Loss of PBX1 function in Leydig cells causes testicular dysgenesis and male sterility.

Leydig cells are essential components of testicular interstitial tissue and serve as a primary source of androgen in males. A functional deficiency in Leydig cells often causes severe reproductive disorders; however, the transcriptional programs underlying the fate decisions and steroidogenesis of these cells have not been fully defined. In this study, we report that the homeodomain transcription factor PBX1 is a master regulator of Leydig cell differentiation and testosterone production in mice. PBX1 was highly expressed in Leydig cells and peritubular myoid cells in the adult testis. Conditional deletion of Pbx1 in Leydig cells caused spermatogenic defects and complete sterility. Histological examinations revealed that Pbx1 deletion impaired testicular structure and led to disorganization of the seminiferous tubules. Single-cell RNA-seq analysis revealed that loss of Pbx1 function affected the fate decisions of progenitor Leydig cells and altered the transcription of genes associated with testosterone synthesis in the adult testis. Pbx1 directly regulates the transcription of genes that play important roles in steroidogenesis (Prlr, Nr2f2 and Nedd4). Further analysis demonstrated that deletion of Pbx1 leads to a significant decrease in testosterone levels, accompanied by increases in pregnenolone, androstenedione and luteinizing hormone. Collectively, our data revealed that PBX1 is indispensable for maintaining Leydig cell function. These findings provide insights into testicular dysgenesis and the regulation of hormone secretion in Leydig cells.

Gestational diabetes mellitus combined with fulminant type 1 diabetes mellitus, four cases of double diabetes: A case report.

BACKGROUND: Fulminant type 1 diabetes mellitus (FT1DM) that occurs during pregnancy or the perinatal period is known as pregnancy-related FT1DM (PF), always without history of abnormal glucose metabolism. Here, we present four patients who developed FT1DM during treatment but were first diagnosed with gestational diabetes mellitus (GDM). CASE SUMMARY: The clinical data of four patients with GDM combined with FT1DM admitted to our hospital between July 2018 and April 2021 were collected, and the patients and their infants were followed up. All patients were diagnosed with GDM during the second trimester and were treated. The blood glucose level elevated suddenly during the third trimester and then were diagnosed with FT1DM. Two patients had an insulin allergy, and two had symptoms of upper respiratory tract infection before onset. One patient developed ketoacidosis, and three developed ketosis. Two patients had cesarean section deliveries, and two had vaginal deliveries. The growth and development of the infants were normal. C-peptide levels were lower than those at onset, suggesting progressive impairment of islet function. The frequencies of the DRB1 09:01, DQB1 03: 03, DQA1 03:02, DPA1 01:03, DPA1 02:02, DPB1 05:01, DRB4 01:03, G 01:01, and G 01:04 human leukocyte antigen (HLA)-G alleles were high in the present study. CONCLUSION: In comparison with pregnancy-associated FT1DM (PF), patients with GDM combined with FT1DM had an older age of onset, higher body mass index, slower onset, fewer prodromal symptoms, and less acidosis. The pathogenesis may be due to various factors affecting the already fragile ß-cells of GDM patients with genetically susceptible class II HLA genotypes. We speculate that GDM combined with FT1DM during pregnancy, referred to as "double diabetes," is a subtype of PF with its own unique characteristics that should be investigated further.

Single-cell transcriptome analyses reveal critical regulators of spermatogonial stem cell fate transitions.

