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SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid

journal of Molecular Cell Biology 2023年第3期15卷 55-66页

作者： A.Sofia F.Oliveira Deborah K.Shoemark Andrew D.Davidson Imre Berger Christiane Schaffitzel adrian j.mulholland School of Chemistry Centre for Computational ChemistryUniversity of BristolBristol BS81TSUK School of Chemistry University of BristolBristol BS81TSUK School of Biochemistry University of BristolBristol BS81TDUK School of Cellular and Molecular Medicine University of BristolUniversity WalkBristol BS81TDUK School of Chemistry Max Planck Bristol Centre for Minimal BiologyBristol BS81TSUK

The SARS-CoV-2 spike protein contains a functionally important fatty acid(FA)binding site,which is also found in some other coronaviruses,***-CoV and *** occupancy of the FA site by linoleic acid(LA)reduces infectivity by‘locking’the spike in a less infectious ***,we use dynamical-nonequilibrium molecular dynamics(D-NEMD)simulations to compare the allosteric responses of spike variants to LA removal.D-NEMD simulations show that the FA site is coupled to other functional regions of the protein,*** receptor-binding motif(RBM),N-terminal domain(NTD),furin cleavage site,and regions surrounding the fusion peptide.D-NEMD simulations also identify the allosteric networks connecting the FA site to these functional *** comparison between the wild-type spike and four variants(Alpha,Delta,Delta plus,and Omicron BA.1)shows that the variants differ significantly in their responses to LA *** allosteric connections to the FA site on Alpha are generally similar to those on the wild-type protein,with the exception of the RBM and the S71–R78 region,which show a weaker link to the FA *** contrast,Omicron is the most different variant,exhibiting significant differences in the RBM,NTD,V622–L629,and furin cleavage *** differences in the allosteric modulation may be of functional relevance,potentially affecting transmissibility and *** comparison of the effects of LA on SARS-CoV-2 variants,including emerging variants,is warranted.

关键词： SARS-CoV-2 spike allosteric modulation D-NEMD simulations fatty acid binding site SARS-CoV-2 variants

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The concept of gene therapy for glaucoma:the dream that has not come true yet

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Neural Regeneration Research 2024年第1期19卷 92-99页

作者： Robert Sulak Xiaonan Liu adrian Smedowski Department of Physiology Faculty of Medical Sciences in KatowiceMedical University of Silesia in KatowiceKatowicePoland Institute of Biotechnology HiLIFEUniversity of HelsinkiHelsinkiFinland GlaucoTech Co. KatowicePoland

Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in *** glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent *** most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic *** gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2j mice model of high-tension glaucoma and the optic nerve *** gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.

关键词： adeno-associated virus gene editing gene therapy glaucoma IOP lowering IOP-independent mechanisms neuroprotection optic nerve optic neuropathy retinal ganglion cells

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Explainable Artificial Intelligence(XAI)Model for Cancer Image Classification

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Computer Modeling in Engineering & Sciences 2024年第10期141卷 401-441页

作者： Amit Singhal Krishna Kant Agrawal Angeles Quezada adrian Rodriguez Aguiñaga Samantha jiménez Satya Prakash Yadav Department of Computer Science&Engineering Raj Kumar Goel Institute of TechnologyGhaziabad201017India Department of School of Computing Science and Engineering Galgotias UniversityGreater Noida203201India Tecnológico Nacional de México Campus Tijuana Baja California22414México Universidad Autónoma de Baja California TijuanaBaja California22414México Department of Computer Science and Engineering G.LBajaj Institute of Technology and Management(GLBITM)Affiliated to Dr.A.P.J.Abdul Kalam Technical UniversityLucknow201306India School of Computer Science Engineering and Technology(SCSET) Bennett UniversityGreater Noida201310India

The use of Explainable Artificial Intelligence(XAI)models becomes increasingly important for making decisions in smart healthcare *** is to make sure that decisions are based on trustworthy algorithms and that healthcare workers understand the decisions made by these *** models can potentially enhance interpretability and explainability in decision-making processes that rely on artificial ***,the intricate nature of the healthcare field necessitates the utilization of sophisticated models to classify cancer *** research presents an advanced investigation of XAI models to classify cancer *** describes the different levels of explainability and interpretability associated with XAI models and the challenges faced in deploying them in healthcare *** addition,this study proposes a novel framework for cancer image classification that incorporates XAI models with deep learning and advanced medical imaging *** proposed model integrates several techniques,including end-to-end explainable evaluation,rule-based explanation,and useradaptive *** proposed XAI reaches 97.72%accuracy,90.72%precision,93.72%recall,96.72%F1-score,9.55%FDR,9.66%FOR,and 91.18%*** will discuss the potential applications of the proposed XAI models in the smart healthcare *** will help ensure trust and accountability in AI-based decisions,which is essential for achieving a safe and reliable smart healthcare environment.

