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Purines:From Diagnostic Biomarkers to Therapeutic Agents in Brain Injury

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Neuroscience Bulletin 2020年第11期36卷 1315-1326页

作者： Bruno G.Frenguelli Nicholas Dale School of Life Sciences The University WarwickCoventry CV47ALUK

The purines constitute a family of inter-related compounds that serve a broad range of important intracellular and extracellular biological *** particular,adenosine triphosphate(ATP)and its metabolite and precursor,adenosine,regulate a wide variety of cellular and systems-level physiological processes extending from ATP acting as the cellular energy currency,to the adenosine arising from the depletion of cellular ATP and responding to reduce energy demand and hence to preserve ATP during times of metabolic *** inter-relationship provides opportunities for both the diagnosis of energy depletion during conditions such as stroke,and the replenishment of ATP after such *** this review we address these opportunities and the broad potential of purines as diagnostics and restorative agents.

关键词： Purines Adenosine ATP Biomarker Stroke Cerebral ischemia Traumatic brain injury Adenine D-ribose

High efficacy of chlorfenapyr-based net Interceptor■G2 against pyrethroid-resistant malaria vectors from Cameroon

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Infectious Diseases of Poverty 2023年第4期12卷 1-16页

作者： Magellan Tchouakui Riccado F.Thiomela Elysee Nchoutpouen Benjamin D.Menze Cyrille Ndo Dorothy Achu Raymond N.Tabue Flobert Njiokou Ateba Joel Charles S.Wondji Centre for Research in Infectious Diseases(CRID) P.O.Box 13501YaoundéCameroon Department of Animal Biology and Physiology Faculty of ScienceUniversity of Yaoundé1P.O.Box 812YaoundéCameroon Department of Biological Sciences Faculty of Medicine and Pharmaceutical SciencesUniversity of DoualaP.O.Box 24157DoualaCameroon Ministry of Public Health National Malaria Control ProgrammeP.O.Box 14386YaoundeCameroon Department of Vector Biology Liverpool School of Tropical MedicinePembroke PlaceLiverpoolL35QAUK International Institute of Tropical Agriculture(IITA) P.O.Box 2008YaoundéCameroon

Background The increasing reports of resistance to pyrethroid insecticides associated with reduced efficacy of pyrethroid-only interventions highlight the urgency of introducing new non-pyrethroid-only control ***,we investigated the performance of piperonyl-butoxide(PBO)-pyrethroid[Permanet 3.0(P3.0)]and dual active ingredients(AI)nets[Interceptor G2(IG2):containing pyrethroids and chlorfenapyr and Royal Guard(RG):containing pyrethroids and pyriproxyfen]compared to pyrethroid-only net Royal Sentry(RS)against pyrethroid-resistant malaria vectors in *** The efficacy of these tools was firstly evaluated onAnopheles gambiae *** funestus *** Gounougou,Mibellon,Mangoum,Nkolondom,and Elende using cone/tunnel *** addition,experimental hut trials(EHT)were performed to evaluate the performance of unwashed and 20 times washed nets in semi-field ***,pyrethroid-resistant markers were genotyped in dead vs alive,blood-fed vs unfed mosquitoes after exposure to the nets to evaluate the impact of these markers on net *** XLSTAT software was used to calculate the various entomological outcomes and the Chi-square test was used to compare the efficacy of various *** odds ratio and Fisher exact test were then used to establish the statistical significance of any association between insecticide resistance markers and bed net *** Interceptor G2 was the most effective net against wild *** followed by Permanet *** EHT,this net induced up to 87.8%mortality[95%confidence interval(CI):83.5-92.1%)and 55.6%(95%CI:48.5-62.7%)after 20 washes whilst unwashed pyrethroid-only net(Royal Sentry)killed just 18.2%(95%CI:13.4-22.9%)of *** unwashed Permanet 3.0 killed up to 53.8%(95%CI:44.3-63.4%)of field-resistant mosquitoes and 47.2%(95%CI:37.7-56.7%)when washed 20 times,and the Royal Guard 13.2%(95%CI:9.0-17.3%)for unwashed net and 8.5%(95%CI:5.7-11.4%)for t

关键词： Malaria Anopheles Insecticide resistance Dual active ingredient nets Interceptor G2

Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

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Frontiers of Chemical Science and Engineering 2016年第2期10卷 186-195页

作者： Andrew Best Katherine James Gerald Hysenaj Alison Tyson-Capper David J. Elliott Institute of Genetic Medicine Newcastle University Newcastle NE1 3BZ UK Interdisciplinary Computing and Complex BioSystems Research Group and Centre for Bacterial Cell Biology Newcastle University Newcastle NE1 3BZ UK Institute for Cellular Medicine Newcastle University Newcastle NE2 4HH UK

Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and the highly similar Tra2a protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2fl reduces splicing inclu- sion of a poison exon in the mRNA encoding Tra2a, thereby up-regulating Tra2a protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2fl alone. Discovery of this cross-regulation pathway, and its by-pass by joint deple- tion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 （CHK1） gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.