BACKGROUND: Spermatogonial stem cells (SSCs) are the foundation cells for continual spermatogenesis and germline regeneration in mammals. SSC activities reside in the undifferentiated spermatogonial population, and currently, the molecular identities of SSCs and their committed progenitors remain unclear. RESULTS: We performed single-cell transcriptome analysis on isolated undifferentiated spermatogonia from mice to decipher the molecular signatures of SSC fate transitions. Through comprehensive analysis, we delineated the developmental trajectory and identified candidate transcription factors (TFs) involved in the fate transitions of SSCs and their progenitors in distinct states. Specifically, we characterized the Asingle spermatogonial subtype marked by the expression of Eomes. Eomes+ cells contained enriched transplantable SSCs, and more than 90% of the cells remained in the quiescent state. Conditional deletion of Eomes in the germline did not impact steady-state spermatogenesis but enhanced SSC regeneration. Forced expression of Eomes in spermatogenic cells disrupted spermatogenesis mainly by affecting the cell cycle progression of undifferentiated spermatogonia. After injury, Eomes+ cells re-enter the cell cycle and divide to expand the SSC pool. Eomes+ cells consisted of 7 different subsets of cells at single-cell resolution, and genes enriched in glycolysis/gluconeogenesis and the PI3/Akt signaling pathway participated in the SSC regeneration process. CONCLUSIONS: In this study, we explored the molecular characteristics and critical regulators of subpopulations of undifferentiated spermatogonia. The findings of the present study described a quiescent SSC subpopulation, Eomes+ spermatogonia, and provided a dynamic transcriptional map of SSC fate determination.

Pancreatic lipase-related protein 2 is selectively expressed by peritubular myoid cells in the murine testis and sustains long-term spermatogenesis.

Spermatogenesis is a complicated process of germ cell differentiation that occurs within the seminiferous tubule in the testis. Peritubular myoid cells (PTMCs) produce major components of the basement membrane that separates and ensures the structural integrity of seminiferous tubules. These cells secrete niche factors to promote spermatogonial stem cell (SSC) maintenance and mediate androgen signals to direct spermatid development. However, the regulatory mechanisms underlying the identity and function of PTMCs have not been fully elucidated. In the present study, we showed that the expression of pancreatic lipase-related protein 2 (Pnliprp2) was restricted in PTMCs in the testis and that its genetic ablation caused age-dependent defects in spermatogenesis. The fertility of Pnliprp2 knockout animals (Pnliprp2-/-) was normal at a young age but declined sharply beginning at 9 months. Pnliprp2 deletion impaired the homeostasis of undifferentiated spermatogonia and severely disrupted the development and function of spermatids. Integrated analyses of single-cell RNA-seq and metabolomics data revealed that glyceride metabolism was changed in PTMCs from Pnliprp2-/- mice. Further analysis found that 60 metabolites were altered in the sperm of the Pnliprp2-/- animals; notably, lipid metabolism was significantly dysregulated. Collectively, these results revealed that Pnliprp2 was exclusively expressed in PTMCs in the testis and played a novel role in supporting continual spermatogenesis in mice. The outcomes of these findings highlight the function of lipid metabolism in reproduction and provide new insights into the regulation of PTMCs in mammals.

Immune functions of the Dscam extracellular variable region in Chinese mitten crab.

In arthropods, there is only a single copy of Down Syndrome Cell Adhesion Molecule (Dscam) in the genome, but it can exist as numerous splice variants. There are three hypervariable exons in the extracellular domain and one hypervariable exon in the transmembrane domain. In Chinese mitten crab (Eriocheir sinensis), exons 4, 6 and 14 can produce 25, 34 and 18 alternative splice variants, respectively. In this study, through Illumina sequencing, we identified additional splice variants for exons 6 and 14, hence there may be > 50,000 Dscam protein variants. Sequencing of exons 4, 6 and 14 showed that alternative splicing was altered after bacterial stimulation. Therefore, we expressed and purified the extracellular variable region of Dscam (EsDscam-Ig1-Ig7). Exons 4.3, 6.46 and 14.18, three variable exons of the recombinant protein, were randomly selected. The functions of EsDscam-Ig1-Ig7 in immune defences of E. sinensis were subsequently explored. EsDscam-Ig1-Ig7 was discovered to bind to both Gram-positive Staphylococcus aureus and Gram-negative Vibrio parahaemolyticus, but it did not exhibit antibacterial activity. By promoting hemocyte phagocytosis and bacterial removal, EsDscam-Ig1-Ig7 can also shield the host from bacterial infection. The findings highlight the immunological activities of Dscam alternative splicing and reveal the potential for many more Dscam isoforms than were previously predicted in E. sinensis.

ARHGEF15 is expressed in undifferentiated spermatogonia but is not required for spermatogenesis in mice.

