This book examines the daily details of slave work routines and plantation agriculture in the eighteenth-century British Atlantic, focusing on case studies of large plantations in Barbados, Jamaica ...and Virginia. Work was the most important factor in the slaves' experience of the institution. Slaves' day-to-day work routines were shaped by plantation management strategies that drew on broader pan-Atlantic intellectual and cultural principles. Although scholars often associate the late eighteenth-century Enlightenment with the rise of notions of liberty and human rights and the dismantling of slavery, this book explores the dark side of the Enlightenment for plantation slaves. Many planters increased their slaves' workloads and employed supervisory technologies to increase labor discipline in ways that were consistent with the process of industrialization in Europe. British planters offered alternative visions of progress by embracing restrictions on freedom and seeing increasing labor discipline as central to the project of moral and economic improvement.
The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many ...small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.
The aim of this systematic review and meta-analysis was to identify a list of common, candidate genes associated with the three components of fitness, specifically cardiovascular fitness, muscular ...strength, and anaerobic power, and how these genes are associated with exercise response phenotype variability, in previously untrained participants. A total of 3,969 potentially relevant papers were identified and processed for inclusion. After eligibility and study selection assessment, 24 studies were selected for meta-analysis, comprising a total of 3,012 participants (male n = 1,512; females n = 1,239; not stated n = 261; age 28 ± 9 years). Meta-Essentials spreadsheet 1.4 (Microsoft Excel) was used in creating the forest plots and meta-analysis. IBM SPSS statistics V24 was implemented for the statistical analyses and the alpha was set at p ≤ 0.05. 13 candidate genes and their associated alleles were identified, which were associated with the phenotypes of interest. Analysis of training group data showed significant differential phenotypic responses. Subgroup analysis showed; 44%, 72% and 10% of the response variance in aerobic, strength and power phenotypes, respectively, were explained by genetic influences. This analysis established that genetic variability explained a significant proportion of the adaptation differences across the three components of fitness in the participants post-training. The results also showed the importance of analysing and reporting specific gene alleles. Information obtained from these findings has the potential to inform and influence future exercise-related genes and training studies.
Before 1667, Surinam was the next major frontier for Barbadians who wanted to expand the sugar plantation complex. A proprietary colony under the control of Francis Willoughby, governor of Barbados, ...Surinam was occupied by the Dutch during the Second Anglo-Dutch War. The English Crown, in a key moment of metropolitan intervention in the design of the empire, turned its back on the Surinam colony in the Treaty of Breda, trading it to the Dutch for Manhattan. The Willoughby family recaptured Surinam after the treaty was signed and encouraged the English state to retain it as a royal colony, but Charles II insisted on its surrender. The loss of Surinam changed the trajectory of English expansion in the Americas. Surinam's English planters with capital for investment and agricultural expertise in sugar planting were redirected toward Jamaica, the colony favored by the crown. These planters faced labor shortages under Dutch rule and the vast majority left for Jamaica in 1671 and 1675. An increasing supply of slaves from the Royal African Company had made Jamaica a more attractive option. These Surinam migrants spurred the growth of the Jamaican sugar economy.
N6-methyladenosine (m6A) modification of RNA regulates normal and cancer biology, but knowledge of its function on long noncoding RNAs (lncRNAs) remains limited. Here, we reveal that m6A regulates ...the breast cancer-associated human lncRNA HOTAIR. Mapping m6A in breast cancer cell lines, we identify multiple m6A sites on HOTAIR, with 1 single consistently methylated site (A783) that is critical for HOTAIR-driven proliferation and invasion of triple-negative breast cancer (TNBC) cells. Methylated A783 interacts with the m6A "reader" YTHDC1, promoting chromatin association of HOTAIR, proliferation and invasion of TNBC cells, and gene repression. A783U mutant HOTAIR induces a unique antitumor gene expression profile and displays loss-of-function and antimorph behaviors by impairing and, in some cases, causing opposite gene expression changes induced by wild-type (WT) HOTAIR. Our work demonstrates how modification of 1 base in an lncRNA can elicit a distinct gene regulation mechanism and drive cancer-associated phenotypes.
Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription ...elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation. In contrast to the selective effect of bromodomain inhibition on transcription, BET degradation prompts a collapse of global elongation that phenocopies CDK9 inhibition. Notably, BRD4 loss does not directly affect CDK9 localization. These studies, performed in translational models of T cell leukemia, establish a mechanism-based rationale for the development of BET bromodomain degradation as cancer therapy.
