Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating ...hypercholesterolemia, is associated with improved disease-free survival. Here, we show that cholesterol mediates the metastatic effects of a high-fat diet via its oxysterol metabolite, 27-hydroxycholesterol. Ablation or inhibition of CYP27A1, the enzyme responsible for the rate-limiting step in 27-hydroxycholesterol biosynthesis, significantly reduces metastasis in relevant animal models of cancer. The robust effects of 27-hydroxycholesterol on metastasis requires myeloid immune cell function, and it was found that this oxysterol increases the number of polymorphonuclear-neutrophils and γδ-T cells at distal metastatic sites. The pro-metastatic actions of 27-hydroxycholesterol requires both polymorphonuclear-neutrophils and γδ-T cells, and 27-hydroxycholesterol treatment results in a decreased number of cytotoxic CD8
T lymphocytes. Therefore, through its actions on γδ-T cells and polymorphonuclear-neutrophils, 27-hydroxycholesterol functions as a biochemical mediator of the metastatic effects of hypercholesterolemia.High cholesterol is a risk factor for breast cancer recurrence. Here the authors show that cholesterol promotes breast cancer metastasis via its metabolite 27-hydroxycholesterol (27HC) that acts on immune myeloid cells residing at the distal metastatic sites, thus promoting an immune suppressive environment.
An examination of the role and struggles of dockworkers—enslaved and free—in Charleston between the American Revolution and the Civil War Working on the Dock of the Bay explores the history of ...waterfront labor and laborers—black and white, enslaved and free, native and immigrant—in Charleston, South Carolina, between the American Revolution and Civil War. Michael D. Thompson explains how a predominantly enslaved workforce laid the groundwork for the creation of a robust and effectual association of dockworkers, most of whom were black, shortly after emancipation. In revealing these wharf laborers' experiences, Thompson's book contextualizes the struggles of contemporary southern working people. Like their postbellum and present-day counterparts, stevedores and draymen laboring on the wharves and levees of antebellum cities—whether in Charleston or New Orleans, New York or Boston, or elsewhere in the Atlantic World—were indispensable to the flow of commodities into and out of these ports. Despite their large numbers and the key role that waterfront workers played in these cities' premechanized, labor-intensive commercial economies, too little is known about who these laborers were and the work they performed. Though scholars have explored the history of dockworkers in ports throughout the world, they have given little attention to waterfront laborers and dock work in the pre-Civil War American South or in any slave society. Aiming to remedy that deficiency, Thompson examines the complicated dynamics of race, class, and labor relations through the street-level experiences and perspectives of workingmen and sometimes workingwomen. Using this workers'-eye view of crucial events and developments, Working on the Dock of the Bay relocates waterfront workers and their activities from the margins of the past to the center of a new narrative, reframing their role from observers to critical actors in nineteenth-century American history. Organized topically, this study is rooted in primary source evidence including census, tax, court, and death records; city directories and ordinances; state statutes; wills; account books; newspapers; diaries; letters; and medical journals.
Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering ...technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non-genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.
Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing ...cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA, and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis, and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.
► MYCN-amplified neuroblastomas overexpress genes critical for glutamine metabolism ► PUMA, NOXA, and TRB3 are executers of Myc-mediated cell death upon glutamine deprivation ► MYCN transgenic mice treated with glutaminolysis inhibitors develop smaller tumors ► ATF4 agonists and glutaminolysis inhibitors are potential cancer therapeutics
Nonalcoholic fatty liver disease (NAFLD) is increased in offspring exposed to parental obesity. Mechanisms for increased risk for disease are emerging. These mechanisms will guide the development of ...preventative approaches for NAFLD.
The surge of obesity across generations has become an increasingly relevant issue, with consequences for associated comorbidities in offspring. Data from longitudinal birth cohort studies support an association between maternal obesity and offspring nonalcoholic fatty liver disease (NAFLD), suggesting that perinatal obesity or obesogenic diet exposure reprograms offspring liver and increases NAFLD susceptibility. In preclinical models, offspring exposed to maternal obesogenic diet have increased hepatic steatosis after diet‐induced obesity; however, the implications for later NAFLD development and progression are still unclear. Although some models show increased NAFLD incidence and progression in offspring, development of nonalcoholic steatohepatitis with fibrosis may be model dependent. Multigenerational programming of NAFLD phenotypes occurs after maternal obesogenic diet exposure; however, the mechanisms for such programming remain poorly understood. Likewise, emerging data on the role of paternal obesity in offspring NAFLD development reveal incomplete mechanisms. This review will explore the impact of parental obesity and obesogenic diet exposure on offspring NAFLD and areas for further investigation, including the impact of parental diet on disease progression, and consider potential interventions in preclinical models.
The AspireAssist System (AspireAssist) is an endoscopic weight loss device that is comprised of an endoscopically placed percutaneous gastrostomy tube and an external device to facilitate drainage of ...about 30% of the calories consumed in a meal, in conjunction with lifestyle (diet and exercise) counseling.
In this 52-week clinical trial, 207 participants with a body-mass index (BMI) of 35.0-55.0 kg/m
were randomly assigned in a 2:1 ratio to treatment with AspireAssist plus Lifestyle Counseling (n=137; mean BMI was 42.2±5.1 kg/m
) or Lifestyle Counseling alone (n=70; mean BMI was 40.9±3.9 kg/m
). The co-primary end points were mean percent excess weight loss and the proportion of participants who achieved at least a 25% excess weight loss.
At 52 weeks, participants in the AspireAssist group, on a modified intent-to-treat basis, had lost a mean (±s.d.) of 31.5±26.7% of their excess body weight (12.1±9.6% total body weight), whereas those in the Lifestyle Counseling group had lost a mean of 9.8±15.5% of their excess body weight (3.5±6.0% total body weight) (P<0.001). A total of 58.6% of participants in the AspireAssist group and 15.3% of participants in the Lifestyle Counseling group lost at least 25% of their excess body weight (P<0.001). The most frequently reported adverse events were abdominal pain and discomfort in the perioperative period and peristomal granulation tissue and peristomal irritation in the postoperative period. Serious adverse events were reported in 3.6% of participants in the AspireAssist group.
The AspireAssist System was associated with greater weight loss than Lifestyle Counseling alone.
Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT ...cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.
We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited ...elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5–7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5–7 months after SARS-CoV-2 infection.
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•Using independent SARS-CoV-2 antigens improves the specificity of serological assays•Neutralizing and spike-specific antibody production persists for at least 5–7 months•Nucleocapsid antibodies frequently become undetectable by 5–7 months•Antibody production is higher in severe disease than in mild cases
Serological assays for SARS-CoV-2 exposures are challenging due to poor positive predictive values. Ripperger et al. show that the combinatorial use of spike receptor binding domain and S2 eliminates almost all false positives. This serological assay is used to show durable antibody production for at least 5–7 months after infection.
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