During aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We found that the ability of MuSCs to regenerate is ...regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia inhibited MuSC proliferation in vitro and severely impaired injury-induced muscle regeneration in vivo. In aged muscle, a cell intrinsic defect in MuSC ciliation was associated with the decrease in regenerative capacity. Exogenous activation of Hedgehog signaling, known to be localized in the primary cilium, promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG1.3) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aged MuSCs and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.
Abstract
The thymus is a primary lymphoid organ for T cell development. Increasing evidence found that the thymus is also an important site for development of innate lymphoid cells (ILCs). ILCs ...generated in thymi acquire unique homing properties that direct their localization into barrier tissues such as the skin and intestine, where they help local homeostasis. Mechanisms underlying the developmental programming of unique tissue-homing properties of ILCs are poorly understood. We report in this article that thymic stroma-derived Notch signaling is differentially involved in thymic generation of a population of NK1.1+ group 1 ILCs (ILC1s) with the CCR10+ skin-homing property in adult and neonatal mice. We found that thymic generation of CCR10+NK1.1+ ILC1s is increased in T cell–deficient mice at adult, but not neonatal, stages, supporting the notion that a large number of developing T cells interfere with signals required for generation of CCR10+NK1.1+ ILC1s. In an in vitro differentiation assay, increasing Notch signals promotes generation of CCR10+NK1.1+ ILC1s from hematopoietic progenitors. Knockout of the Notch ligand Delta-like 4 in thymic stroma impairs generation of CCR10+NK1.1+ ILC1s in adult thymi, but development of CCR10+NK1.1+ ILC1s in neonatal thymi is less dependent on Delta-like 4–derived Notch signals. Mechanistically, the Notch signaling is required for proper expression of the IL-7R CD127 on thymic NK1.1+ ILC1s, and deficiency of CD127 also impairs thymic generation of CCR10+NK1.1+ ILC1s at adult, but not perinatal, stages. Our findings advanced understanding of regulatory mechanisms of thymic innate lymphocyte development.
To estimate and compare the prevalences of overweight, obesity, pre-diabetes and diabetes among a nationally representative sample of Mexican-American, non-Latino white and black adults, and by ...acculturation for Mexican-Americans.
The NHANES 1999-2008 data sets were used. Binomial regression models were used to compute prevalence ratios and their respective 95% confidence intervals to assess the relationships of race/ethnicity and acculturation with obesity, overweight, pre-diabetes and diabetes.
Overweight, obesity, pre-diabetes, and diabetes.
Mexican Americans had a higher prevalence of overweight than white non-Latinos and Black non-Latinos. Obesity was significantly more prevalent among the most acculturated Mexican Americans but not the least acculturated. In contrast, the least acculturated Mexican Americans had the highest prevalence of overweight. The prevalence of pre-diabetes was higher among Mexican Americans than white non-Latinos and black non-Latinos. The most acculturated Mexican Americans had a higher prevalence of diabetes and the prevalence of pre-diabetes was elevated in less acculturated Mexican Americans. In both unadjusted and adjusted models, the less acculturated were significantly more likely to be overweight and significantly less likely to be obese, compared to more acculturated Mexican Americans, and acculturation was not associated with diabetes or prediabetes in adjusted models.
Our results suggest that obesity was less prevalent among the least acculturated Mexican-Americans but overweight was more prevalent.
Defective receptor editing or defective B cell checkpoints have been associated with increased frequency of multireactive autoantibodies in autoimmune disease. However, Ig somatic hypermutation ...and/or class switch recombination may be mechanisms enabling the development of pathogenic multireactive autoantibodies. In this study, we report that, in the BXD2 mouse model of autoimmune disease, elevated expression of activation-induced cytidine deaminase (AID) in recirculating follicular CD86(+) subsets of B cells and increased germinal center B cell activity are associated with the production of pathogenic multireactive autoantibodies. CD4 T cells from BXD2 mice that expressed increased levels of CD28 and an increased proliferative response to anti-CD3 and anti-CD28 stimulation are required for this process. Inhibition of the CD28-CD86 interaction in BXD2 mice with AdCTLA4-Ig resulted in normalization of AID in the B cells and suppression of IgG autoantibodies. This treatment also prevented the development of germinal center autoantibody-producing B cells, suggesting that an optimal microenvironment enabling AID function is important for the formation of pathogenic autoantibodies. Taken together, our data indicate that AID expression in B cells is a promising therapeutic target for the treatment of autoimmune diseases and that suppression of this gene may be a molecular target of CTLA4-Ig therapy.
