Associations of Dietary Cholesterol, Serum Cholesterol, and Egg Consumption With Overall and Cause-Specific Mortality, and Systematic Review and Updated Meta-Analysis

Background: Despite substantial attention underscoring the importance of exogenous dietary and endogenous serum cholesterol to human health, thorough evaluation of the associations is lacking. Our study objective was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption, and conduct an updated meta-regression analysis of cohort studies. Methods: We conducted a prospective analysis of 27,078 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Multivariable-controlled cause-specific Cox proportional hazards regression models calculated hazard ratios (HR) and 31-year absolute mortality risk differences (ARD). A systematic review and meta-analysis of cohort studies was also performed (PROSPERO: CRD42021272756). Results: Based on 482,316 person-years of follow-up, we identified 22,035 deaths, including 9,110 deaths from cardiovascular disease (CVD). Greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD mortality. HRs for each additional 300 mg cholesterol intake per day were 1.10 and 1.13 for overall and CVD mortality (respectively), and for each additional 50 g egg consumed daily HRs were 1.06 and 1.09, respectively, for overall and CVD mortality (all P-values<0.0001). After multivariable adjustment, higher serum total cholesterol concentrations were associated with increased risk of CVD mortality (HRs per 1-SD increment: 1.14; P-value<0.0001). The observed associations were generally similar across cohort subgroups. The updated meta-analysis of cohort studies based on 49 risk estimates, 3,601,401 participants, and 255,479 events) showed consumption of one additional 50 g egg daily was associated with significantly increased CVD risk: pooled RR=1.04 (95% CI: 1.00, 1.08); I 2 =80.1%). In the subgroup analysis of geographical regions (P-value-for-interaction=0.02), an increase of 50 g egg consumed daily was associated with a higher risk of CVD among US cohorts (pooled-RR=1.08, 95% CI: 1.02, 1.14), appeared related to a higher CVD risk in European cohorts with a borderline significance (pooled-RR=1.05), but was not associated with CVD risk in Asian cohorts. Conclusions: In this prospective cohort study and updated meta-analysis, greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD mortality. Our findings support restricted consumption of dietary cholesterol as a means to improve long-term health and longevity.

New insights into TCR β-selection

The Emerging Role of m6A Modification in Regulating the Immune System and Autoimmune Diseases

Over the past several decades, RNA modifications have rapidly emerged as an indispensable topic in epitranscriptomics. N6-methyladenosine (m6A), namely, methylation at the sixth position of an adenine base in an RNA molecule, is the most prevalent RNA modification in both coding and noncoding RNAs. m6A has emerged as a crucial posttranscriptional regulator involved in both physiological and pathological processes. Based on accumulating evidence, m6A participates in the pathogenesis of immune-related diseases by regulating both innate and adaptive immune cells through various mechanisms. Autoimmune diseases are caused by a self-destructive immune response in the setting of genetic and environmental factors, and recent studies have discovered that m6A may play an essential role in the development of autoimmune diseases. In this review, we focus on the important role of m6A modification in biological functions and highlight its contributions to immune cells and the development of autoimmune diseases, thereby providing promising epitranscriptomic targets for preventing and treating autoimmune disorders.

Ldb1 is required for Lmo2 oncogene–induced thymocyte self-renewal and T-cell acute lymphoblastic leukemia

Abstract Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell acute lymphoblastic leukemia (T-ALL), designated early T-cell precursor ALL, which is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. It has been suggested that Lmo2 exerts these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors; however, direct experimental evidence for this mechanism is lacking. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in an Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in Lmo2-induced thymocyte self-renewal and thymocyte radiation resistance and for the transition of preleukemic thymocytes to overt T-ALL. Moreover, Ldb1 was also required for acquisition of the aberrant preleukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Co-binding of Ldb1 and Lmo2 was detected at the promoters of key upregulated T-ALL driver genes (Hhex, Lyl1, and Nfe2) in preleukemic Lmo2 transgenic thymocytes, and binding of both Ldb1 and Lmo2 at these sites was reduced following Cre-mediated deletion of Ldb1. Together, these results identify a key role for Ldb1, a nonproto-oncogene, in T-ALL and support a model in which Lmo2-induced T-ALL results from failure to downregulate Ldb1/Lmo2-nucleated transcription complexes which normally function to enforce self-renewal in bone marrow hematopoietic progenitors.

Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12

Expression of the IFNAR1 chain of type 1 interferon receptor in benign cells protects against progression of acute leukemia

Downregulation of the IFNAR1 chain of type 1 interferon receptor contributes to the maintenance of the haematopoietic stem cells

Type I interferons mediate pancreatic toxicities of PERK inhibition

The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERK-deficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.

Ubiquitin-specific Protease 19 (USP19) Regulates Hypoxia-inducible Factor 1α (HIF-1α) during Hypoxia

The ubiquitin specific protease-4 (USP4) interacts with the S9/Rpn6 subunit of the proteasome

The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway