Abstract Background X‐linked hyper‐IgM (X‐HIGM), which results from mutations in the CD40LG gene located on chromosome Xq26.3, is the most common form of HIGM. To date, more than 130 variants of the CD40L gene have been reported. We described a patient with novel de novo nuclear mitochondrial DNA sequences (NUMTs) in the CD40LG gene that have resulted in X‐HIGM. Methods Whole‐exome sequencing (WES) analysis was used to screen for causal variants in the genome, and the candidate breakpoint was confirmed by Sanger sequencing. Results A new mutation of CD40LG , which deletes A at position 17 followed by a 147‐nucleotide from mitochondrial DNA copies insertion in exon 1, was detected in a 20‐month‐old boy harbouring an X‐HIGM combined with immunodeficiency syndrome. Conclusion This is one of the few cases of a human genetic disease caused by nuclear mitochondrial DNA sequences (NUMTs). The presented data serve to demonstrate that de novo NUMT transfer of nucleic acid is a novel mechanism of X‐HIGM.
WD40-Repeat protein 62 (WDR62) is a spindle pole protein required for normal cell division and neuroprogenitor differentiation during brain development. Microcephaly mutations lead to mitotic mislocalization highlighting a critical requirement for precise WDR62 spatiotemporal distribution although the regulatory mechanisms are unknown. Here we demonstrate that the WD40-repeat region of WDR62 is required for microtubule association while the disordered C-terminal region regulates cell-cycle dependent compartmentation. In agreement with a functional requirement for WDR62/JNK1 complex during neurogenesis, WDR62 specifically recruits JNK1, but not JNK2, to the spindle pole. However, JNK-mediated phosphorylation of WDR62 T1053 negatively regulated microtubule association and loss of JNK signalling resulted in constitutive WDR62 localization to microtubules irrespective of cell cycle stage. In contrast, we identified that Aurora A kinase (AURKA) and WDR62 were in complex and AURKA-mediated phosphorylation was required for spindle localization of WDR62 during mitosis. Our studies highlight complex regulation of WDR62 localization with opposing roles for JNK and AURKA in determining its spindle association.
Abstract Introduction: Postoperative pulmonary complications (PPCs) are common and associated with increased morbidity, mortality, and medical cost. They are gaining increasing concerns among patients receiving neurological surgery. Chronic obstructive pulmonary disease (COPD) affect a large section of whole population and is also one of the risk factors of PPCs in the perioperative setting. Ipratropium bromide is the inhalation solution for the treatment of COPD. Studies showed the perioperative nebulization of ipratropium bromide could increase the lung function and decrease the incidence of postoperative pneumonia in COPD patients underwent thoracic surgery. The purpose of this study is to investigate the effect of perioperative nebulization of ipratropium bromide on PPCs in COPD patients underwent neurosurgical surgery. Methods and analysis: This study is a multicenter retrospective study in China. Patients who meet the inclusion/exclusion criteria are selected from 7 neurosurgical centers in China. According to whether ipratropium bromide is used in perioperative period, the patients are divided into exposure group and control group. The primary outcome is the incidence of postoperative pneumonia. Secondary outcomes are unplanned intubation, postoperative mechanical ventilation ≥ 48 hours, respiratory failure, atelectasis, death, and length of stay. Ethics and dissemination: This study was approved by the ethics committee (EC) of the School of Public Health, Fudan University, Shanghai, China. Waived by the ethics committee, no written consent form was obtained since we used the registry data. The study results will be communicated via publication. Trial Registration Number: ChiCTR1900022552.
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a clinically heterogeneous disorder characterized by epileptic seizures, psychosis, dyskinesia, consciousness impairments, and autonomic instability. Symptoms are always various. Sometimes it presents in milder or incomplete forms. We report 4 cases of anti-NMDAR encephalitis with incomplete forms, 3 cases of which were accompanied by neuromyelitis optica spectrum disorder or neurosyphilis respectively.A 33-year-old man presented with dysarthria, movement disorder and occasional seizures. He had 6 relapses in 28 years. When suffered from upper respiratory tract syndrome, he developed behavioral and consciousness impairment. Cranial MRI was normal. Viral PCR studies and oncologic work-up were negative. Anti-NMDAR antibody was detected in CSF and serum. A 21-year-old female manifested dizziness and diplopia ten months and six months before, respectively. Both responded to steroid therapy and improved completely. This time she presented with progressive left limb and facial anesthesia, walking and holding unsteadily. Spinal cord MRI follow-up showed abnormality of medulla oblongata and cervical cord(C1). Anti-AQP4 and anti-NMDAR were positive in CSF. Steroid-pulse therapy ameliorated her symptoms. A 37-year-old male experienced worsening vision. He was confirmed neurosyphilis since the CSF tests for syphilis were positive. Protein was elevated and the oligoclonal IgG bands(OB) and anti-NMDAR was positive in CSF. Anti-aquaporin 4(AQP4) antibodies and NMO-IgG were negative. Cranial MRI showed high FLAIR signal on frontal lobe and low T2 signal adjacent to the right cornu posterious ventriculi lateralis. Treatment for neurosyphlis was commenced with gradual improvement. A 39-year-old male, developed serious behavioral and psychiatric symptoms. Examination showed abnormal pupils and unsteady gait. He was confirmed neurosyphilis according to the CSF tests for syphilis. Anti-NMDAR was positive in CSF and serum. Cranial MRI showed lateral ventricles and the third ventricle enlargement and signal abnormality involving bilateral temporal lobe, corona radiate and centrum semiovale. PenicillinG, pulsed methylprednisolone and intravenous immunoglobulin was administered. He was stable.Anti-NMDAR encephalitis can present in atypical types. When relapsing, it may present with partial aspects or with isolated symptoms of the full-blown syndrome. Anti-NMDAR encephalitis may be related to neuromyelitis optica spectrum disorder or neurosyphilis.
The epidermal growth factor (EGF) is a member of the growth factor superfamily that can stimulate the proliferation of many types of cells. Overexpression of EGF receptor (EGFR) was observed in many types of cancer cells. Anti-EGFR antibodies or antisense nucleic acid sequences of EGFR can suppress the growth of hepatoma cells. In order to further investigate the proteome alterations associated with malignant growth of the human hepatoma cells and the influence of EGFR signal pathway on the cellular proteome, we have comparatively analyzed the proteomes of human hepatoma cells transfected with antisense EGFR sequence (cell strain JX-1) and its control cells (cell strain JX-0) by two-dimensional (2-D) gel electrophoresis and mass spectrometry. Image analysis of silver-stained 2-D gels revealed that 40 protein spots showed significant expression changes in JX-1 cells compared to JX-0 cells. Three of them, including the tumor suppressor protein maspin, changed with tendency to the normal levels. Two protein spots were identified as HSP27 in the same gel, and one of them had a reduced level in JX-1 cells. The apparent alterations of HSP27 in expression level might be the results from their differential chemical modifications, suggesting the effect of dynamic post-translational modifications of proteins on the growth of hepatoma cells. Other proteins such as glutathione peroxidase (GPX-1) and 14–3-3-sigma also exhibited altered expression in JX-1 cells, and their functional implications are discussed.
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