Abstract Aims Patients with type 2 diabetes mellitus (T2DM) have increased fracture risk yet higher bone mineral density (BMD), but data are inconsistent in men. We compared skeletal and non-skeletal ...(e.g., muscle mass, strength) factors in men with/without T2DM. Methods Cross-sectional study of 1137 Boston men 30–79 years in the Boston Area Community Health/Bone Survey. Diabetes status was self-reported, and BMD and body composition were measured by DXA, and grip strength by hand dynamometer. Physical function was assessed by walking speed and chair stands. Multivariable linear regressions examined associations of T2DM with skeletal/non-skeletal factors. Results Mean age was 48 years. The population was 24.6% Black, 13.0% Hispanic, and 62.4% White. Prevalence of T2DM was 12.5%; average disease duration was 7.4 years. While subjects with T2DM did not differ in skeletal factors (e.g., BMD), they had significantly lower appendicular lean mass mean difference (MD) = − 1.04 kg; standard error (SE) = 0.50; p = 0.04, arms lean mass (MD = − 0.42 kg; SE = 0.15; p = 0.006) and grip strength (MD = − 3.02 kg; SE = 1.25; p = 0.025) after adjustment for age, race/ethnicity, and BMI. Conclusions Men with T2DM have lower muscle mass and strength, but similar BMD, compared to their non-diabetic counterparts. These differences in non-skeletal factors might explain, at least in part, the higher incidence of falls and fractures observed in T2DM patients.
The thymus is a primary lymphoid organ for the T cell development. Increasing evidence found that the thymus is also an important site for development of innate lymphoid cells (ILCs). ILCs generated ...in thymi acquire unique homing properties that direct their localization into barrier tissues such as the skin and intestine where they help local homeostasis. Mechanisms underlying the developmental programming of unique tissue-homing properties of ILCs are poorly understood. We report herein that thymic stroma-derived Notch signaling is differentially involved in thymic generation of a population of NK1.1
+
group 1 ILCs (ILC1s) with the CCR10
+
skin-homing property in adult and neonatal mice. We found that thymic generation of CCR10
+
NK1.1
+
ILC1s is increased in T cell-deficient mice at adult but not neonatal stages, supporting the notion that a large number of developing T cells interfere with signals required for generation of CCR10
+
NK1.1
+
ILC1s. In an
in vitro
differentiation assay, increasing Notch signals promote generation of CCR10
+
NK1.1
+
ILC1s from hematopoietic progenitors. Knockout of the Notch ligand delta-like 4 (DL4) in thymic stroma impairs generation of CCR10
+
NK1.1
+
ILC1s in adult thymi but development of CCR10
+
NK1.1
+
ILC1s in neonatal thymi is less dependent on DL4-derived Notch signals. Mechanistically, the Notch signaling is required for proper expression of the IL-7 receptor CD127 on thymic NK1.1
+
ILC1s and deficiency of CD127 also impairs thymic generation of CCR10
+
NK1.1
+
ILC1s at adult but not perinatal stages. Our findings advanced understanding of regulatory mechanisms of thymic innate lymphocyte development.
Patients and referring physicians often ask about the significance of lymphovascular invasion (LVI) on pathology reports from radical prostatectomy specimens. However, limited data are available ...concerning the relationship between LVI and preoperative screening characteristics, pathologic tumor features, and patient prognosis.
LVI was evaluated for its ability to predict elevated prostate-specific antigen velocity, adverse pathologic features, and biochemical progression in 1709 men who underwent radical prostatectomy for clinically localized disease.
LVI was present in 118 (7%) of the 1709 men. On univariate analysis, LVI was significantly associated with tumor grade, tumor volume, and other adverse pathologic features. Prostate-specific antigen velocity was not significantly associated with the presence of LVI. Biochemical progression occurred in 34% of those with LVI compared with 10% of those without LVI (P <0.0001). However, on multivariate analysis with other pathologic tumor features, LVI was not an independent predictor of progression.
LVI is a relatively uncommon finding in radical prostatectomy specimens for clinically localized disease. Although LVI was seen primarily in large-volume, high-grade tumors, it was not an independent predictor of progression in the multivariate model.
Global evaluations of the progress towards the WHO End TB Strategy 2020 interim milestones on mortality (35% reduction) and incidence (20% reduction) have not been age specific. We aimed to assess ...global, regional, and national-level burdens of and trends in tuberculosis and its risk factors across five separate age groups, from 1990 to 2021, and to report on age-specific progress between 2015 and 2020.
