Objective To investigate the correct diagnosis and treatment of myeloid and lymophoid neoplasms with eosinophilia and the FIP1L1-PDGFR fusion gene. Methods A case of patient who was diagnosed as myeloid and lymophoid neoplasms with eosinophilia and the FIP1L1-PDGFR fusion gene was reported, and the literature was reviewed. Results The patient was diagnosed as typical T-lymphoblast lymphoma (T-LBL) by the lymph node pathologic diagnosis, while the diagnosis of myeloid and lymophoid neoplasms with eosinophilia and the FIP1L1-PDGFR fusion gene was made correctly by the whole examination and analysis. The patient acquired deep complete remission quickly after taking the low dose of imatinib. Conclusions Myeloid and lymophoid neoplasms with eosinophilia and the FIP1L1-PDGFR fusion gene are a rare hematologic tumor. Though pathological diagnosis is the golden standard for lymphoma, sometimes the other factors should be taken into consideration and make an overall analysis of clinical picture and a correct view of the pathological diagnosis, which could avoid the misdiagnosis and improper treatment.

Objective To explore the mutation characteristics of neurexin 1(NRXN1)gene in children with Tourette syndrome(TS).Methods A total of 524 children with TS were enrolled.DNA extracted from peripheral blood was sequenced for NRXN1 gene by using target region sequencing which was further verified by using Sanger sequencing.DNAMAN software,SIFT,PolyPhen2,Mutation Taster,FATHMM and ClinPred were used to analyze the hazard of suspected variants.Finally,the genotype and phenotype of the patients with NRXN1 gene variants were analyzed.Results We found 13 variants of the NRXN1 gene in 13 TS patients such as 11 point mutations and 2 deletion mutations including two novel point mutations:c.79G>T(p.A27S)and c.58G>T(p.G20C).The other nine point mutations and two deletion mutations were c.3523A>G(p.I1175V),c.4180A>T(p.T1394S),c.1697A>T(p.H566L),c.3715G>A(p.A1239T),c.878A>C(p.N293T),c.475C>T(p.P159S),c.320C>T(p.T107M),c.365A>G(p.Q122R),c.611T>A(p.L204Q)c.68_79del(p.G23_G26del),c.65_79del(p.G22_G26del).Bioinformatics analysis showed that the six gene variants c.58G>T,c.1697A>T,c.475C>T,c.365A>G,c.878A>C,c.79G>T were relatively harmful.There were 6 children with different parts of the tic,1 child with obsessive-compulsive symptoms,1 child with emotional instability,3 children with irritability,6 children did not have repetitive language,attention deficit,hyperactivity disorder,sleep disorder and depression.Conclusion NRXN1 gene mutation sites are detected in TS children,which expands the NRXN1 mutation spectrum.Children with different gene variants exhibit different clinical manifestations and the relationship between genotype and phenotype need further exploration.

Objective:To investigate the characteristic of mild cognitive impairment (MCI) in the adults aged 48 years and over in a coal mine community, and to analyze its associated risk factors.Methods:From July to October 2019, a questionnaire survey for basic information was conducted among 180 middle-aged and elderly adults who met the inclusion criteria in the Datong coal mine community. The cognitive function was evaluated by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The effects of gender, age, years of education, sleep, living alone, physical exercise, social activities, smoking and drinking status, body mass index and chronic diseases on cognitive level were analyzed by single factor stratification and multiple linear regression.Results:There was no significant difference in the positive rate of MCI screened by MMSE and MoCA in the age groups of 48-<64, 64-<72 and 72-90 (original and corrected P>0.05); The positive rate of MCI in MoCA screening (64.4%, 66.7%, 60.9%) was significantly higher than that in MMSE (35.6%, 45.6%, 28.1%) (all P<0.05); MMSE was positively correlated with MoCA score ( r=0.762, P<0.001). With the increase of age, the scores of memory, execution and visual space detected by MoCA decreased significantly (all P<0.05), while the scores of attention, language and orientation did not change significantly (all P>0.05). Univariate stratification showed that the significant influencing factors of MMSE or MoCA scores were gender, age, years of education and sleep status (all P<0.05). Multiple linear regression analysis showed that gender ( βMMSE=-0.192; βMoCA=-0.140), years of education ( βMMSE=0.209; βMoCA=0.328) and sleep status( βMMSE=-0.162; βMoCA=-0.136) were risk factors affecting MMSE and MoCA scores ( P<0.05). Conclusions:More middle-aged and elderly adults with MCI might be observed in a coal mine community, and the main characteristics of MCI are impaired memory, executive function and visual space. To prevent and reduce the occurrence of dementia, early interventions of MCI should be carried out among the adults with female, old age, low years of education and poor sleep quality.

RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient's iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.

The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

Aging/metabolism* ; Animals ; Gene Expression Regulation ; Macaca fascicularis ; Retina/metabolism* ; Single-Cell Analysis

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.
Mice ; Animals ; Transcriptome ; Aging/metabolism* ; Cochlea ; Stria Vascularis ; Presbycusis

The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms' Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.
Animals ; Male ; Testis ; Sertoli Cells/metabolism* ; Transcriptome ; Spermatogenesis/genetics* ; Primates ; Aging/genetics* ; Stem Cells