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Two novel mutations in theGAN gene causing giant axonal neuropathy

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World Journal of Pediatrics 2018年第3期14卷 298-304页

作者： Monica Irad Normendez-Martínez Lucero Monterde-Cruz Roberto Martínez magdalena marquez-harper Nayelli Esquitin-Garduno Margarita Valdes-Flores Leonora Casas-Avila Valeria Ponce de Leon-Suarez Viktor Javier Romero-Díaz Alberto Hidalgo-Bravo Medical Specialties Hospital Boulevard Milenio 130San Carlos la Roncha37660 LeonGuanajuatoMexico Department of Gene tics National Institute of R ehabilitationAvenue Mexico-Xochimilco 28914389 Me xico CityMexico Department ofHis tology School ofMedicineAutonomous University oft heS tate ofN uevo LeonMonterreyMexico

Background Giant axonal neuropathy (GAN) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. This disorder presents motor and sensitive symptoms with an onset in early childhood. Progressive neurodegeneration makes the patients wheelchair dependent by the end of the second decade of life. Affected individuals do not survive beyond the third decade of life. Molecular analysis has identified mutations in the gene GAN in patients with this disorder. This gene produces a protein called gigaxonin which is presumably involved in protein degradation via the ubiquitin-proteasome system. However, the underlying molecular mechanism is not clearly understood yet. Methods Here we present the fi rst patient from Mexico with clinical data suggesting GAN. Sequencing of the GAN gene was carried out. Changes in the nucleotide sequence were investigated for their possible impact on protein function and structure using the publicly available prediction tools PolyPhen-2 and PANTHER. Results The patient is a compound heterozygous carrying two novel mutations in the GAN gene. The sequence analy-sis revealed two missense mutations in the Kelch repeats domain. In one allele, a C>T transition was found in exon 9 at the nucleotide position 55393 (g.55393C>T). In the other allele, a transversion G>T in exon 11 at the nucleotide position 67471 (g.67471G>T) was observed. Both of the bioinformatic tools predicted that these amino acid substitutions would have a negative impact on gigaxonin's function. Conclusion This work provides useful information for health professionals and expands the spectrum of disease-causing mutations in the GAN gene and it is the first documented case in Mexican population.

关键词： GAN Genetics Giant axonal neuropathy Incapacity Neurodegenerative

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“末日焦虑”再次来袭

世界科学 2024年第5期 50-53页

作者：陈洁培泰勒·奥斯汀·哈珀贝茨学院

“你认为我们需要购买枪支吗？”一名学生的问题仿佛使得房间里的温度骤降了几度。当时，我正和其他几位学者、学生以及一位演讲嘉宾共进晚餐。这位演讲嘉宾刚刚发表了一个令人振奋的关于气候正义的演讲。这名学生看到大家困惑不解，继...

“你认为我们需要购买枪支吗？”一名学生的问题仿佛使得房间里的温度骤降了几度。当时，我正和其他几位学者、学生以及一位演讲嘉宾共进晚餐。这位演讲嘉宾刚刚发表了一个令人振奋的关于气候正义的演讲。这名学生看到大家困惑不解，继续澄清道：如果大灾难在短期内不可避免，这意味着人们很快将不得不生活在有围墙的社区里。到时，执政人员都会配枪。她只是想知道应该如何保护自己关心的人。演讲嘉宾花了一点时间消化了这些信息，然后建议这名学生多关心种植蔬菜，而不是购买枪支。

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Fiduciary Responsibility: Facilitating Public Trust in Automated Decision Making

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Journal of Social Computing 2022年第4期3卷 345-362页

作者： Shannon B.harper Eric S.Weber Department of Sociology and Criminal Justice Iowa State UniversityAmesIA 50011USA. Department of Mathematics Iowa State UniversityAmesIA 50011USA.

Automated decision-making systems are being increasingly deployed and affect the public in a multitude of positive and negative ways.Governmental and private institutions use these systems to process information according to certain human-devised rules in order to address social problems or organizational challenges.Both research and real-world experience indicate that the public lacks trust in automated decision-making systems and the institutions that deploy them.The recreancy theorem argues that the public is more likely to trust and support decisions made or influenced by automated decision-making systems if the institutions that administer them meet their fiduciary responsibility.However,often the public is never informed of how these systems operate and resultant institutional decisions are made.A“black box”effect of automated decision-making systems reduces the public’s perceptions of integrity and trustworthiness.Consequently,the institutions administering these systems are less able to assess whether the decisions are just.The result is that the public loses the capacity to identify,challenge,and rectify unfairness or the costs associated with the loss of public goods or benefits.The current position paper defines and explains the role of fiduciary responsibility within an automated decision-making system.We formulate an automated decision-making system as a data science lifecycle(DSL)and examine the implications of fiduciary responsibility within the context of the DSL.Fiduciary responsibility within DSLs provides a methodology for addressing the public’s lack of trust in automated decision-making systems and the institutions that employ them to make decisions affecting the public.We posit that fiduciary responsibility manifests in several contexts of a DSL,each of which requires its own mitigation of sources of mistrust.To instantiate fiduciary responsibility,a Los Angeles Police Department(LAPD)predictive policing case study is examined.We examine the development and deployment by the LAPD of predicti