关键词： Explainable artificial intelligence artificial intelligence XAI healthcare cancer image classification

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Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease

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Neural Regeneration Research 2025年第6期20卷 1644-1664页

作者： Gabriela Seplovich Yazan Bouchi juan Pablo de Rivero Vaccari jennifer C.Munoz Pareja Andrew Reisner Laura Blackwell Yehia Mechref Kevin K.Wang j.adrian Tyndall Binu Tharakan Firas Kobeissy Department of Surgery Morehouse School of MedicineAtlantaGAUSA Department of Neurobiology Center for NeurotraumaMultiomics&Biomarkers(CNMB)Neuroscience InstituteMorehouse School of MedicineAtlantaGAUSA Department of Neurological Surgery and the Miami Project to Cure Paralysis University of Miami Miller School of MedicineMiamiFLUSA Division of Pediatric Critical Care Department of PediatricsUniversity of Miami Miller School of MedicineMiamiFLUSA Department of Pediatrics Emory UniversityAtlantaGAUSA Department of Neurosurgery Children’s Healthcare of AtlantaAtlantaGAUSA Department of Chemistry and Biochemistry Texas Tech UniversityLubbockTXUSA Morehouse School of Medicine AtlantaGAUSA

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

关键词： Alzheimer's disease caspase-1 chronic traumatic encephalopathy inflammasomes neurodegeneration neuroinflammation NLRP1 NLRP3 pyroptosis tauopathy traumatic brain injury

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aSA-negative/Iow prostate cancer cells： the true villains of 3RPC？

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Asian journal of Andrology 2012年第5期14卷 663-664页

作者： David j.mulholland Department of Molecular and Medical Pharmacology UCLA School of Medicine Los Angeles CA 90095 USA

Prostate cancer remains a leading cause of death in men in the United States.1＇2 Treatment for advanced disease almost always includes androgen deprivation therapy （ADT）3 largely because the androgen receptor （AR） is expressed at high levels at many stages of disease progression. The clinical res- ponse to ADT typically includes a reduc- tion in overall tumor burden and reduced serum levels of the AR target, prostate- specific antigen （PSA）.4

关键词： CASTRATION AUTOPSY PTEN

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Lipogenic metabolism： a viable target for prostate cancer treatment？

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Asian journal of Andrology 2014年第5期16卷 661-663页

作者： Mengmeng Liang David j.mulholland Icahn School of Medicine at Mount Sinai New York NY USA I

Cancer cells often depend on altered metabolism compared with their normal counterparts.1-4 As observed in 1924 by Otto Warburg, cancer cells show preferential glucose consumption by way of aerobic glycolysis while normal cells generally assume mitochondrial oxidative phosphorylation.4 Another metabolic hallmark of carcinogenesis is altered lipid metabolism, whereby cancer cells may adopt enhanced de novo lipid production （lipogenesis）.l-3 Enhanced lipid metabolism is also observed in individuals with metabolic syndromes potentially a consequence of increasing popularity of the Standard American Diet, composed of high levels of saturated fats and carbohydrates.5 A growing body of epidemiological data indicates a positive correlation between the occurrence of metabolic syndromes, such as cardiovascular disease, obesity, type-2 diabetes and associated hyperinsulemia, with the aggressiveness of cancer.6-9 Remarkably, it is estimated that for every 1% reduction in saturated fats, replaced by polyunsaturated, there would be a 2%-3% reduction in cardiovascular disease.10 Thus, it is conceivable that an equally remarkable attenuation in cancer progression might be achieved with such a reduction in lipid accumulation.

关键词： Lipogenic metabolism a viable target

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Efficient Cloud Resource Scheduling with an Optimized Throttled Load Balancing Approach

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Computers, Materials & Continua 2023年第11期77卷 2179-2188页

作者： V.Dhilip Kumar j.Praveenchandar Muhammad Arif adrian Brezulianu Oana Geman Atif Ikram Department of Computer Science and Engineering Vel Tech Rangarajan Dr.Sagunthala R&D Institute of Science and TechnologyChennai600062India Department of Computer Science and Engineering Karunya Institute of Technology and SciencesCoimbatoreTamil Nadu641114India Department of Computer Science Superior UniversityLahorePakistan Faculty of Electronics Telecommunications and Information Technology Gheorghe Asachi Technical University of IasiIa¸si700050Romania Department of Health and Human Development Stefan cel Mare University of SuceavaSuceava720229Romania Faculty of Ocean Engineering Technology and Informatics University Malaysia TerengganuKuala NerusMalaysia

Cloud Technology is a new platform that offers on-demand computing Peripheral such as storage,processing power,and other computer system *** is also referred to as a system that will let the consumers utilize computational resources like databases,servers,storage,and intelligence over the *** a cloud network,load balancing is the process of dividing network traffic among a cluster of available servers to increase *** is also known as a server pool or server *** a single node is overwhelmed,balancing the workload is needed to manage unpredictable *** load balancer sends the load to another free node in this *** focus on the Balancing of workflows with the proposed approach,and we present a novel method to balance the load that manages the dynamic scheduling *** of the preexisting load balancing techniques is considered,however it is somewhat modified to fit the scenario at *** on the experimentation’s findings,it is concluded that this suggested approach improves load balancing consistency,response time,and throughput by 6%.

