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The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis

Neural Regeneration Research 2020年第12期15卷 2186-2194页

作者： Adriana Delice Foster sarah lyn rea Harry Perkins Institute of Medical Research University of Western Australia Perron Institute for Neurological and Translational Science Centre for Neuromuscular and Neurological DisordersThe University of Western AustraliaNedlandsWestern AustraliaAustralia Centre for Molecular Medicine and Innovative Therapeutics Murdoch University Murdoch Western Australia Australia

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic,pathological and clinical overlap.One such overlap is the presence of SQSTM1/p62 mutations.While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget’s disease of bone,mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients.p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system,and also regulates cell survival via the Nrf2 antioxidant response pathway,the nuclear factor-kappa B signaling pathway and apoptosis.Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration,and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis.In this review we discuss the role of p62 in these pathways,the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1,in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis.

关键词： aggregate/inclusion body formation amyotrophic lateral sclerosis-frontotemporal lobar degeneration autophagy cell signaling mitophagy p62/SQSTM1 protein degradation

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Novel,non-colonizing,single-strain live biotherapeutic product ADS024 protects against Clostridioides difficile infection challenge in vivo

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世界胃肠病理生理学杂志:英文版(电子版) 2023年第4期14卷 71-85页

作者： Christopher K Murphy Michelle M O’Donnell James W Hegarty sarah Schulz Colin Hill R Paul Ross Mary C rea Ronald Farquhar Laurent Chesnel Research and Development Adiso Therapeutics Inc.ConcordMA 01742United States APC Microbiome Ireland University College CorkCork T12 K8AFIreland Teagasc Food Research Centre Moorepark FermoyCork P61 C996Ireland Executive Leadership Team Adiso Therapeutics Inc.ConcordMA 01742United States

BACKGROUND The Centers for Disease Control and Prevention estimate that Clostridioides difficile(C.difficile)causes half a million infections(CDI)annually and is a major cause of total infectious disease death in the United States,causing inflammation of the colon and potentially deadly diarrhea.We recently reported the isolation of ADS024,a Bacillus velezensis(B.velezensis)strain,which demonstrated direct in vitro bactericidal activity against C.difficile,with minimal collateral impact on other members of the gut microbiota.In this study,we hypothesized that in vitro activities of ADS024 will translate in vivo to protect against CDI challenge in mouse models.AIM To investigate the in vivo efficacy of B.velezensis ADS024 in protecting against CDI challenge in mouse models.METHODS To mimic disruption of the gut microbiota,the mice were exposed to vancomycin prior to dosing with ADS024.For the mouse single-dose study,the recovery of ADS024 was assessed via microbiological analysis of intestinal and fecal samples at 4 h,8 h,and 24 h after a single oral dose of 5×108 colony-forming units(CFU)/mouse of freshly grown ADS024.The single-dose study in miniature swine included groups that had been pre-dosed with vancomycin and that had been exposed to a dose range of ADS024,and a group that was not pre-dosed with vancomycin and received a single dose of ADS024.The ADS024 colonies[assessed by quantitative polymerase chain reaction(qPCR)using ADS024-specific primers]were counted on agar plates.For the 28-d miniature swine study,qPCR was used to measure ADS024 levels from fecal samples after oral administration of ADS024 capsules containing 5×109 CFU for 28 consecutive days,followed by MiSeq compositional sequencing and bioinformatic analyses to measure the impact of ADS024 on microbiota.Two studies were performed to determine the efficacy of ADS024 in a mouse model of CDI:Study 1 to determine the effects of fresh ADS024 culture and ADS024 spore preparations on the clinical manifestations of CDI in mice,and Study 2 to compare

关键词： Gut Single-strain live biotherapeutic product ADS024 Clostridioides difficile Clostridioides difficile challenge model Microbiota

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Long-term mental health outcomes after unintentional burns sustained during childhood:a retrospective cohort study

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Burns & Trauma 2018年第4期6卷 269-278页

作者： Janine M.Duke Sean M.Randall Thirthar P.Vetrichevvel sarah McGarry James H.Boyd Suzanne rea Fiona M.Wood Burn Injury Research Unit Faculty Health and Medical SciencesThe University of Western AustraliaM31835 Stirling HighwayCrawleyPerthWestern Australia 6009Australia Centre for Data Linkage Curtin UniversityPerthWestern AustraliaAustralia Curtin Medical School Curtin UniversityPerthWestern AustraliaAustralia School of Occupational Therapy Social work and Speech Pathology Curtin UniversityPerthWestern AustraliaAustralia Burns Service of Western Australia Royal Perth Hospital and Princess Margaret HospitalPerthWestern AustraliaAustralia

Background:Burns are a devastating injury that can cause physical and psychological issues. Limited data exist on long-term mental health (MH) after unintentional burns sustained during childhood. This study assessed long-term MH admissions after paediatric burns. Methods:This retrospective cohort study included all children (<18 years) hospitalised for a first burn (n=11,967) in Western Australia, 1980–2012, and a frequency matched uninjured comparison cohort (n=46,548). Linked hospital, MH and death data were examined. Multivariable negative binomial regression modelling was used to generate incidence rate ratios (IRR) and 95%confidence intervals (CI). Results:The burn cohort had a significantly higher adjusted rate of post-burn MH admissions compared to the uninjured cohort (IRR, 95%CI:2.55, 2.07–3.15). Post-burn MH admission rates were twice as high for those younger than 5 years at index burn (IRR, 95%CI 2.06, 1.54–2.74), three times higher for those 5–9 years and 15–18 years (IRR, 95%CI:3.21, 1.92–5.37 and 3.37, 2.13–5.33, respectively) and almost five times higher for those aged 10–14 (IRR, 95%CI:4.90, 3.10–7.76), when compared with respective ages of uninjured children. The burn cohort had higher admission rates for mood and anxiety disorders (IRR, 95%CI:2.79, 2.20–3.53), psychotic disorders (IRR, 95%CI:2.82, 1.97–4.03) and mental and behavioural conditions relating to drug and alcohol abuse (IRR, 95%CI:4.25, 3.39–5.32). Conclusions:Ongoing MH support is indicated for paediatric burn patients for a prolonged period after discharge to potentially prevent psychiatric morbidity and associated academic, social and psychological issues.

关键词： Paediatric burns Depression Anxiety Substance abuse Longitudinal study Mental health

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