs to a depth of
g
,
i
∼ 25.5 mag. Here, we present an overview of the DELVE program and progress to date. We also summarize the first DELVE public data release (DELVE DR1), which provides point-source and automatic aperture photometry for ∼520 million astronomical sources covering ∼5000 deg
2
of the southern sky to a 5
σ
point-source depth of
g
= 24.3 mag,
r
= 23.9 mag,
i
= 23.3 mag, and
z
= 22.8 mag. DELVE DR1 is publicly available via the NOIRLab Astro Data Lab science platform.
Abstract
Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within ...hours. This dedifferentiation can be ameliorated when PHHs are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the 6 participating laboratories evaluated the robustness of these 2 model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-laboratory variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms. We found that expression levels of proteins involved in drug absorption, distribution, metabolism, and excretion, as well as catalytic activities of 5 different CYPs, were significantly higher in 3D spheroid cultures, potentially affecting the exposure of the cells to drugs and their metabolites. Furthermore, global proteomic analyses revealed that PHH in 3D spheroid configuration were temporally stable whereas proteomes from the same donors in 2Dsw cultures showed substantial alterations in protein expression patterns over the 14 days in culture. Overall, spheroid cultures were more sensitive to the hepatotoxic compounds investigated, particularly upon long-term exposures, across testing sites with little inter-laboratory or inter-donor variability. The data presented here suggest that repeated-dosing regimens improve the predictivity of in vitro toxicity assays, and that PHH spheroids provide a sensitive and robust system for long-term mechanistic studies of drug-induced hepatotoxicity, whereas the 2Dsw system has a more dedifferentiated phenotype and lower sensitivity to detect hepatotoxicity.
5-hydroxytryptamine type 3 (5-HT
3
) receptor antagonists are used in the prevention of chemotherapy- induced, radiation-induced and postoperative nausea and vomiting.
CYP2D6
polymorphisms can ...influence the metabolism of some of these drugs (i.e. ondansetron and tropisetron) thereby affecting drug efficacy. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for ondansetron and tropisetron based on
CYP2D6
genotype (updates at
www.pharmgkb.org
).
Phenotypes in phylogeography Zamudio, Kelly R.; Bell, Rayna C.; Mason, Nicholas A.
Proceedings of the National Academy of Sciences - PNAS,
07/2016, Letnik:
113, Številka:
29
Journal Article
Recenzirano
Odprti dostop
Almost 30 y ago, the field of intraspecific phylogeography laid the foundation for spatially explicit and genealogically informed studies of population divergence. With new methods and markers, the ...focus in phylogeography shifted to previously unrecognized geographic genetic variation, thus reducing the attention paid to phenotypic variation in those same diverging lineages. Although phenotypic differences among lineages once provided the main data for studies of evolutionary change, the mechanisms shaping phenotypic differentiation and their integration with intraspecific genetic structure have been underexplored in phylogeographic studies. However, phenotypes are targets of selection and play important roles in species performance, recognition, and diversification. Here, we focus on three questions. First, how can phenotypes elucidate mechanisms underlying concordant or idiosyncratic responses of vertebrate species evolving in shared landscapes? Second, what mechanisms underlie the concordance or discordance of phenotypic and phylogeographic differentiation? Third, how can phylogeography contribute to our understanding of functional phenotypic evolution? We demonstrate that the integration of phenotypic data extends the reach of phylogeography to explain the origin and maintenance of biodiversity. Finally, we stress the importance of natural history collections as sources of high-quality phenotypic data that span temporal and spatial axes.
cGMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) sensing has emerged as a key regulator of innate immune responses to both exogenous and endogenous DNA. Recent studies reveal critical ...roles for this pathway in natural antitumor immunity across cancer types as well as in immune checkpoint blockade therapy. However, it is also clear that some tumors evade cGAS–STING-mediated immune responses, and immunomodulatory therapeutics are currently being explored to target this pathway. Finally, we also discuss recent observations that cGAS–STING-mediated inflammation may promote tumor initiation, growth, and metastasis in certain malignancies and how this may complicate the utility of this pathway in therapeutic development.
cGMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) recognizes cytosolic DNA and induces a type I interferon response in both tumor and phagocytic immune cells.
cGAS–STING-induced immunity has potent antitumor effects and magnifies the effects of a variety of anticancer therapeutics.
In certain tumor types, cGAS–STING promotes cancer growth and metastasis through modulation of the tumor microenvironment.
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