关键词： Load balancing throttled algorithm efficient resource allocation

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Update on risk scoring systems for patients with upper gastrointestinal haemorrhage

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World journal of Gastroenterology 2012年第22期18卷 2739-2744页

作者： adrian j Stanley Gastrointestinal Unit Glasgow Royal Infirmary Glasgow G4 OSF United Kingdom

Upper gastrointestinal haemorrhage (UGIH) remains a common medical emergency worldwide. It is increasingly recognised that early risk assessment is an important part of management, which helps direct appropriate patient care and the timing of endoscopy. Several risk scores have been developed, most of which include endoscopic findings, although a minority do not. These scores were developed to identify various end-points including mortality, rebleeding or clinical intervention in the form of transfusion, endoscopic therapy or surgery. Recent studies have reported accurate identification of a very low risk group on presentation, using scores which require simple clinical or laboratory parameters only. This group may not require admission, but could be managed with early out-patient endoscopy. This article aims to describe the existing pre- and post-endoscopy risk scores for UGIH and assess the published data comparing them in the prediction of outcome. Recent data assessing their use in clinical practice, in particular the early identification of low-risk patients, are also discussed.

关键词：上消化道出血风险评估评分系统患者早期识别临床实践组成部分内镜

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Endoscopic ultrasound-guided elastography in the nodal staging of oesophageal cancer

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World journal of Gastroenterology 2012年第9期18卷 889-895页

作者： Stuart Paterson Fraser Duthie adrian j Stanley Department of Gastroenterology Forth Valley Royal Hospital Department of Pathology Glasgow Royal Infirmary Department of Gastroenterology Glasgow Royal Infirmary

AIM:To assess quantitative endoscopic ultrasound (EUS)guided elastography in the nodal staging of oesophagogastric ***:This was a single tertiary centre study assessing 50 patients with established oesophago-gastric cancer undergoing EUS-guided fine needle aspiration biopsy (FNAB) of lymph nodes between july 2007 and july ***-guided elastography of lymph nodes was performed before *** EUS characteristics were also *** determination of whether a lymph node was malignant or benign was used as the gold standard for this *** of elastography and standard EUS characteristics were made between the cytologically benign and malignant *** main outcome measure was the accuracy of elastography in differentiating between benign and malignant lymph nodes in oesophageal ***:EUS elastography and FNAB were performed on 53 lymph *** malignancy was found in 23 nodes,one was indeterminate,one was found to be a gastrointestinal stromal tumor and 25 of the nodes were negative for *** 3 occasions insufficient material was obtained for *** area under the curve for the receiver operating characteristic curve for elastography strain ratio was 0.87 (P<0.0001).Elastography strain ratio had a sensitivity 83%,specificity 96%,positive predictive value 95%,and negative predictive value 86% for distinguishing between malignant and benign *** overall accuracy of elastography strain ratio was 90%.Elastography was more sensitive and specific in determining malignant nodal disease than standard EUS ***:EUS elastography is a promising modality that may complement standard EUS and help guide EUS-FNAB during staging of upper gastrointestinal tract cancer.

关键词：淋巴结肿大食管癌弹性内镜引导超声细胞学检测高等教育

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Gene therapy and genome editing for primary immunodeficiency diseases

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Genes & Diseases 2020年第1期7卷 38-51页

作者： Zhi-Yong Zhang adrian j.Thrasher Fang Zhang Molecular and Cellular Immunology Great Ormond Street Institute of Child HealthUniversity Colleage LondonUK Department of Immunology and Rheumatology Children’s Hospital of Chongqing Medical UniversityChina

In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells(HSCs)transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency diseases(PIDs).Despite of some pitfalls at early stage clinical trials,the field of gene therapy has advanced significantly in the last decade with improvements in viral vector safety,preparatory regime for manufacturing high quality virus,automated CD34 cell ***,the overall outcome from the clinical trials for the different PIDs has been very *** addition to the viral vector based gene therapy,the recent fast moving forward developments in genome editing using engineered nucleases in HSCs has provided a new promising platform for the treatment of *** review provides an overall outcome and progress in gene therapy clinical trials for SCID-X,ADA-SCID,WAS,X-CGD,and the recent developments in genome editing technology applied in HSCs for developing potential therapy,particular in the key studies for PIDs.

关键词： Adenosine deaminase deficient Chronic granulomatous disease Gene therapy Genome editing Hematopoietic progenitor stem cells Primary immunodeficiency diseases Wiskott-Aldrich syndrome X-liked severe combined immunodeficiency

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