Spermatogenesis is a continual process that relies on the activities of undifferentiated spermatogonia, which contain spermatogonial stem cells (SSCs) that serve as the basis of spermatogenesis. The gene expression pattern and molecular control of fate decisions of undifferentiated spermatogonia are not well understood. Rho guanine nucleotide exchange factor 15 (ARHGEF15, also known as EPHEXIN5) is a guanine nucleotide-exchange factor (GEF) that activates the Rho protein. Here, we reported that ARHGEF15 was expressed in undifferentiated spermatogonia and spermatocytes in mouse testes; however, its deletion did not affect spermatogenesis. Arhgef15-/- mice were fertile, and histological examination of the seminiferous tubules of Arhgef15-/- mice revealed complete spermatogenesis with the presence of all types of spermatogenic cells. Proliferation and differentiation of the undifferentiated spermatogonia were not impacted; however, further analysis showed that Arhgef15 deletion resulted in decreased expression of Nanos2, Lin28a and Ddx4. Together, these findings suggest that ARHGEF15 was specifically enriched in undifferentiated spermatogonia and regulated gene expression but dispensable for spermatogenesis in mice.

Ldha-Dependent Metabolic Programs in Sertoli Cells Regulate Spermiogenesis in Mouse Testis.

Sertoli cells play indispensable roles in spermatogenesis by providing the advanced germ cells with structural, nutritional, and regulatory support. Lactate is regarded as an essential Sertoli-cell-derived energy metabolite that nurses various types of spermatogenic cells; however, this assumption has not been tested using genetic approaches. Here, we have reported that the depletion of lactate production in Sertoli cells by conditionally deleting lactate dehydrogenase A (Ldha) greatly affected spermatogenesis. Ldha deletion in Sertoli cells significantly reduced the lactate production and resulted in severe defects in spermatogenesis. Spermatogonia and spermatocytes did not show even mild impairments, but the spermiogenesis of Ldha conditional knockout males was severely disrupted. Further analysis revealed that 2456 metabolites were altered in the sperm of the knockout animals, and specifically, lipid metabolism was dysregulated, including choline, oleic acid, and myristic acid. Surprisingly, choline supplementation completely rescued the spermiogenesis disorder that was caused by the loss of Ldha activities. Collectively, these data have demonstrated that the interruption of Sertoli-cell-derived lactate impacted sperm development through a choline-mediated mechanism. The outcomes of these findings have revealed a novel function of lactate in spermatogenesis and have therapeutic applications in treating human infertility.

Influence of Self-Perceived Burden on Quality of Life in Patients with Urostomy Based on Structural Equation Model: The Mediating Effects of Resilience and Social Support.

Objective: To investigate the current situation of self-perceived burden in patients with urostomy, analyze the correlation between self-perceived burden and quality of life, and explore the intermediary role of resilience and social support. Methods: The convenience sampling method was used to select 303 patients with urostomy of outpatient departments of the three tertiary hospitals in Yinchuan, Ningxia region, China, from April 1, 2020, to October 1, 2020, who then completed a survey questionnaire. The survey questionnaire contained a general data questionnaire and self-perceived burden scale, city of hope-quality of life-ostomy questionnaire, Connor-Davidson resilience scale, and social support rating scale. Results: Self-perceived burden was present among 89.8% patients with urostomy; the quality of life of patients with urostomy is low. The results showed that the self-perceived burden and quality of life, resilience, and social support are related in pairs; self-perceived burden was significantly negatively correlated with quality of life，resilience, and social support; there was a significant positive correlation between quality of life, resilience, and social support; resilience and social support were parallel mediators. Conclusions: Patients with urostomy had a heavy self-perceived burden and low quality of life. Reducing the self-perceived burden of patients with urostomy by improving the level of resilience and social support, could raise the level of quality of life. This study could provide empirical basis for nurses to take continuous nursing intervention measures in order to reduce the self-perceived burden of patients with urostomy and ultimately to improve the quality of life.

A structural equation model-based study on the status and influencing factors of acute exacerbation readmission of elderly patients with chronic obstructive pulmonary disease within 30 days.

