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Pik3c3 deficiency in myeloid cells imparts partial resistance to experimental autoimmune encephalomyelitis associated with reduced IL-1βproduction

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Cellular & Molecular Immunology 2021年第8期18卷 2024-2039页

作者： Guan Yang Wenqiang Song Jielin Xu JLuke Postoak Feixiong Cheng jennifer martinez Jianhua Zhang Lan Wu Luc Van Kaer Department of Pathology Microbiology and ImmunologyVanderbilt University School of MedicineNashvilleTN37232USA Genomic Medicine Institute Lerner Research InstituteCleveland ClinicClevelandOH44195USA Department of Molecular Medicine Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandOH44195USA Case Comprehensive Cancer Center Case Western Reserve University School of MedicineClevelandOH44106USA Immunity Inflammationand Disease LaboratoryNational Institute of Environmental Health SciencesResearch Triangle ParkDurhamNC27709USA Department of Pathology University of Alabama at BirminghamBirminghamAL35294USA Birmingham Veterans Affairs Medical Center BirminghamAL35233USA

The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase(PtdIns3K)complex plays a role in both canonical and noncanonical autophagy,key processes that control immune-cell responsiveness to a variety of *** previous studies found that PIK3C3 is a critical regulator that controls the development,homeostasis,and function of dendritic and T *** this study,we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient *** found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex(MHC)class I and class II *** addition,myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor ***3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery(initiation/nucleation)of the classical autophagy ***,myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis(EAE),a primarily CD4^(^(+))T-cell-mediated mouse model of multiple sclerosis(MS).This disease protection was associated with reduced accumulation of myelin-specific CD4^(^(+))T cells in the central nervous system and decreased myeloid cell IL-1β***,administration of SAR405,a selective PIK3C3 inhibitor,delayed disease ***,our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of *** findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.

关键词： PIK3C3 Autophagy Myeloid cells Experimental autoimmune encephalomyelitis IL-1β

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Lysosome-mediated chemoresistance in acute myeloid leukemia

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Cancer Drug Resistance 2022年第1期5卷 233-244页

作者： Laia Cuesta-Casanovas jennifer Delgado-martinez Josep ***-Masana Jose M.Carbo Lise Clement-Demange Ruth M.Risueno Josep Carreras Leukaemia Research Institute(IJC) Barcelona 08916Spain Faculty of Biosciences Autonomous University of BarcelonaBellaterra(Cerdanyola del Valles)08193Spain Faculty of Pharmacy University of BarcelonaBarcelona 08028Spain Leukos Biotech Muntaner383Barcelona 08036Spain

Despite the outstanding advances in understanding the biology underlying the pathophysiology of acute myeloid leukemia(AML)and the promising preclinical data published lastly,AML treatment still relies on a classic chemotherapy regimen largely unchanged for the past five ***,new drugs have been approved for AML,but the real clinical benefit is still under ***,primary refractory and relapse AML continue to represent the main clinical challenge,as the majority of AML patients will succumb to the disease despite achieving a complete remission during the induction *** such,treatments for chemoresistant AML represent an unmet need in this *** great efforts have been made to decipher the biological basis for leukemogenesis,the mechanism by which AML cells become resistant to chemotherapy is largely *** identification of the signaling pathways involved in resistance may lead to new combinatory therapies or new therapeutic approaches suitable for this subset of *** mechanisms of chemoresistance have been identified,including drug transporters,key secondary messengers,and metabolic ***,no therapeutic approach targeting chemoresistance has succeeded in clinical trials,especially due to broad secondary effects in healthy *** research has highlighted the importance of lysosomes in this ***’key role in resistance to chemotherapy includes the potential to sequester drugs,central metabolic signaling role,and gene expression *** results provide further evidence to support the development of new therapeutic approaches that target lysosomes in AML.

