Metabolites isolated from Penicillium HDS-Z-1E, an endophytic fungal strain isolated from Taxus cuspidata and their activation effect of catalase

Objective:To study the compounds isolated from Penicillium HDS-Z-1E,an endophytic fungal strain isolated from Taxus cuspidata and their activation effect of catalase(CAT).Methods:The chemical constituents were isolated from Penicillium HDS-Z-1E,by using silica gel,Sephadex LH-20 and HPLC.The structural elucidations of five metabolites were elucidated on the basis of spectroscopic including 1 H-NMR,13C-NMR,HMBC and HSQC.Their activation sites of catalase have been investigated by molecular docking.Results:Five metabolites,compounds(1–5)were isolated from Penicillium HDS-Z-1E and identified as 4-hydroxy-4-methyltetrahydro-2H-pyran-2-one(1),4-hydroxymethyl-5,6-dihydro-pyran-2-one(2),5,6-dihydro-2-oxo-2H-pyran-4-carboxylic(3),N-acetyl-hydrazinobenzoic acid(4),and methyl 2-(2,5-dihydroxyphenyl)acetate(5).Conclusion:Compound 3 is a new compound.Compounds 3 and 4 may have potential activators of catalase,providing a theoretical basis for the development of CAT activators.

Clinical analysis of CHD2 gene mutations in pediatric patients with epilepsy

Importance:CHD2 is a member of the chromodomain helicase DNA-binding(CHD)family of proteins,which have important roles in the regulation of gene expression.Dysregulation of this protein may lead to various disorders.Objective:To delineate the genotypes and phenotypes of CHD2-related epilepsy.Methods:We analyzed the medical history,magnetic resonance imaging findings,and video-electroencephalogram recordings of 17 patients withCHD2 mutations in the Neurology Department of Beijing Children’s Hospital from June 2016 to June 2021.Results:Age at seizure onset ranged from 6 months to 10 years;the median age at onset was 4 years.Generalized tonic-clonic,myoclonic,eyelid myoclonic,atonic,atypical absence,myoclonic-atonic,and spasm seizures were observed.Ten of the 17 patients had multiple types of seizures.One patient exhibited photosensitivity epilepsy and one patient exhibited grid image-induced visual reflex epilepsy.Developmental disability was present in 14 patients,while autism features were present in five patients.Sixteen patients hadde novo mutations ofCHD2;one patient had an inherited variant.Eleven mutations were novel.One patient had two mutations;that patient exhibited development delay and refractory epilepsy.Seizures were controlled in eight patients,improved in seven patients,and resistant to treatment in two patients.Interpretation:Phenotype severity in patients withCHD2 variants ranged from drug-responsive seizures to severe epileptic encephalopathy.Most patients exhibited developmental disorders.

Chinese patients with p.Arg756 mutations of ATP1A3: Clinical manifestations, treatment, and follow-up

Importance:The phenotypes of ATP1A3 gene mutations are diverse.Relapsing encephalopathy with cerebellar ataxia and fever-induced paroxysmal weakness and encephalopathy(FIPWE)are considered non-classical phenotypes caused by p.Arg756 mutations of ATP1A3.Objective:To summarize the clinical manifestations,treatment,and followup of Chinese patients with p.Arg756 mutations of ATP1A3.Methods:We analyzed the clinical features,treatment,and genotypes of eight children with p.Arg756 mutations of ATP1A3 who were treated in Beijing Children’s Hospital from January 2014 to December 2019.Results:Eight patients(six boys and two girls)were included;seven had been misdiagnosed with encephalitis.The age of onset ranged from 0.8 to 4.5 years.All patients had encephalopathy and had at least one episode of FIPWE.Cerebellar ataxia was present in nine episodes.Reversible splenial lesions of the corpus callosum were found in two patients in the acute phase.Three types of heterozygous ATP1A3 mutations were found:c.2267G>T(p.R756L)(patient 3[P3]),c.2266C>T(p.R756C)(P2 and P4),and c.2267G>A(p.R756H)(P1,P5,P6,P7,and P8).Six mutations were de novo;two mutations were inherited.Both patients with p.R756C and one patient(P7)with p.R756H had four episodes of severe ataxia as the main manifestations.However,in the other three episodes,limb weakness was more prominent than ataxia.P5 with p.R756H exhibited overlap with FIPWE and rapid-onset dystonia-parkinsonism.Interpretation:Acute encephalopathy followed by febrile disease was characteristic of the disease in patients with p.Arg756 mutations of ATP1A3.However,the weakness and ataxia were variable.Phenotypic crossover and overlap were observed among these patients.