OBJECTIVE: To investigate the circumstances that lead to acute exacerbation readmission of elderly patients with chronic obstructive pulmonary disease (COPD) within 30 days and to explore the influencing factors of readmission using a structural equation model to provide evidence for medical staff so that effective intervention measures can be taken. METHODS: The convenience sampling method was used to select 1120 elderly patients with COPD from the respiratory departments of thirteen general hospitals in the Ningxia region, China, from April 2019 to August 2020, who then completed a survey questionnaire. The survey questionnaire contained a general data questionnaire and the modified Medical Research Council, activities of daily living, geriatric depression scale and COPD assessment test scales. RESULTS: The readmission rate of patients with COPD presenting with acute exacerbation within 30 days was determined to be 21.52%. Therefore, the modified model measures data accurately. The results showed that seasonal factors, family rehabilitation, age factors and overall health status were direct factors in the acute exacerbation readmission of patients with COPD within 30 days of hospital discharge. Smoking is not only a direct factor for acute exacerbation readmission within 30 days but also an indirect factor through disease status; disease status and chronic disease are not only direct factors for acute exacerbation readmission within 30 days but also indirect factors through the patient's overall health status. CONCLUSIONS: The rate of patients with COPD presenting with acute exacerbation within 30 days is high; while taking measures to prevent readmission based on influencing factors that directly impact admission rates, attention should also be paid to the interaction between these factors.

Pathological Change of Chronic Hepatitis B Patients with Different Tongue Coatings by Circular Multi-Omics Integrated Analysis.

OBJECTIVE: To compare the circular pathological changes of chronic hepatitis B (CHB) patients according to the tongue diagnosis. METHODS: Totally 41 CHB patients with typical white tongue coating (WTC) or yellow tongue coating (YTC) were enrolled and 14 healthy volunteers with normal tongue manifestation served as controls. The mRNA expression of peripheral leukocytes was detected by GeneChips, and 9 genes were randomly selected for expression validation. Circular metabolites were detected by gas chromatographymass spectrometry. Biological information was analyzed based on ingenuity pathways analysis or metabolomics database and the integrated networks were constructed by ClueGO. RESULTS: A total of 945 and 716 differentially expressed genes were found in patients with WTC and YTC relative to healthy volunteers respectively. The biological information analysis indicated that CHB patients had obviously increased functions in cell death, apoptosis and necrosis (Z-score ⩾2, P<0.05) and decreased activation in T lymphocytes (Z-score ⩽-2, P<0.05), regardless of the tongue manifestation. Compared to patients with WTC, the YTC patients were predicted to be more active in functions related to virus replication (Z-score ⩾2, P<0.05), and the content of circular fatty acids, such as oleic acid (P=0.098) and lauric acid (P=0.035), and citric acid cycle-related metabolites were higher in the YTC patients (P<0.1). The integrated analysis based on differential genes and metabolites indicated that the most difference in the biological function network between the WTC and YTC patients was tumor necrosis factor receptor associated factor 6 mediated-nuclear factor kappa-B activation process. CONCLUSIONS: CHB patients with YTC had more severe inflammation and fatty acids metabolism aberrant than patients with WTC. The results facilitate the modern pathological annotation of Chinese medicine tongue diagnosis theory and provide a reference for the interpretation of pharmacological mechanisms of Chinese medicine treatment.

Long non-coding RNAs as epigenetic mediator and predictor of glioma progression, invasiveness, and prognosis.

Gliomas are aggressive brain tumors with high mortality rate. Over the past several years, non-coding RNAs, specifically the long non-coding RNAs (lncRNAs), have emerged as biomarkers of considerable interest. Emerging data reveals distinct patterns of expressions of several lncRNAs in the glioma tissues, relative to their expression in normal brains. This has led to the speculation for putative exploitation of lncRNAs as diagnostic biomarkers as well as biomarkers for targeted therapy. With a focus on lncRNAs that have shown promise as epigenetic biomarkers in the proliferation, migration, invasion, angiogenesis and metastasis in various glioma models, we discuss several such lncRNAs. The data from cell line / animal model-based studies as well as analysis from human patient samples is presented for the most up-to-date information on the topic. Overall, the information provided herein makes a compelling case for further evaluation of lncRNAs in clinical settings.

