Summary
Background
Inherited epidermodysplasia verruciformis (EV) is a rare skin disorder characterized by susceptibility to specific types of human papilloma virus (HPV) and is strongly associated ...with skin carcinomas. Inactivating mutations in EVER1/EVER2 account for most cases of EV. However, more phenotypes related to but distinct from EV have been reported with an immunodeficiency state but without EVER1/EVER2 mutation, and the genetic basis for these atypical EV cases is poorly understood.
Objectives
To identify the causative gene responsible for three siblings affected by atypical EV but without EVER1/EVER2 mutation.
Methods
Whole‐exome sequencing followed by Sanger sequencing was performed to identify the gene responsible for the patients with atypical EV enrolled in our study.
Results
A homozygous splicing mutation was detected in LCK (c.188‐2A>G). This mutation resulted in an exon 3 deletion T lymphocyte‐specific protein tyrosine kinase isoform, which further led to frameshift mutation and subsequent mRNA decay.
Conclusions
We demonstrate a novel mutation in LCK in a family affected by atypical EV with T‐cell defects, HPV infection and virus‐induced malignancy, providing new clues in the understanding of host defences against HPV and better genetic counselling of patients with the EV phenotype.
What's already known about this topic?
Epidermodysplasia verruciformis (EV) is an unusual genodermatosis characterized by an increased susceptibility to β‐human papillomavirus and is associated with a high risk of skin carcinoma.
Inactivating mutations in EVER1/EVER2 account for most cases of EV.
What does this study add?
Our study suggests an association between a novel splicing mutation in LCK and EV susceptibility.
What is the translational message?
Patients with EV should be tested for T lymphocyte‐specific protein tyrosine kinase deficiency and T‐cell function, which will help guide treatment.
Linked Comment: Uitto and Vahidnezhad. Br J Dermatol 2016; 175:1138–1139.
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid ...leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
Background
Thymic stromal lymphopoietin (TSLP), IL‐25, and IL‐33 system contribute to the initiation and development of Th2 responses. This study aimed to explore the involvement of TSLP, IL‐25, ...IL‐33, and their receptors in type 2 T‐helper (Th) responses in chronic rhinosinusitis with nasal polyps (CRSwNPs) and their cross‐regulation in human nasal epithelial cells (HNECs).
Methods
Immunohistochemistry, quantitative RT‐PCR, ELISA, Bio‐Plex assay, and flow cytometry were used to detect the expression of TSLP/common γ‐like TSLP receptor (TSLPR)/IL‐7 receptor α (IL‐7Rα), IL‐25/IL‐17B receptor (IL‐17RB), and IL‐33/membrane‐bound ST2 (ST2L)/soluble ST2 (sST2) in sinonasal mucosa and HNECs. HNECs cultured at an air–liquid interface were used to explore the expression in regulation of these cytokine systems.
Results
Compared with controls and noneosinophilic CRSwNP, the expression of TSLP/TSLPR/IL‐7Rα and ST2L/sST2 was significantly increased in eosinophilic CRSwNP, predominantly in epithelial cells. In contrast, the expression of IL‐33 and IL‐25/IL‐17RB was enhanced in epithelial cells in both eosinophilic and noneosinophilic CRSwNP compared to controls. The expression of TSLP, TSLPR, and ST2L was positively correlated with symptom and computer tomography scan scores in eosinophilic CRSwNP and with Th2 cytokine expression in sinonasal mucosa. The expression of ST2L was correlated with TSLP and its receptor expression. TSLP could induce ST2L expression that promoted IL‐33‐induced TSLP expression in HNECs. In addition, TSLP/TSLPR/IL‐7Rα and ST2L could be induced by Th2 cytokines, while IL‐25/IL‐17RB and IL‐33 could be upregulated by Th1/Th17 cytokines, in HNECs.
Conclusions
The positive feedback loop between TSLP, IL‐33 and their receptors, and Th2 cytokines may facilitate Th2‐skewed inflammation in eosinophilic CRSwNP.
In recent decades, increased attention has been paid to the impact of socioeconomic status (SES) on cognition function and dementia, however, an ongoing debate continues to exist. The objective of ...our study was to explore the potential effect of SES on the risks of cognitive dysfunction and dementia.