A 5-year-old child presenting with tumor-like primary angiitis of the central nervous system

Introduction:Primary angiitis of the central nervous system(PACNS)is a vasculitis confined to the CNS.A small proportion of the lesions may present as a tumor-like mass,which is rarely seen in children.Case presentation:A 5-year-old girl was admitted to our hospital because of an intermittent headache.Brain imaging suggested a space-occupying lesion in the right cerebral hemisphere.The final diagnosis was PACNS with a lymphocytic pattern by stereotactic brain biopsy.Her condition improved after immunotherapy.Conclusion:Pediatricians should consider the possibility of PACNS when encountering intracranial tumor-like lesions.Early diagnosis of tumor-like PACNS and prompt immunotherapy could improve the long-term prognosis and avoid surgery.

Cerebral small vessel disease caused by PLOD3 mutation:Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency

Introduction:Pathogenic variants inPLOD3,encoding lysyl hydroxylase-3(LH3),can cause a hereditary connective tissue disorder that has rarely been reported.It is a multi-system disease,presenting with craniofacial dysmorphisms,skeletal and eye manifestations,sensorineural hearing loss,and variable skin manifestations.Severe central nervous system involvement has not been reported.Case presentation:A 10-month-old girl was admitted with development delay and clustered epileptic spasms.Hypertelorism,an upturned nose,and low-set ears were noted in physical examination.Cerebral magnetic resonance imaging showed multiple intracranial malacias and bleeding foci,extensive abnormal signals in the white matter,and obvious brain atrophy,which was consistent with cerebral small vessel disease(SVD).Electroencephalography suggested hypsarrhythmia.The vertebrae were flattened.The distal end of the metacarpal bone in the left hand was irregular.She was diagnosed with West syndrome.Whole-exome sequencing revealed a novel homozygous variant of c.12161218delCTC(p.L406del)inPLOD3,which was found to be inherited from her heterozygous parents.Conclusion:We report a patient with pathogenicPLOD3 mutation who presented with cerebral SVD.This report expands the phenotypic spectrum of LH3 deficiency.

Epidermal growth factor receptor stabilizes programmed death ligand 1 by glycosylation in colorectal cancer with microstatellite instability status

Programmed death ligand-1(PD-L1)is involved in inhibiting of T lymphocyte proliferation,producing cytokine,cytolytic activity,and suppressing of the immune response.Genes with molecular alterations involved in DNA mismatch repair promote cancer initiation and tumor progression.Clinical studies show that colorectal cancer(CRC)patients harboring microsatellite instability(MSI)have a higher anti-programmed cell death protein 1/PD-L1 immunotherapy response ratio compared with microsatellite stable subgroup patients.The underlying mechanism has however remained unclear.Here,we found that compared with microsatellite stable samples,PD-L1 was glycosylated and highly expressed both in MSI CRC cell lines and tissue samples.Specifically,PD-L1 was Nglycosylated at its N35,N192,N200,and N219 sites,and the four glycosylation sites were all responsible for PD-L1 degradation.Additionally,non-glycosylated PD-L1 underwent rapid degradation compared with glycosylated PD-L1 through the 26S proteasome pathway.The faster degradation of the non-glycosylated PD-L1 was ascribed to its binding to glycogen synthase kinase 3b via ubiquitination.This degradation phenotype was,however,not observed for glycosylated PD-L1.Significantly,glycosylated PD-L1 was up-regulated by activated epidermal growth factor receptor in MSI CRC cells.Together,our results indicate that epidermal growth factor receptor stabilized PD-L1 via glycosylation in MSI CRC cells,uncovering a novel role of PD-L1 in MSI CRC immunosuppression and disease progression.The study was approved by the Clinical Ethics Review Committee at the Six Affiliated Hospital of Sun Yat-sen University,China(Approval No.2019ZSLYEC-005).