关键词： RNA splicing gene expression breast cancer,DNA damage CHK1

αβ T cell receptors as predictors of health and disease

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Cellular & Molecular Immunology 2015年第4期12卷 391-399页

作者： Meriem Attaf Eric Huseby Andrew K Sewell Cardiff University School of Medicine Cardiff UK and ZDepartment of Pathology University of Massachusetts Medical School Worcester MA USA Correspondence: Professor AK Sewell Division of Infection and Immunity Cardiff University School of Medicine Henry Wellcome Building University Hospital Wales Cardiff CF14 4XN UK.

The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. It has been known for several decades that T lymphocytes recognize short peptides derived from degraded proteins presented by major histocompatibility complex （MHC） molecules at the cell surface. Interaction between peptide-MHC （pMHC） and the T cell receptor （TCR） is central to both thymic selection and peripheral antigen recognition. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. Finally, we suggest that with the development of high-throughput sequencing, common TCR ＇signatures＇ raised against specific antigens could provide important diagnostic biomarkers and surrogate predictors of disease onset, progression and outcome.

关键词： T cell receptor (TCR) TCR repertoire TCR diversity TCR clonotype TCR bias Deep sequencing

Surgical reconstruction of spinal cord circuit provides functional return in humans

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Neural Regeneration Research 2017年第12期12卷 1960-1963页

作者： Thomas Carlstedt Nicholas James Marten Risling The Wolfson Centre for Age-Related Diseases King's College London Department of Neuroscience Karolinska Institutet

This mini review describes the current surgical strategy for restoring function after traumatic spinal nerve root avulsion in brachial or lumbosacral plexus injury in man. As this lesion is a spinal cord or central nervous injury functional return depends on spinal cord nerve cell growth within the central nervous system. Basic science, clinical research and human application has demonstrated good and useful motor function after ventral root avulsion followed by spinal cord reimplantation. Recently, sensory return could be demonstrated following spinal cord surgery bypassing the injured primary sensory neuron. Experimental data showed that most of the recovery depended on new growth reinnervating peripheral receptors. Restored sensory function and the return of spinal reflex was demonstrated by electrophysiology and functional magnetic resonance imaging of human cortex. This spinal cord surgery is a unique treatment of central nervous system injury resulting in useful functional return. Further improvements will not depend on surgical improvements. Adjuvant therapy aiming at ameliorating the activity in retinoic acid elements in dorsal root ganglion neurons could be a new therapeutic avenue in restoring spinal cord circuits after nerve root avulsion injury.

关键词： plexus injury root avulsion spinal cord surgery motor sensory recovery adjuvant therapy

National prevalence and risk factors for tungiasis in Kenya

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Infectious Diseases of Poverty 2023年第5期12卷 97-97页

作者： Lynne Elson Christopher Kamau Sammy Koech Christopher Muthama George Gachomba Erastus Sinoti Elwyn Chondo Eliud Mburu Miriam Wakio Jimmy Lore Marta Maia Ifedayo Adetifa Benedict Orindi Phillip Bejon Ulrike Fillinger Kenya Medical Research Institute-wellcome trust Research Programme Kilifi Kenya Nuffield Department of Medicine University of Oxford Oxford UK Department of Health Muranga Kenya Department of Health Kericho Kenya Department of Health Makueni Kenya Department of Health Nakuru Kenya Department of Health Samburu Kenya Department of Health Kilifi Kenya Department of Health Kajiado Kenya Department of Health Taita Taveta Kenya Department of Health Turkana Kenya London School of Hygiene and Tropical Medicine London UK International Centre for Insect Physiology and Ecology (Icipe) Nairobi Kenya