Paternal hypoxia exposure impairs fertilization process and preimplantation embryo development.

Environmental hypoxia exposure causes fertility problems in human and animals. Compelling evidence suggests that chronic hypoxia impairs spermatogenesis and reduces sperm motility. However, it is unclear whether paternal hypoxic exposure affects fertilization and early embryo development. In the present study, we exposed male mice to high altitude (3200 m above sea level) for 7 or 60 days to evaluate the effects of hypoxia on sperm quality, zygotic DNA methylation and blastocyst formation. Compared with age-matched controls, hypoxia-treated males exhibited reduced fertility after mating with normoxic females as a result of defects in sperm motility and function. Results of in vitro fertilization (IVF) experiments revealed that 60 days' exposure significantly reduced cleavage and blastocyst rates by 30% and 70%, respectively. Immunohistochemical staining of pronuclear formation indicated that the pronuclear formation process was disturbed and expression of imprinted genes was reduced in early embryos after paternal hypoxia. Overall, the findings of this study suggested that exposing male mice to hypoxia impaired sperm function and affected key events during early embryo development in mammals.

The mechanism behind activation of the Nod-like receptor family protein 3 inflammasome in Parkinson's disease.

Previous studies have shown that the ATP-P2X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3 (NLRP3) inflammasome. The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy. As inflammation also plays an important role in the pathogenesis of Parkinson's disease, we hypothesized that the ATP-P2X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease. A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra. The P2X4 receptor and the NLRP3 inflammasome (interleukin-1ß and interleukin-18) were activated. Intracerebroventricular injection of the selective P2X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) or knockdown of P2X4 receptor expression by siRNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation. Our results suggest that the ATP-P2X4 receptor signaling pathway mediates NLRP3 inflammasome activation, dopaminergic neurodegeneration, and dopamine levels. These findings reveal a novel role of the ATP-P2X4 axis in the molecular mechanisms underlying Parkinson's disease, thus providing a new target for treatment. This study was approved by the Animal Ethics Committee of Qingdao University, China, on March 5, 2015 (approval No. QYFYWZLL 26119).

[Clinical Value of 1.5-T Non-contrast Whole-heart Magnetic Resonance Coronary Angiography in Evaluating the Severity of Coronary Stenosis].

Objective To evaluate the diagnostic performance of 1.5-T non-contrast free-breathing whole-heart magnetic resonance coronary angiography(MRCA)for≥50% and≥70% coronary artery stenosis in coronary artery disease(CAD).Methods Forty-one patients clinically scheduled for invasive coronary angiography(ICA)underwent 1.5-T non-contrast free-breathing whole-heart MRCA.The diagnostic performance for≥50% and≥70% stenosis was evaluated and compared using ICA as a reference standard.Results MRCA was completed in all the 41 patients with the total acquisition time of(10.1 ± 2.2)min.The sensitivity,specificity,and accuracy of MRCA for≥50% and≥70% stenosis were 100%(95% CI:89%-100%)and 82%(95%CI:63%-94%),38%(95%CI:9%-76%)and 54%(95%CI:25%-81%),and 88%(95%CI:73%-95%)and 73%(95%CI:57%-85%)on a per-patient basis,respectively;they were 95%(95%CI:87%-99%)and 86%(95%CI:73%-95%),58%(95%CI:45%-71%)and 76%(95%CI:65%-85%),and 78%(95%CI:69%-84%)and 80%(95%CI:71%-86%)on a per-vessel basis,respectively.The sensitivity of MRCA for≥50% stenosis was higher than that for≥70% stenosis(97%vs.88%,χ 2=5.73,P=0.017),and the specificity showed an opposite trend(86% vs. 94%,χ 2=14.12,P<0.001)on a per-segment basis.Conclusions The 1.5-T non-contrast whole-heart MRCA can detect both≥50% and≥70% coronary artery stenosis with high sensitivity and accuracy.MRCA showed lower sensitivity while higher specificity for≥70% stenosis than for≥50% stenosis on a per-segment basis.

Nurses' turnover intention in secondary hospitals in China: A structural equation modelling approach.