We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021) analytical framework to compute age-specific tuberculosis mortality and incidence estimates for 204 countries and territories (1990–2021 inclusive). We quantified tuberculosis mortality among individuals without HIV co-infection using 22 603 site-years of vital registration data, 1718 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, 680 site-years of mortality surveillance data, and 9 site-years of minimally invasive tissue sample (MITS) diagnoses data as inputs into the Cause of Death Ensemble modelling platform. Age-specific HIV and tuberculosis deaths were established with a population attributable fraction approach. We analysed all available population-based data sources, including prevalence surveys, annual case notifications, tuberculin surveys, and tuberculosis mortality, in DisMod-MR 2.1 to produce internally consistent age-specific estimates of tuberculosis incidence, prevalence, and mortality. We also estimated age-specific tuberculosis mortality without HIV co-infection that is attributable to the independent and combined effects of three risk factors (smoking, alcohol use, and diabetes). As a secondary analysis, we examined the potential impact of the COVID-19 pandemic on tuberculosis mortality without HIV co-infection by comparing expected tuberculosis deaths, modelled with trends in tuberculosis deaths from 2015 to 2019 in vital registration data, with observed tuberculosis deaths in 2020 and 2021 for countries with available cause-specific mortality data.
We estimated 9·40 million (95% uncertainty interval UI 8·36 to 10·5) tuberculosis incident cases and 1·35 million (1·23 to 1·52) deaths due to tuberculosis in 2021. At the global level, the all-age tuberculosis incidence rate declined by 6·26% (5·27 to 7·25) between 2015 and 2020 (the WHO End TB strategy evaluation period). 15 of 204 countries achieved a 20% decrease in all-age tuberculosis incidence between 2015 and 2020, eight of which were in western sub-Saharan Africa. When stratified by age, global tuberculosis incidence rates decreased by 16·5% (14·8 to 18·4) in children younger than 5 years, 16·2% (14·2 to 17·9) in those aged 5–14 years, 6·29% (5·05 to 7·70) in those aged 15–49 years, 5·72% (4·02 to 7·39) in those aged 50–69 years, and 8·48% (6·74 to 10·4) in those aged 70 years and older, from 2015 to 2020. Global tuberculosis deaths decreased by 11·9% (5·77 to 17·0) from 2015 to 2020. 17 countries attained a 35% reduction in deaths due to tuberculosis between 2015 and 2020, most of which were in eastern Europe (six countries) and central Europe (four countries). There was variable progress by age: a 35·3% (26·7 to 41·7) decrease in tuberculosis deaths in children younger than 5 years, a 29·5% (25·5 to 34·1) decrease in those aged 5–14 years, a 15·2% (10·0 to 20·2) decrease in those aged 15–49 years, a 7·97% (0·472 to 14·1) decrease in those aged 50–69 years, and a 3·29% (–5·56 to 9·07) decrease in those aged 70 years and older. Removing the combined effects of the three attributable risk factors would have reduced the number of all-age tuberculosis deaths from 1·39 million (1·28 to 1·54) to 1·00 million (0·703 to 1·23) in 2020, representing a 36·5% (21·5 to 54·8) reduction in tuberculosis deaths compared to those observed in 2015. 41 countries were included in our analysis of the impact of the COVID-19 pandemic on tuberculosis deaths without HIV co-infection in 2020, and 20 countries were included in the analysis for 2021. In 2020, 50 900 (95% CI 49 700 to 52 400) deaths were expected across all ages, compared to an observed 45 500 deaths, corresponding to 5340 (4070 to 6920) fewer deaths; in 2021, 39 600 (38 300 to 41 100) deaths were expected across all ages compared to an observed 39 000 deaths, corresponding to 657 (–713 to 2180) fewer deaths.
Despite accelerated progress in reducing the global burden of tuberculosis in the past decade, the world did not attain the first interim milestones of the WHO End TB Strategy in 2020. The pace of decline has been unequal with respect to age, with older adults (ie, those aged >50 years) having the slowest progress. As countries refine their national tuberculosis programmes and recalibrate for achieving the 2035 targets, they could consider learning from the strategies of countries that achieved the 2020 milestones, as well as consider targeted interventions to improve outcomes in older age groups.
Bill & Melinda Gates Foundation.
Objective To characterize the histological and epidemiological features of male lung cancer patients in China. Methods The demographic and histological information about male lung cancer patients ...identified from 2000-01-01 to 2012-12-31, was collected from the Cancer Hospital of the Chinese Academy of Medical Sciences. Relative frequencies （RF） were estimated for major histological subtypes and compared according to the years of diagnosis and birth. Results The RF of adenocarcinoma （ADC） increased from 21.96% to 43.36% and the RF of squamous cell carcinoma （SCC） decreased from 39.11% to 32.23% from 2000 to 2012 in the 15 427 male lung cancer patients included in this study （Z=17,909, P〈0.0001; Z=-6.117, P〈0.0001）. The RF of ADC increased from 28.72% in 2000-2004, 36.88% in 2005-2008 to 48.61% in 2009-2012 in patients born after 1960. The age-adjusted RF of ADC in 2007-2012 increased consistently in all the investigated areas. Conclusion The increased RF of ADC in male lung cancer patients highlights the need for further investigation of the etiologic factors of these tumors. Smoke-free policies rather than modifying tobacco products should be enforced.
Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. ...Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes.
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