关键词： Lysosome chemoresistance AML lysosomotropic drug lysosomal sequestration refractory AML

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Working toward an integrated plasticity/network framework for repetitive transcranial magnetic stimulation to inform tailored treatments

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Neural Regeneration Research 2024年第7期19卷 1423-1424页

作者： Jessica Moretti jennifer Rodger Experimental and Regenerative Neurosciences School of Biological SciencesUniversity of Western AustraliaCrawleyWAAustralia Brain Plasticity Lab Perron Institute for Neurological and Translational ScienceNedlandsWAAustralia

Non-invasive brain stimulation techniques(NIBS),including repetitive transcranial magnetic stimulation(rTMS) and transcranial electric stim ulation(tES),are increasingly being adopted clinically for treatment of neuropsychiatric and neurological disorders,albeit with varying *** rationale behind the use of NIBS has historically been that stim ulation techniques modulate neuronal activity in the targeted region and consequently induce plasticity which can lead to therapeutic outcomes.

关键词： stimulation transcranial treatment

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Implications of regional identity for neural stem and progenitor cell transplantation in the injured or diseased nervous system

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Neural Regeneration Research 2024年第4期19卷 715-716页

作者： Prakruthi Amar Kumar jennifer N.Dulin Department of Biology Texas A&M UniversityCollege Station Texas A&M Institute for Neuroscience Texas A&M UniversityCollege Station

Neural stem and progenitor cell(NSPC)transpla ntation has emerged as a promising therapeutic strategy for replacing lost neuronal populations and repairing damaged neural circuits following nervous system injury and disease.A great deal of experimental work has investigated the biology of NSPC grafting in preclinical animal models;more recently.

关键词： neural system injured

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Classifying moisture sources associated with snowfall in the mountains of Lesotho

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Journal of Mountain Science 2024年第6期21卷 1941-1953页

作者： Alexi M.MARINAKI jennifer M.FITCHETT School of Geography Archaeology and Environmental StudiesUniversity of the WitwatersrandPrivate Bag X3Wits 2050South Africa

An average of eight snowfall events occur each year in the eastern Lesotho *** snowfall events are typically associated with cut-off low(CoLs)systems and mid-latitude ***,the moisture sources of the snowfall are unclassified and *** Hybrid Single-Particle Lagrangian Integrated Trajectory(HYSPLIT)model,an air mass back trajectory model,has been used to evaluate moisture source waters locally in southern Africa and internationally in China and *** study uses HYSPLIT to determine the source moisture of snow in Lesotho.A list of all 82 snowfall events in Lesotho spanning 2017 to 2022 was compiled using the Snow Report SA Instagram page,including the date and location of snowfall.A 72-hour back trajectory for each snowfall event was initiated for both Afriski and the whole of *** amounts to models of moisture source trajectories for 28 and 82 snowfall days,*** air mass pathways are classified according to their frequency per snowfall event,per month in the snow season,per year and for the full *** this,associated moisture source regions and dominant air mass trajectories were *** study reports that the air mass trajectories associated with Afriski and Lesotho as a whole are very *** most common pathway of air mass trajectories transporting snow-bearing moisture to Lesotho was an inland trajectory from the northern regions of southern *** pathway makes up 16.6%of all trajectories reported and is associated with the Angola Low,the Congo Air Boundary and the *** High Pressure.

关键词： Eastern Lesotho Highlands Afriski Snow Cut-off Lows HYSPLIT Synoptic Climatology

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Exercise and exerkine upregulation:Brain-derived neurotrophic factor as a potential non-pharmacological therapeutic strategy for Parkinson’s disease

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BIOCELL 2024年第5期48卷 693-706页

作者： VIRAAJ VISHNU PRASAD jennifer SALLY SAMSON VENKATACHALAM DEEPA PARVATHI Department of Biomedical Sciences Sri Ramachandra Institute of Higher Education and ResearchChennai600116India

Physical activity and exercise have several beneficial roles in enhancing both physiological and psychological well-being of an *** addition to aiding the regulation of aerobic and anaerobic metabolism,exercise can stimulate the synthesis of exerkine hormones in the circulatory *** several exerkines that have been investigated for their therapeutic potential,Brain-derived neurotrophic factor(BDNF)is considered the most promising candidate,especially in the management of neurodegenerative *** to the ability of physical activity to enhance BDNF synthesis,several experimental studies conducted so far have validated this hypothesis and produced satisfactory results at the pre-clinical *** review highlights some of the recent animal model studies that have evaluated the efficiency of exercise in enhancing BDNF synthesis and promoting neuroprotective ***,this review focuses on understanding the therapeutic benefits of exercise-induced exerkine synthesis as a non-pharmacological strategy in Parkinson’s disease(PD).Regarding physical activity and exerkine induction,the neuromuscular electrical stimulation(NMES)strategy could be considered as an alternate treatment modality for patients affected with PD.