PubMed, Cochrane Library, and EMBASE were searched for prospective studies from inception to 9 January 2022. Meta-analyses using random-effect models were performed, and then subgroup analyses stratified by study characteristics for specific outcomes were conducted.
Thirty-nine prospective studies (1,485,702 individuals) were eligible for inclusion, of which 25 reported the incidence of dementia and 14 reported cognitive decline. Primary results of the meta-analyses found an elevated combined risk of cognitive impairment and dementia (relative risk RR = 1.31, 95% confidence interval CI = 1.16-1.49) in low-SES participants compared with high-SES participants. We also found an elevated risk of all-cause dementia (RR = 1.40, 95% CI = 1.12-1.74) in low-SES participants. Further subgroup analyses stratified by education, occupation, and income showed that low education subgroup (RR = 1.21, 95% CI = 1.04-1.41) and low-income subgroup (RR = 1.22, 95% CI = 1.10-1.35) had an increased combined risks of cognitive impairment and dementia, but only individuals with lower education had a higher risk of dementia (RR = 1.66, 95% CI = 1.20-2.32).
Low SES substantially increased the risk of dementia and cognitive dysfunction, suggesting that public health strategies could reduce the dementia burden by reducing social inequalities.
Tuberculosis, smoking, and alcohol drinking are major public health and social issues worldwide. We investigated the joint effect of smoking plus alcohol drinking on TB treatment. Retrospective study ...was conducted among TB patients in 49 units from eight provinces in China. All patients enrolled were classified into four groups according to their smoking and/or alcohol status. Current smokers plus drinkers belonged to group 1; ex-smokers plus ex-drinkers were in group 2; current smokers and ex-drinkers, current smokers and never drinkers, ex-smokers and current drinkers, ex-smokers and never drinkers, never smokers and current drinkers, and never smokers and ex-drinkers belonged to group 3; while the never smokers plus never drinkers were in group 4. We used a chi-square test to compare adverse drug reaction, lesions absorption and cavities of lung, sputum culture at the end of the second month, and treatment outcomes among the four groups. Among the 1256 participants enrolled in the study, 6.1% (76/1256) were current smokers plus drinkers; 25.9% (325/1256) were ex-smokers plus drinkers; 29.1% (366/1256) were current/never/ex-smokers and/or drinkers, and 38.9% (489/1256) were never smokers plus drinkers, respectively. Compared to the never smokers and drinkers, smoker plus drinker TB patients were more likely to experience adverse drug reaction (
x
2
= 8.480,
P
= 0.037), less proportion of lesions absorption in lungs (
x
2
= 10.330,
P
= 0.016), lower proportion of culture conversion (
x
2
= 18.83,
P
= 0.04), and more unfavorable outcomes. Smoking plus alcohol drinking adversely affect response against TB treatment, which increase adverse drug reactions, sputum culture–positive rate at the end of the second month, and failure rate of pulmonary tuberculosis patients.
Trehalose, which plays important roles in resistance to abiotic stresses and preservation of biological activity in plants, is synthesized by two key enzymes, trehalose-6-phosphate synthase (TPS) and ...trehalose-6-phosphate phosphatase (TPP). Therefore, the expressions of the TPS and TPP genes directly affect trehalose synthesis and stress resistance of plants. In this study, CkTPS and CkTPP from Caragana korshinskii were identified, and the role of trehalose synthesis in the adaptation of this desert plant to adverse conditions was investigated. Higher CkTPS and CkTPP expressions were observed in the roots, whereas expressions were much lower in leaves and stems, and their expressions were upregulated under drought stress. Histochemical analyses showed that β-glucuronidase expression driven by the CkTPS and CkTPP promoters was strongly induced by abiotic stresses and phytohormones, such as abscisic acid, gibberellin, methyl jasmonate, and mannitol, which suggests that trehalose synthesis may be regulated by various signaling pathways. To determine the functional mechanism underlying the role of trehalose synthesis in regulating drought response in plants, CkTPS and CkTPP were introduced into Arabidopsis. Compared to wild-type (WT) plants, these transgenic plants showed higher germination rate, survival, less damage, better shoot growth, and longer roots under drought stress. Moreover, transgenic plants had a significantly higher content of proline, chlorophyll, trehalose, and activities of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), and lower malondialdehyde (MDA) content than WT controls. Double-transgenic plants carrying CkTPS and CkTPP showed better growth and stronger drought tolerance than either single transgenic plant line. These results provide a theoretical and experimental basis for further understanding the function and regulatory mechanism of CkTPS and CkTPP, as well as the possibility of their application for improving drought tolerance in crops through genetic engineering.
