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Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown 1 . Hair follicles—mini-epithelial organs that grow hair—are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs) 2 . Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction. Obesity in mice, caused by a high-fat diet, induces hair loss as a result of changes in the differentiation of hair follicle stem cells.

Objectives:To assess whether smoking is a risk factor for developing rheumatoid arthritis (RA).Design:Meta-analysis.Method:Data sources were observational studies that examined the association between smoking history and the risk of developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books and a reference search. Two authors independently extracted the following: authors’ names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design and area where the study was conducted. Data syntheses were based upon random effects model. Summarised syntheses effects were expressed by OR.Results:Sixteen studies were selected from among 433 articles. For men, summary OR for ever, current and past smokers were 1.89 (95% CI 1.56 to 2.28), 1.87 (1.49 to 2.34) and 1.76 (1.33 to 2.31), respectively. For rheumatoid factor-positive (RF+) RA, summary OR for ever, current and past smokers were 3.02 (2.35 to 3.88), 3.91 (2.78 to 5.50) and 2.46 (1.74 to 3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31 (1.55 to 3.41). For women, summary OR for ever, current and past smokers were 1.27 (1.12 to 1.44), 1.31 (1.12 to 1.54) and 1.22 (1.06 to 1.40), respectively. For RF+ RA, summary OR for ever, current and past smokers were 1.34 (0.99 to 1.80), 1.29 (0.94 to 1.77) and 1.21 (0.83 to 1.77). Summary OR for 20 or more pack-years of smoking was 1.75 (1.52 to 2.02).Conclusion:Smoking is a risk factor for RA, especially RF+ RA men and heavy smokers.

Hair graying is the most obvious sign of aging in humans, yet its mechanism is largely unknown. Here, we used melanocyte-tagged transgenic mice and aging human hair follicles to demonstrate that hair graying is caused by defective self-maintenance of melanocyte stem cells. This process is accelerated dramatically with Bcl2 deficiency, which causes selective apoptosis of melanocyte stem cells, but not of differentiated melanocytes, within the niche at their entry into the dormant state. Furthermore, physiologic aging of melanocyte stem cells was associated with ectopic pigmentation or differentiation within the niche, a process accelerated by mutation of the melanocyte master transcriptional regulator Mitf.

Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH. ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.

Background:IgG4-related disease (IgG4RD) is a chronic and systemic disease that is characterised by multiple organ inflammation, elevated serum IgG4, and storiform fibrosis. IgG4RD often presents with organ enlargement and can affect the submandibular glands, lacrimal glands, orbits, pancreas, bile ducts, retroperitoneum, lungs, kidneys, aorta and pachymeninges [1]. One of the most commonly involved organs is the submandibular glands. However, methods for evaluating the severity and treatment response of IgG4-related sialadenitis have not been established. Ultrasound shear wave elastography (SWE) is a technique to quantify tissue elasticity using shear wave velocity (SWV), and is considered to be a useful noninvasive method for diagnosing fibrosis. Recently, SWE has been reported as a valid diagnostic method for primary Sjogren’s syndrome (pSS) [2].Objectives:The purpose of this study was to investigate whether ultrasound SWE evaluate disease activity of IgG4-related sialadenitis.Methods:We retrospectively investigated the submandibular gland sonographic features of IgG4RD patients who fulfilled the 2020 revised comprehensive diagnostic criteria for IgG4RD [3]. Submandibular gland ultrasonography was performed in Kurashiki Central Hospital from April 2016 to December 2022. We assessed sex, age, affected organs, disease duration, use of glucocorticoid and immunosuppressive agents, serum IgG/IgG4, and ultrasonographic findings. We choose patients with pSS as controls for ultrasound image. The volume of the submandibular gland was calculated using the following formula: Volume = (long diameter) x (transverse diameter) x (cranial-caudal diameter) x 0.52 [4]. Submandibular gland SWV was compared between IgG4RD and pSS patients. In addition, it was compared in IgG4RD patients with and without submandibular gland lesions. Submandibular gland SWV was compared before and after treatment among patients with IgG4-related sialadenitis.Results:Twenty-nine patients (18 males, 11 females) with IgG4RD and 35 patients (4 males, 31 females) with pSS underwent submandibular gland SWE. The median age [interquartile range (IQR)] of IgG4RD and pSS was 69 (64-77) and 67 (52.5-78), respectively. The median time (IQR) since IgG4RD diagnosis was 4 days (0-547). Of the IgG4RD patients, 4 were treated with glucocorticoid (maximum 10 mg/day of prednisolone equivalent) and 2 with immunosuppressive agents (azathioprine and methotrexate). PSS patients were all untreated. The submandibular gland was the most common organ affected in 19 patients with IgG4RD, followed by the lacrimal gland (n=8), aorta (n=7), retroperitoneum (n=7), pancreas (n=6), parotid gland (n=3), lungs (n=3), pituitary gland (n=1), bile duct (n=1), pachymeninges (n=1) and vertebra (n=1). Nineteen patients with IgG4RD showed multiple hypoechoic areas in the submandibular gland. The median SWV (IQR) of the submandibular gland was 1.88 (1.59-2.40) in the IgG4RD group and 1.59 (1.43-1.72) in the pSS group, which was significantly higher in the IgG4RD group (p <0.001). The median SWV (IQR) of IgG4RD was 1.59 (1.50-1.70) in the group without sialadenitis and 2.06 (1.79-2.65) in the group with sialadenitis (p < 0.05) (Figure 1A). Among patients treated with immunosuppressive therapy for IgG4RD, 7 patients were followed up for submandibular gland ultrasonography. The median observation period (IQR) was 408.5 days (81.25-630.25). Ultrasound-estimated submandibular gland volume was reduced from 2.4 cm3 to 1.7 cm3 and submandibular gland SWV was significantly decreased from 1.98 to 1.55 (p < 0.05), respectively (Figure 1B).Conclusion:Submandibular gland SWV was significantly higher in IgG4RD than in pSS. Submandibular gland SWV was elevated in IgG4-related sialadenitis, and SWV was decreased by immunosuppressive treatment. Ultrasound SWE is a useful tool for evaluating the disease activity of IgG4-related sialadenitis.REFERENCES:[1] Perugino CA, et al. Nat Rev Rheumatol 2020;16(12):702-714.[2] Ma H, et al. Int J Rheum Dis. 2023;26(7):1314-1320.[3] Umehara H, Mod Rheumatol 2021;31(3):529-533.[4] Badea AF, et al. Med Ultrason 2013;15(3):173-9.Acknowledgements:NIL.Disclosure of Interests:None declared.