Background Tungiasis is a highly neglected tropical skin disease caused by the sand flea,Tunga penetrans,the female of which burrows into the skin,causing pain and *** disease occurs throughout South America and sub-Saharan Africa but there are few systematic data on national disease *** tungiasis research community is keen to develop survey methods to fill this *** we used a school-based,thorough examination method to determine the prevalence and risk factors for tungiasis in *** We conducted the first nationally representative survey of tungiasis,including nine counties covering the major ecological zones of Kenya.A stratified multistage random sampling was used to select 22 primary schools from each of the nine counties and to select up to 114 pupils aged 8 to 14 years in each *** were examined thoroughly for *** surveys were conducted,the first between May and July 2021 and the second between October 2021 and April 2023 when pupils were also interviewed for risk *** effect logistic regression models were used to test associations of independent variables with tungiasis using the school as a random *** The overall prevalence of tungiasis in the first survey was 1.35%[95%confidence interval(CI):1.15-1.59%],and 0.89%in the second *** prevalence ranged from 0.08%(95%CI:0.01-0.59%)in Taita Taveta county to 3.24%(95%CI:2.35-4.44%)in Kajiado *** infection was associated with county of residence,male sex[adjusted odds ratio(aOR)=2.01,95%CI:1.52-2.67],and lower age(aOR=0.81,95%CI:0.75-0.88).For the first time we demonstrate an association with attending public schools rather than private schools(aOR=5.62,95%CI:1.20-26.22)and lower socioeconomic status(aOR=0.10,95%CI:0.03-0.33).Using a rapid screening method of the top of feet only,would have missed 62.9%of all cases,78.9%of mild cases and 20.0%of severe *** Tungiasis is widely but heterogeneously distributed across K

关键词： Tungiasis Neglected tropical diseases Prevalence Disease burden Kenya

Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease

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World Journal of Hepatology 2023年第12期15卷 1272-1283页

作者： Sana Raza Sangam Rajak Rajani Singh Jin Zhou Rohit A Sinha Amit Goel Department of Endocrinology Sanjay Gandhi Postgraduate Institute of Medical SciencesUttar PradeshLucknow 226014India Department of Hepatology Sanjay Gandhi Postgraduate Institute of Medical SciencesUttar PradeshLucknow 226014India CVMD Duke-NUS Medical SchoolSingapore 169857Singapore

Autophagy,a cellular degradative process,has emerged as a key regulator of cellular energy production and stress *** autophagy is a common phenomenon observed in several human diseases,and its restoration offers curative ***-alcoholic fatty liver disease(NAFLD),more recently renamed metabolic dysfunction-associated steatotic liver disease,is a major metabolic liver disease affecting almost 30%of the world ***,NAFLD has no pharmacological therapies available to *** regulates several hepatic processes including lipid metabolism,inflammation,cellular integrity and cellular plasticity in both parenchymal(hepatocytes)and non-parenchymal cells(Kupffer cells,hepatic stellate cells and sinusoidal endothelial cells)with a profound impact on NAFLD *** cell type-specific autophagy in the liver is essential in order to develop targeted treatments for liver diseases such as *** autophagy in specific cell types can have varying effects on liver function and pathology,making it a promising area of research for liver-related *** review aims to summarize our present understanding of cell-type specific effects of autophagy and their implications in developing autophagy centric therapies for NAFLD.

关键词： Autophagy Non-alcoholic fatty liver disease Hepatocytes Macrophages Hepatic stellate cells

Protein synthesis,degradation,and energy metabolism in T cell immunity

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Cellular & Molecular Immunology 2022年第3期19卷 303-315页

作者： Julia M.Marchingo Doreen A.Cantrell Cell Signalling and Immunology Division School of Life SciencesUniversity of DundeeDundeeDD15EHUK

T cell activation,proliferation,and differentiation into effector and memory states involve massive remodeling of T cell size and molecular content and create a massive increase in demand for energy and amino *** synthesis is an energy-and resource-demanding process;as such,changes in T cell energy production are intrinsically linked to proteome *** this review,we discuss how protein synthesis and degradation change over the course of a T cell immune response and the crosstalk between these processes and T cell energy *** highlight how the use of high-resolution mass spectrometry to analyze T cell proteomes can improve our understanding of how these processes are regulated.

关键词： T lymphocyte Protein Translation Proteomics Immunometabolism Protein degradation

Extracellular DNA and autoimmune diseases

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Cellular & Molecular Immunology 2018年第8期15卷 746-755页

作者： Hantao Lou Matthew C Pickering Molecular Immunology Imperial College LondonLondon W120NNUK Centre for Complement and Inflammation Research Imperial College LondonLondon W120NNUK

Extracellular DNA is secreted from various sources including apoptotic cells,NETotic neutrophils and bacterial *** DNA can stimulate innate immune responses to induce type-I IFN production after being *** process is central in antiviral responses but it also plays important role in the pathogenesis of a range of autoimmune diseases such as systemic lupus *** discuss the recent advances in the understanding of the role of extracellular DNA,released from apoptotic and NETotic cells,in autoimmunity.

关键词： DNA type I IFN autoimmunity