关键词： trust artificial intelligence automated decision-making recreancy theorem fiduciary responsibility

The demands of the extra-time period of soccer:A systematic review

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Journal of Sport and Health Science 2022年第3期11卷 403-414页

作者： Adam Field Robert Joseph Naughton Matthew Haines Steve Lui Liam David Corr Mark Russell Richard Michael Page Liam David harper School of Human and Health Sciences University of HuddersfieldHuddersfieldHD13DHUK School of Social and Health Sciences Leeds Trinity UniversityBrownberrie LaneHorsforthLeedsLS185HDUK Department of Sport&Physical Activity Edge Hill UniversitySt.Helens RoadOrmskirkLancashireL394QPUK

Background:Soccer match-play is typically contested over 90 min;however,in some cup and tournament scenarios,when matches are tied,they proceed to an additional 30 min,which is termed "extra-time^(ET).This systematic review sought to appraise the literature available on 120-min of soccer-specific exercise,with a view to identifying practical recommendations and future research opportunities.Methods:The review was conducted according to the PRISMA guidelines.Independent researchers performed a systematic search of PubMed,CINAHL,and PsycINFO in May 2019,with the following keywords entered in various combinations:"soccer","football","extra-time","extra time","extratime","120 minutes","120 min","additional 30 minutes",and "additional 30 min".Results:The search yielded an initial 73 articles.Following the screening process,11 articles were accepted for analyses.Articles were subsequently organized into the following 5 categories:movement demands of ET,performance responses to ET,physiological and neuromuscular response during ET,nutritional interventions,and recovery and ET.The results highlighted that during competitive match-play,players cover5%-12% less distance relative to match duration(i.e.,meters per minute) during ET compared to the preceding 90 min.Reductions in technical performance(i.e.,shot speed,number of passes and dribbles) were also observed during ET.Additionally,carbohydrate provision may attenuate and improve dribbling performance during ET.Moreover,objective and subjective measures of recovery may be further compromised following ET when compared to 90 min.Conclusion:Additional investigations are warranted to further substantiate these findings and identify interventions to improve performance during ET.

关键词： Movement demands Neuromuscular fatigue Nutritional intervention Performance Physiology

Recent Advances in the Science of Burst Wave Lithotripsy and Ultrasonic Propulsion

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Biomedical Engineering Frontiers 2022年第1期3卷 48-53页

作者： Dima Raskolnikov Michael R.Bailey Jonathan D.harper Department of Urology University of Washington School of MedicineSeattleWAUSA Center for Industrial and Medical Ultrasound Applied Physics LaboratoryUniversity of WashingtonSeattleWAUSA

Nephrolithiasis is a common,painful condition that requires surgery in many patients whose stones do not pass spontaneously.Recent technologic advances have enabled the use of ultrasonic propulsion to reposition stones within the urinary tract,either to relieve symptoms or facilitate treatment.Burst wave lithotripsy(BWL)has emerged as a noninvasive technique to fragment stones in awake patients without significant pain or renal injury.We review the preclinical and human studies that have explored the use of these two technologies.We envision that BWL will fill an unmet need for the noninvasive treatment of patients with nephrolithiasis.

关键词： urinary surgery advances

The TNFα/TNFR2 axis mediates natural killer cell proliferation by promoting aerobic glycolysis

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Cellular & Molecular Immunology 2023年第10期20卷 1140-1155页

作者： Abrar Ul Haq Khan Alaa Kassim Ali Bryan Marr Donghyeon Jo Simin Ahmadvand Claire Fong-McMaster Saeedah Musaed Almutairi Lisheng Wang Subash Sad Mary-Ellen harper Seung-Hwan Lee Department of Biochemistry Microbiologyand ImmunologyFaculty of MedicineUniversity of OttawaOttawaONCanada The University of Ottawa Centre for Infection Immunityand InflammationOttawaONCanada Botany and Microbiology Department College of SciencesKing Saud UniversityRiyadhSaudi Arabia

Natural killer(NK)cells are predominant innate lymphocytes that initiate the early immune response during infection.NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection.Tumor necrosis factor-alpha(TNFα)is a well-known inflammatory cytokine that enhances NK cell function;however,the mechanism underlying NK cell proliferation in response to TNFαis not well established.Here,we demonstrated that upon infection/inflammation,NK cells upregulate the expression of TNF receptor 2(TNFR2),which is associated with increased proliferation,metabolic activity,and effector function.Notably,IL-18 can induce TNFR2 expression in NK cells,augmenting their sensitivity toward TNFα.Mechanistically,TNFα-TNFR2 signaling upregulates the expression of CD25(IL-2Rα)and nutrient transporters in NK cells,leading to a metabolic switch toward aerobic glycolysis.Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice.Accordingly,our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis,leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo.Collectively,our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation,glycolysis,and effector function.