AIM: To identify the factors affecting nurses' turnover intention. BACKGROUND: The shortage of nurses has been a great challenge worldwide, and nurses' turnover may exacerbate the situation. METHODS: A cross-sectional study was conducted among nurses in six secondary hospitals in China. A model was constructed, and structured questionnaires were adopted to measure model variables. Structural equation modelling was used to verify the model. RESULTS: Totally, 594 valid questionnaires were collected. The final model showed an acceptable fit, and 35.0% of the total variation was explained. Nine of the ten pathways were statistically significant. The model verified the contribution of professional value, nursing practice, job stress and social support to turnover intention and their effects were mediated by job satisfaction and organisational commitment. As hypothesized, there existed a significant effect between job satisfaction and organisational commitment. Unexpectedly, job stress had a greater direct effect on turnover intention than job satisfaction and organisational commitment. CONCLUSIONS: The structural model provided a feasible model that could explain nurses' turnover intention in China. IMPLICATIONS FOR NURSING MANAGEMENT: To prevent the turnover of nurses, administrators and managers should advisably prioritize the effect of job stress, especially in hospitals with similar medical context.

P2X4 receptor participates in autophagy regulation in Parkinson's disease.

Dysfunctional autophagy often occurs during the development of neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia, astrocytes, and neurons of the central and peripheral nervous systems. P2X4R is involved in the regulation of cellular excitability, synaptic transmission, and neuroinflammation. However, the role played by P2X4R in Parkinson's disease remains poorly understood. Rat models of Parkinson's disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta. P2X4R-targeted small interfering RNA (siRNA) was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor. The results showed that the inhibition of P2X4 receptor expression in Parkinson's disease model rats reduced the rotation behavior induced by apomorphine treatment, increased the latency on the rotarod test, and upregulated the expression of tyrosine hydroxylase, brain-derived neurotrophic factor, LC3-II/LC3-I, Beclin-1, and phosphorylated tropomyosin receptor kinase B (TrkB) in brain tissue, while simultaneously reducing p62 levels. These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway, leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy. These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson's disease. This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University (approval No. QYFYWZLL26119) on April 12, 2016.

Two Zn(II)-based Coordination Polymers: Treatment Activity on Chronic Periodontitis by Inhibiting the Relative Expression of the Porphyria gingivalis Survival Gene.

Two mixed-ligand complexes on the basis of L ligand [L = 3,6-bis(imidazol-1-yl)pyridazine] have been prepared under the solvothermal reaction conditions via the Zn(II) salts reacting with the ligands of L in the existence of two positional isomerous carboxylic acid ligands and their chemical formula respectively are [Zn5(L)(1,2-BDC)4(µ3-OH)2] n (1, 1,2-H2BDC = 1,2-benzenedicarboxylic acid ) and {[Zn4(L)2(1,3-HBDC) (1,3-BDC)(µ3-OH)4]·ClO4·3H2O} n (2, 1,3-H2BDC = 1,3-benzenedicarboxylic acid). The inhibitory influence of the two compounds against the inflammatory response in periodontium was evaluated by measuring the inflammatory cytokines releasing with ELISA detection kit. The results of ELISA assay indicated that compound 1 showed much stronger inhibitory influences than compound 2 against the inflammatory cytokines releasing. In addition to this, the suppression activity of the compounds against the survival gene of Porphyria gingivalis was detected via the real time Reverse Transcription-Polymerase Chain Reaction, and the results suggested that compound 1 could evidently suppresses the survival gene expression of Porphyria gingivalis, which is much better than the biological activity of compound 2. Above all, compound 1 was more outstanding than compound 2 on chronic periodontitis treatment by inhibiting the Porphyria gingivalis survival.

Biallelic XPR1 mutation associated with primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia with infantile convulsions.