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•Competitive BET bromodomain inhibition differs from BET protein degradation•BET proteins are master regulators of productive transcription elongation•BET protein degradation is inconsequential for CDK9 recruitment•BET degradation provokes an assembly defect of a transcription elongation complex
Winter et al. delineate fundamental differences in the molecular pharmacology of BET bromodomain inhibition and BET protein degradation. Comparative studies led to the identification of BET proteins as master regulators of transcription elongation. Acute BET protein degradation prompts a global collapse of productive elongation that is independent of CDK9 recruitment.
Gastrointestinal (GI) ischemia during exercise is associated with luminal permeability and increased systemic lipopolysaccharides (LPS). This study aimed to assess the impact of a multistrain ...pro/prebiotic/antioxidant intervention on endotoxin unit levels and GI permeability in recreational athletes. Thirty healthy participants (25 males, 5 females) were randomly assigned either a multistrain pro/prebiotic/antioxidant (LAB⁴
; 30 billion CFU·day
containing 10 billion CFU·day
CUL-60 (NCIMB 30157), 10 billion CFU·day
CUL-21 (NCIMB 30156), 9.5 billion CFU·day
CUL-20 (NCIMB 30172) and 0.5 billion CFU·day
subspecies
CUL-34 (NCIMB 30153)/55.8 mg·day
fructooligosaccharides/ 400 mg·day
α-lipoic acid, 600 mg·day
-acetyl-carnitine); matched pro/prebiotic (LAB⁴) or placebo (PL) for 12 weeks preceding a long-distance triathlon. Plasma endotoxin units (via
amebocyte lysate chromogenic quantification) and GI permeability (via 5 h urinary lactulose (L): mannitol (M) recovery) were assessed at baseline, pre-race and six days post-race. Endotoxin unit levels were not significantly different between groups at baseline (LAB⁴
: 8.20 ± 1.60 pg·mL
; LAB⁴: 8.92 ± 1.20 pg·mL
; PL: 9.72 ± 2.42 pg·mL
). The use of a 12-week LAB⁴
intervention significantly reduced endotoxin units both pre-race (4.37 ± 0.51 pg·mL
) and six days post-race (5.18 ± 0.57 pg·mL
;
= 0.03, ηp² = 0.35), but only six days post-race with LAB⁴ (5.01 ± 0.28 pg·mL
;
= 0.01, ηp² = 0.43). In contrast, endotoxin units remained unchanged with PL. L:M significantly increased from 0.01 ± 0.01 at baseline to 0.06 ± 0.01 with PL only (
= 0.004, ηp² = 0.51). Mean race times (h:min:s) were not statistically different between groups despite faster times with both pro/prebiotoic groups (LAB⁴
: 13:17:07 ± 0:34:48; LAB⁴: 12:47:13 ± 0:25:06; PL: 14:12:51 ± 0:29:54;
> 0.05). Combined multistrain pro/prebiotic use may reduce endotoxin unit levels, with LAB⁴
potentially conferring an additive effect via combined GI modulation and antioxidant protection.
In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been ...systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1 pathway, we identified many genes that impact mTORC1 activity, including
,
,
,
,
, and
Using the genome-wide screening data, we generated a focused sublibrary containing single guide RNAs (sgRNAs) targeting hundreds of genes and carried out epistasis screens in cells lacking nutrient- and stress-responsive mTORC1 modulators, including GATOR1, AMPK, GCN2, and ATF4. From these data, we pinpointed mitochondrial function as a particularly important input into mTORC1 signaling. While it is well appreciated that mitochondria signal to mTORC1, the mechanisms are not completely clear. We find that the kinases AMPK and HRI signal, with varying kinetics, mitochondrial distress to mTORC1, and that HRI acts through the ATF4-dependent up-regulation of both Sestrin2 and Redd1. Loss of both AMPK and HRI is sufficient to render mTORC1 signaling largely resistant to mitochondrial dysfunction induced by the ATP synthase inhibitor oligomycin as well as the electron transport chain inhibitors piericidin and antimycin. Taken together, our data reveal a catalog of genes that impact the mTORC1 pathway and clarify the multifaceted ways in which mTORC1 senses mitochondrial dysfunction.
Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, ...and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12
with expression of FKBP12
in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRAS
loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.
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