关键词： Natural killer cells TNFa TNFR2 Glycolysis Proliferation Murine cytomegalovirus

Task sharing: situation analysis about capacity and resources for management of diabetic retinopathy in Pakistan

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International Journal of Ophthalmology(English edition) 2019年第5期12卷 809-814页

作者： Mufarriq Shah Ayesha Noor C Alex harper Jill Elizabeth Keeffe Pakistan Institute of Community Ophthalmology Hayatabad Medical Complex Vision and Dental Care Clinic Centre for Eye Research Australia Department of OphthalmologyUniversity of Melbourneand Royal Victorian Eye and Ear Hospital LV Prasad Eye Institute

AIM: To assess the capacity and resources of eye care facilities, using the WHO Health Systems Framework, to manage diabetic retinopathy(DR) through task sharing.METHODS: Using purposive sampling, four participants(administrators) from four selected hospitals in two provinces in Pakistan were recruited for this cross-sectional study. A survey, to assess the capacity and resources of the selected eye care facilities for the feasibility to adopt task sharing in management of DR to prevent vision loss, was emailed to participants who were asked to complete. Responses to open-ended questions were entered into a Microsoft Excel spread sheet and inductive approach was applied for analysis.RESULTS: All the surveyed eye care facilities offer eye care services for people with diabetes and DR. All surveyed eye care facilities have a shortage in the number of human resources across all cadres. Optometrists and mid-level eye care workers did not have active roles in DR screening and management in all four hospitals. All the hospitals surveyed did not have a computerized record management system for patients who visit ophthalmologists for eye examinations. Equipment for detection and management of DR were short in number and main users were ophthalmologists. There was no policy for population-based screening program for detection of DR in any of the surveyed hospitals.CONCLUSION: A system-based approach to manage DR is needed. The capacity of eye care facilities and the potential to improve access of people with diabetes to eyecare services can be enhanced through implementation of task sharing.

关键词： task sharing capacity diabetes diabetic retinopathy Pakistan

Controlling human platelet activation with calcium-binding nanoparticles

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Nano Research 2020年第10期13卷 2697-2705页

作者： David Cabrera Karen Walker Sandhya Moise Neil D.Telling Alan G.S.harper School of Pharmacy and Bioengineering Keele UniversityGuy Hilton Research CenireThormburrow DriveHartshill Stoke-on Trent ST47QBUK ?Central Electron Microscope Unit School of Life SciencesKeele UniversityNewcastle-under LIymeStaffordshireST55BGUK Department of Chemical Engineering University of BathBath BA27AYUK School of Medicine Keele UniversityNewcastle-under-LymeStaffordshireST55BGUK

Human platelets aggregate at sites of blood vessel damage in response to a rise in their cytosolic calcium concentration.Controlling these cytosolic calcium rises would provide a method to inhibit platelet activation and prevent the unwanted blood clots that causes heart attack and strokes.Previously we have predicted that calcium accumulation within the lumen of an infolded portion of the platelet plasma membrane called the open canalicular system(OCS)is essential for maintaining this cytosolic calcium rise.Due to its nanometer dimensions of the OCS,it has been difficult to measure or interfere with the predicted luminal calcium accumulation.Here we utilise iron oxide magnetic nanoparticles coated with the known calcium chelator,citrate,to create calcium-binding nanoparticles.These were used to assess whether an OCS calcium store plays a role in controlling the dynamics of human platelet activation and aggregation.We demonstrate that citrate-coated nanoparticles are rapidly and selectively uptaken into the OCS of activated human platelets,where they act to buffer the accumulation of calcium there.Treatment with these calcium-binding nanoparticles reduced thrombin-evoked cytosolic calcium rises,and slowed platelet aggregation and clot retraction in human platelets.In contrast,nanoparticles that cannot bind calcium have no effect.This study demonstrates that the OCS acts as a key source of calcium for maintaining cytosolic calcium rises and accelerating platelet aggregation,and that calcium-binding nanoparticles targeted to the OCS could provide an anti-platelet therapy to treat patients at risk of suffering heart attacks or strokes.

关键词： nanochelators human platelets open canalicular system calcium signaling nanoparticles

The Golden Spike Still Glitters:The(Re)construction of a Global Chronostratigraphy

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Acta Geologica Sinica(English Edition) 2019年第S1期93卷 24-27页

作者： David A.T.harper Palaeoecosystems Group Department of Earth SciencesDurham UniversityDurham DH13LEUK

1 Introduction Stratigraphy,placing the sequence of events in Earth history into order,is a fundamental part of the geosciences.Traditionally the starting point is a regional stratigraphy,based on lithological,mappable units,correlated by fossils with local,regional and global chronostratigraphical schemes.Chronostratigraphic units were traditionally defined on their fossil content,as essentially unit stratotypes.But,commonly there were no clear boundaries.

关键词： stratigraphy biostratigraphy GSSPs milankovitch cycles timescale