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•Cu/Mg enrichment was found at the interphase boundary in a B4C/Al composite.•Atomic scale quasi in-situ TEM revealed the dealloying of the Mg/Cu- rich layer.•Decomposition of the ...Mg(Al)B2 promoted the liberation of Cu remnant and pitting of the matrix.•Dissolved Cu ions were then redeposited upon the cathodic phases, i.e. B4C and Mg(Al)B2.
The present study reports an atomic level quasi in-situ TEM observation of the redistribution of alloying element Cu in the corrosion process of a B4C-reinforced Al-Mg-Si-Cu composite. Cu atoms were found to combine with Mg and form a thin layer at the interfaces between the aluminum matrix and nano-reinforcements (i.e. Mg(Al)B2 and Al3BC). Dealloying of the Cu/Mg-rich layer was revealed. The following decomposition of Mg(Al)B2 resulted in narrow corrosion trenches forming around Mg(Al)B2 and then the localized pitting of the matrix. In addition, the liberated Cu ions were then redeposited and formed noble Cu nano-particles upon cathodic Mg(Al)B2 and B4C particles.
Summary
Background
Eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) display distinct patterns of inflammation. However, the pathogenic mechanisms underlying the ...heterogeneity of CRSwNP need further investigation.
Objective
To investigate local immunoglobulin E (IgE) production and phenotype of mast cells in eosinophilic and non‐eosinophilic CRSwNP in Chinese.
Methods
Total and specific IgE levels were analysed by means of the ImmunoCAP system. The molecular steps involved in class‐switch recombination to IgE were investigated using RT‐PCR assays. Mast cell phenotypes, IgE‐ and high‐affinity IgE receptor (FcεRI)‐positive cells, and allergen binding to specific IgE in sinonasal mucosa were determined by means of immunohistochemistry.
Results
Compared with controls and non‐eosinophilic CRSwNP, local total IgE levels were increased, and local specific IgE to common aeroallergens was more frequently found, in Chinese eosinophilic CRSwNP independent of atopy and without significant association with Staphylococcus aureus enterotoxins. The ε germline gene transcript was also more frequently detected in eosinophilic CRSwNP. The number of IgE‐ and FcεRI‐positive cells was increased in eosinophilic CRSwNP. Most IgE‐ and FcεRI‐positive cells were mast cells. Dust mite antigens could bind to IgE on mast cells in situ. The number of mast cells positive for both tryptase and chymase and activated mast cells was increased in eosinophilic CRSwNP and the number of activated mast cells positively correlated with local IgE level, eotaxin‐1 level, and eosinophil count in CRSwNP.
Conclusions and Clinical Relevance
The local IgE induced by common aeroallergens may mediate mast cell activation and contribute to subsequent eosinophilic inflammation in Chinese CRSwNP. This study offers a rationale for considering intervention strategies designed to target ‘local allergy’ in eosinophilic CRSwNP.
After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and ...during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.
Forkhead Box P3 (FoxP3) is thought to be a key transcription factor in regulatory T cells (Tregs), and recent data indicate that it is expressed in several tumour cells. However, its precise roles in ...gastric cancer (GC) and the underlying mechanisms regulating the interaction between GC cells and lymphocytes remain unclear.
FoxP3 expression was examined in tumour cells and Tregs in 150 cases of gastric precancer and cancer, and their prognostic significances were evaluated, respectively, using a tissue microarray containing 135 GC patient samples with a mean 102-month follow-up. FoxP3 involvement in the tumour cells-lymphocytes interaction and its gene function were further investigated.
strong cytoplasmic staining of FoxP3 was observed in GC cells. FoxP3 protein expression in tumour cells predicts a good prognosis, whereas high-density Treg predicts a poor prognosis. Moreover, FoxP3 expression in GC cells increased after coculture with peripheral blood mononuclear cells through coculture systems. Upregulation of FoxP3 inhibited tumour growth in tumour-bearing nude mice.
High FoxP3 expression in tumour cells predicts better survival in GC, possibility in relation to interaction between tumour cells and lymphocytes in microenvironment. Interfering with FoxP3 expression may open a new therapeutic strategy against tumour progression.
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