BACKGROUND: Mutations in the XPR1 gene are associated with primary familial brain calcifications (PFBC). All reported mutations are missense and inherited as an autosomal dominant trait. PFBC patients exhibited movement disorders, neuropsychiatric symptoms, and other associated symptoms with diverse severity, even within the same family. MATERIALS AND METHODS: We identified and enrolled a patient with PFBC. Clinical data were comprehensively collected, including the age of onset, seizure types and frequency, trigger factors of paroxysmal dyskinesia, response to drugs, and general and neurological examination results. Whole-exome sequencing (WES) was performed to detect pathogenic variants. We further systematically reviewed the phenotypic and genetic features of patients with XPR1 mutations. RESULTS: The patient showed bilateral calcification involving basal ganglia and cerebellar dentate. Clinically, he presented as paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) with favorable outcome. We identified a compound heterozygous XPR1 mutation (c.786_789delTAGA/p.D262Efs*6, c.1342C>T/p.R448W), which were inherited from unaffected parents respectively. Further literature review shows a wide range of clinical manifestations of patients with XPR1 mutations, with movement disorders being the most common. CONCLUSIONS: This is the first report of biallelic mutations in XPR1. The findings suggest for the first time a possible link between PKD/IC and XPR1 mutations.

A clinical strategy to improve the diagnostic accuracy of 1.5-T non-contrast MR coronary angiography for detection of coronary artery disease: combination of whole-heart and volume-targeted imaging.

OBJECTIVES: To evaluate the diagnostic performance of 1.5-T non-contrast MR coronary angiography (MRCA) for detection of coronary artery disease (CAD) using whole-heart imaging combined with volume-targeted imaging. METHODS: Forty-five patients scheduled for conventional coronary angiography (CAG) underwent 1.5-T free-breathing non-contrast steady-state free-precession MRCA, including whole-heart and subsequent three-vessel volume-targeted imaging. Coronary stenosis was evaluated as follows: (1) by whole-heart MRCA alone; (2) by combined MRCA (whole-heart plus volume-targeted images). The diagnostic performance for significant stenosis (≥ 50% diameter reduction) was evaluated and compared using CAG as a reference standard. RESULTS: Combined MRCA was completed in all 45 patients with a total acquisition time of 16.6 ± 3.3 min. The sensitivity, specificity, and accuracy of combined MRCA per patient were 97% (95% confidence interval 84-100%), 83% (52-98%), and 93% (82-98%), respectively. The areas under the receiver operating characteristic curve of combined MRCA were significantly higher than those of whole-heart MRCA on a per patient (0.97 versus 0.85, p = 0.0078) and per vessel (0.96 versus 0.86, p < 0.0001) basis. Compared with whole-heart MRCA, combined MRCA showed equally high sensitivity but significantly improved specificity on a per patient (83% versus 25%, p = 0.016) and per vessel (85% versus 50%, p < 0.0001) basis. CONCLUSIONS: 1.5-T non-contrast MRCA combining whole-heart and volume-targeted imaging can detect significant CAD with high sensitivity and moderate specificity. Combined MRCA significantly improves specificity compared with whole-heart imaging alone. KEY POINTS: • 1.5-T non-contrast MRCA with combined whole-heart and volume-targeted imaging can detect CAD with high sensitivity and moderate specificity comparable with coronary CTA. • Compared with whole-heart imaging alone, combined imaging provides improved diagnostic accuracy, especially specificity.

WTAP Function in Sertoli Cells Is Essential for Sustaining the Spermatogonial Stem Cell Niche.

Sertoli cells are the major component of the spermatogonial stem cell (SSC) niche; however, regulatory mechanisms in Sertoli cells that dictate SSC fate decisions remain largely unknown. Here we revealed features of the N6-methyladenosine (m6A) mRNA modification in Sertoli cells and demonstrated the functions of WTAP, the key subunit of the m6A methyltransferase complex in spermatogenesis. m6A-sequencing analysis identified 21,909 m6A sites from 15,365 putative m6A-enriched transcripts within 6,122 genes, including many Sertoli cell-specific genes. Conditional deletion of Wtap in Sertoli cells resulted in sterility and the progressive loss of the SSC population. RNA sequencing and ribosome nascent-chain complex-bound mRNA sequencing analyses suggested that alternative splicing events of transcripts encoding SSC niche factors were sharply altered and translation of these transcripts were severely dysregulated by Wtap deletion. Collectively, this study uncovers a novel regulatory mechanism of the SSC niche and provide insights into molecular interactions between stem cells and their cognate niches in mammals.