关键词： Exercise therapy Dopaminergic neurons Parkinson’s disease Brain-derived neurotrophic factor Electrical stimulation

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Optimizing artificial intelligence in sepsis management: Opportunities in the present and looking closely to the future

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Journal of Intensive Medicine 2024年第1期4卷 34-45页

作者： Darragh O’Reilly jennifer McGrath Ignacio Martin-Loeches Department of Intensive Care Medicine Multidisciplinary Intensive Care Research Organization(MICRO)St James’HospitalDublinIreland Department of Respiratory Intensive care Hospital ClinicUniversitat de BarcelonaIDIBAPSCIBERESBarcelonaSpain

Sepsis remains a major challenge internationally for healthcare *** incidence is rising due to poor public awareness and delays in its recognition and subsequent *** sepsis,mortality increases with every hour left *** intelligence(AI)is transforming worldwide healthcare delivery at *** review has outlined how AI can augment strategies to address this global disease *** and machine learning(ML)algorithms can analyze vast quantities of increasingly complex clinical datasets from electronic medical records to assist clinicians in diagnosing and treating sepsis earlier than traditional *** review highlights how these models can predict the risk of sepsis and organ failure even before it *** gives providers additional time to plan and execute treatment plans,thereby avoiding increasing complications associated with delayed diagnosis of *** potential for cost savings with AI implementation is also discussed,including improving workflow efficiencies,reducing administrative costs,and improving healthcare *** these advantages,clinicians have been slow to adopt AI into clinical *** of the limitations posed by AI solutions include the lack of diverse data sets for model building so that they are widely applicable for routine clinical ***,the subsequent algorithms are often based on complex mathematics leading to clinician hesitancy to embrace such ***,we highlight the need for robust political and regulatory frameworks in this area to achieve the trust and approval of clinicians and patients to implement this transformational technology。

关键词： Artificial intelligence Data science Machine learning Intensive care unit(ICU) Critical care Sepsis

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Germline Gene-Editing Creates Enhanced Livestock-Technical and Especially Ethical Issues Challenge Its Use in Humans

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Engineering 2024年第2期33卷 3-5页

作者： jennifer Welsh Senior Technology Writer

Using clustered regularly interspaced short palindromic repeats(CRISPR)-based molecular tools,scientists are engineering-as they are also doing with plants.-animals with advantageous traits,like disease resistance and improved food *** these innovative techniques could one day be applied in humans,technical hurdles and ethical concerns likely place this possibility far in the future,The enhancements rely on germline gene editing,which alters the genes in a way that passes the changes on to *** m-line gene editing differs from the somatic cell gene editing used in the highly promising new treatment recently approved for the human disease sickle cell anemia.

关键词： likely Create editing

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mRNA vaccines:a new era in vaccine development

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Oncology Research 2024年第10期32卷 1543-1564页

作者： SHUBHRA CHANDRA jennifer C.WILSON DAVID GOOD MING Q.WEI School of Pharmacy&Medical Sciences Gold Coast campusGriffith UniversityBrisbaneQLD-4222Australia Menzies Health Institute Queensland(MHIQ) Gold Coast CampusGriffith UniversityBrisbaneQLD-4215Australia School of Allied Health Australian Catholic UniversityBrisbaneQLD-4014Australia