Stem cells which have the capacity to self-renew and generate differentiated progeny are thought to be maintained in a specific environment known as a niche. The localization of the niche, however, remains largely obscure for most stem-cell systems. Melanocytes (pigment cells) in hair follicles proliferate and differentiate closely coupled to the hair regeneration cycle. Here we report that stem cells of the melanocyte lineage can be identified, using Dct-lacZ transgenic mice, in the lower permanent portion of mouse hair follicles throughout the hair cycle. It is only the population in this region that fulfils the criteria for stem cells, being immature, slow cycling, self-maintaining and fully competent in regenerating progeny on activation at early anagen (the growing phase of hair follicles). Induction of the re-pigmentation process in K14-steel factor transgenic mice demonstrates that a portion of amplifying stem-cell progeny can migrate out from the niche and retain sufficient self-renewing capability to function as stem cells after repopulation into vacant niches. Our data indicate that the niche has a dominant role in the fate determination of melanocyte stem-cell progeny.

The unusual basic amino acid, hypusine [Nε-(4-amino-2-hydroxybutyl)-lysine], is a modified lysine with the addition of the 4-aminobutyl moiety from the polyamine spermidine. This naturally occurring amino acid is a product of a unique posttranslational modification that occurs in only one cellular protein, eukaryotic translation initiation factor 5A (eIF5A, eIF-5A). Hypusine is synthesized exclusively in this protein by two sequential enzymatic steps involving deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The deoxyhypusine/hypusine synthetic pathway has evolved in archaea and eukaryotes, and eIF5A, DHS and DOHH are highly conserved suggesting a vital cellular function of eIF5A. Gene disruption and mutation studies in yeast and higher eukaryotes have provided valuable information on the essential nature of eIF5A and the deoxyhypusine/hypusine modification in cell growth and in protein synthesis. In view of the extraordinary specificity and functional significance of hypusine-containing eIF5A in mammalian cell proliferation, eIF5A and the hypusine biosynthetic enzymes are novel potential targets for intervention in aberrant cell proliferation.

Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages. Currently, there is a lack of animal models that resemble human melanoma initiation and progression. Recent studies using a Tyr-CreER driven mouse model have drawn contradictory conclusions about the potential of melanocyte stem cells (McSCs) to form melanoma. Here, we employ a c-Kit-CreER -driven model that specifically targets McSCs to show that oncogenic McSCs are a bona fide source of melanoma that expand in the niche, and then establish epidermal melanomas that invade into the underlying dermis. Further, normal Wnt and Endothelin niche signals during hair anagen onset are hijacked to promote McSC malignant transformation during melanoma induction. Finally, molecular profiling reveals strong resemblance of murine McSC-derived melanoma to human melanoma in heterogeneity and gene signatures. These findings provide experimental validation of the human melanoma progression model and key insights into the transformation and heterogeneity of McSC-derived melanoma. Currently, few mouse models exist to recapitulate human melanomagenesis. Here, the authors establish a c-Kit-CreER-driven model to target melanocyte stem cells (McSCs) and show that oncogenic McSCs give rise to epidermal melanoma that invade into the dermis, similar to human melanoma.

Air pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications. To assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions. This study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO₂), sulfur dioxide, particulate matter not greater than 10 μm in diameter, and particulate matter not greater than 2.5 μm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant. After adjustment for confounders, a 5-ppb increase in average NO₂ during the first year of life was associated with an odds ratio of 1.17 for physician-diagnosed asthma (95% confidence interval, 1.04-1.31). Early-life NO₂ exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma.

Chondroitin sulfate and heparan sulfate proteoglycans are major components of the cell surface and extracellular matrix in the brain. Both chondroitin sulfate and heparan sulfate are unbranched highly sulfated polysaccharides composed of repeating disaccharide units of glucuronic acid and N -acetylgalactosamine, and glucuronic acid and N -acetylglucosamine, respectively. During their biosynthesis in the Golgi apparatus, these glycosaminoglycans are highly modified by sulfation and C5 epimerization of glucuronic acid, leading to diverse heterogeneity in structure. Their structures are strictly regulated in a cell type-specific manner during development partly by the expression control of various glycosaminoglycan-modifying enzymes. It has been considered that specific combinations of glycosaminoglycan-modifying enzymes generate specific functional microdomains in the glycosaminoglycan chains, which bind selectively with various growth factors, morphogens, axon guidance molecules and extracellular matrix proteins. Recent studies have begun to reveal that the molecular interactions mediated by such glycosaminoglycan microdomains play critical roles in the various signaling pathways essential for the development of the brain.