The advent of RNA therapy,particularly through the development of mRNA cancer vaccines,has ushered in a new era in the field of *** article provides a concise overview of the key principles,recent advancements,and potential implications of mRNA cancer vaccines as a groundbreaking modality in cancer *** cancer vaccines represent a revolutionary approach to combatting cancer by leveraging the body’s innate immune *** vaccines are designed to deliver specific mRNA sequences encoding cancer-associated antigens,prompting the immune system to recognize and mount a targeted response against malignant *** personalized and adaptive nature of mRNA vaccines holds immense potential for addressing the heterogeneity of cancer and tailoring treatments to individual *** breakthroughs in the development of mRNA vaccines,exemplified by the success of COVID-19 vaccines,have accelerated their application in *** mRNA platform’s versatility allows for the rapid adaptation of vaccine candidates to various cancer types,presenting an agile and promising avenue for therapeutic *** trials of mRNA cancer vaccines have demonstrated encouraging results in terms of safety,immunogenicity,and *** candidates,such as BioNTech’s BNT111 and Moderna’s mRNA-4157,have exhibited promising outcomes in targeting melanoma and solid tumors,*** successes underscore the potential of mRNA vaccines to elicit robust and durable anti-cancer immune *** the field holds great promise,challenges such as manufacturing complexities and cost considerations need to be addressed for widespread *** development of scalable and cost-effective manufacturing processes,along with ongoing clinical research,will be pivotal in realizing the full potential of mRNA cancer ***,mRNA cancer vaccines represent a cutting-edge therapeutic approach that holds the promise of transforming cancer treatment.

关键词： Cancer immunotherapy Immune checkpoint Preventive&therapeutic vaccine Delivery system mRNA

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Pancreatic surgery and tertiary pancreatitis services warrant provision for support from a specialist diabetes team

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World Journal of Diabetes 2024年第4期15卷 598-605页

作者： Vasileios K Mavroeidis jennifer Knapton Francesca Saffioti Daniel L Morganstein Department of HPB Surgery Bristol Royal InfirmaryUniversity Hospitals Bristol and Weston NHS Foundation TrustBristol BS28HWUnited Kingdom Department of Gastrointestinal Surgery Southmead HospitalNorth Bristol NHS TrustBristol BS105NBUnited Kingdom Department of Academic Surgery Royal Marsden NHS Foundation TrustLondon SW36JJUnited Kingdom Department of Gastroenterology and Hepatology Oxford University Hospitals NHS Foundation TrustOxford OX39DUUnited Kingdom UCL Institute for Liver and Digestive Health University College LondonLondon NW32PFUnited Kingdom Department of Endocrinology Chelsea and Westminster Hospital NHS Foundation TrustLondon SW109NHUnited Kingdom Department of Gastrointestinal Unit Royal Marsden NHS Foundation TrustLondon SW36JJUnited Kingdom

Pancreatic surgery units undertake several complex operations,albeit with consi-derable morbidity and mortality,as is the case for the management of complicated acute pancreatitis or chronic *** centralisation of pancreatic surgery services,with the development of designated large-volume centres,has contribu-ted to significantly improved *** this editorial,we discuss the complex associations between diabetes mellitus(DM)and pancreatic/periampullary disease in the context of pancreatic surgery and overall management of complex pancreatitis,highlighting the consequential needs and the indispensable role of specialist diabetes teams in support of tertiary pancreatic *** 3c pan-creatogenic DM,refers to DM developing in the setting of exocrine pancreatic disease,and its identification and management can be challenging,while the glycaemic control of such patients may affect their course of treatment and *** preoperative diabetes assessment is warranted to aid identification of patients who are likely to need commencement or escalation of glucose lowering therapy in the postoperative *** incidence of new onset diabetes after pancreatic resection is widely variable in the literature,and depends on the type and extent of pancreatic resection,as is the case with pancreatic parenchymal loss in the context of severe *** involvement of a specialist diabetes team is essential to ensure a holistic *** the current era,large volume pancreatic surgery services commonly abide by the principles of enhanced recovery after surgery,with inclusion of provisions for optimisation of the perioperative glycaemic control,to improve *** various guidelines are available to aid perioperative management of DM,auditing and quality improvement platforms have highlighted deficiencies in the perioperative management of diabetic patients and areas of required *** need for perioperative support of diabetic

关键词： Pancreatectomy Pancreatoduodenectomy Whipple’s Pancreatitis Diabetes specialist Type 3c pancreatogenic diabetes mellitus

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