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The Group A Streptococcus Interleukin-8 Protease SpyCEP Promotes Bacterial Intracellular Survival by Evasion of Autophagy

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Infectious Microbes & Diseases 2022年第3期4卷 116-123页

作者： RenéBergmann Giuseppe Gulotta Federica Andreoni Tomoko Sumitomo Shigetada Kawabata Annelies S.Zinkernagel Gursharan S.Chhatwal Victor Nizet Manfred Rohde satoshi uchiyama Central Unit for Microscopy(ZEIM) Helmholtz Centre for Infection ResearchBraunschweigGermany Division of Infectious Diseases and Hospital Epidemiology University Hospital ZurichZurichSwitzerland Department of Oral and Molecular Microbiology Osaka University Graduate School of DentistrySuita-OsakaJapan Division of Host-Microbe Systems and Therapeutics Department of PediatricsUniversity of CaliforniaSan DiegoLa JollaCalifornia

Autophagy serves an innate immune function in defending the host against invading bacteria,including group A Streptococcus(GAS).Autophagy is regulated by numerous host proteins,including the endogenous negative regulator calpain,a cytosolic protease.Globally disseminated serotypeM1T1 GAS strains associated with high invasive disease potential express numerous virulence factors and resist autophagic clearance.Upon in vitro infection of human epithelial cell lines with representative wild-type GAS M1T1 strain 5448(M1.5448),we observed increased calpain activation linked to a specific GAS virulence factor,the interleukin-8 protease SpyCEP.Calpain activation inhibited autophagy and decreased capture of cytosolic GAS in autophagosomes.In contrast,the serotype M6 GAS strain JRS4(M6.JRS4),which is highly susceptible to host autophagy-mediated killing,expresses low levels of SpyCEP and does not activate calpain.Overexpression of SpyCEP in M6.JRS4 stimulated calpain activation,inhibited autophagy,and significantly decreased bacterial capture in autophagosomes.These paired loss-and gain-of-function studies reveal a novel role for the bacterial protease SpyCEP in enabling GAS M1 evasion of autophagy and host innate immune clearance.

关键词： group A Streptococcus SpyCEP virulence factor epithelial cells intracellular survival autophagy xenophagy calpain

Engineered Biomimetic Platelet Membrane-Coated Nanoparticles Block Staphylococcus aureus Cytotoxicity and Protect Against Lethal Systemic Infection

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Engineering 2021年第8期7卷 1149-1156页

作者： Jwa-Kyung Kim satoshi uchiyama Hua Gong Alexandra Stream Liangfang Zhang Victor Nizet Division of Nephrology Department of Internal Medicine&Kidney Research InstituteHallym University Sacred Heart HospitalAnyang 14068Republic of Korea Department of Clinical Immunology Hallym University Sacred Heart HospitalAnyang 14068Republic of Korea Division of Host-Microbe Systems and Therapeutics Department of PediatricsUniversity of California San DiegoLa JollaCA 92093USA Department of NanoEngineering University of California San DiegoLa JollaCA 92093USA Moores Cancer Center University of California San Diego HealthLa JollaCA 92037USA Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San DiegoLa JollaCA 92093USA

Staphylococcus aureus(S.aureus)is a leading human pathogen capable of producing severe invasive infections such as bacteremia,sepsis,and endocarditis with high morbidity and mortality,exacerbated by the increasingly widespread antibiotic resistance exemplified by methicillin-resistant strains(MRSA).S.aureus pathogenesis is fueled by the secretion of toxins—such as the membrane-damaging pore-forming atoxin,which have diverse cellular targets including the epithelium,endothelium,leukocytes,and platelets.Here,we examine the use of human platelet membrane-coated nanoparticles(PNPs)as a biomimetic decoy strategy to neutralize S.aureus toxins and preserve host cell defense functions.The PNPs blocked platelet damage induced by S.aureus secreted toxins,thereby supporting platelet activation and bactericidal activity.Likewise,the PNPs blocked macrophage damage induced by S.aureus secreted toxins,thus supporting macrophage oxidative burst,nitric oxide production,and bactericidal activity,and diminishing MRSA-induced neutrophil extracellular trap release.In a mouse model of MRSA systemic infection,PNP administration reduced bacterial counts in the blood and protected against mortality.Taken together,the results from the present work provide a proof of principle of the therapeutic benefit of PNPs in toxin neutralization,cytoprotection,and increased host resistance to invasive S.aureus infection.

关键词： Nanoparticle Nanosponge Platelet Staphylococcus aureus Bacterial toxins Sepsis

Protection Against Lethal Multidrug-Resistant Bacterial Infections Using Macrophage Cell Therapy

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Infectious Microbes & Diseases 2019年第2期1卷 61-69页

作者： Robert Tacke Josh Sun satoshi uchiyama Anya Polovina Deborah G.Nguyen Victor Nizet Cellular Approaches San Diego CA92037USA Collaborative to Halt Antibiotic-Resistant Microbes(CHARM) UC San DiegoLa JollaCA 92093USA Department of Pediatrics UC San DiegoLa JollaCA 92093USA Skaggs School of Pharmacy and Pharmaceutical Sciences UC San DiegoLa JollaCA 92093USA

Multidrug-resistant(MDR)bacterial infections exert a tremendous burden on the public health system throughout the developing and developedworld.Slowing development of novel antibiotic scaffolds,over-prescription of antibiotics,extensive agricultural antibiotic use,and the increasingly complex hospitalized patient populations undergoing treatment,all fuel the rise of highly MDR“superbugs.”Unfortunately,host-directed therapies to boost immune resistance to infection are not currently available for treatment of MDR pathogens.Hematopoietic cells are endowed with a variety ofmechanismsto control microbial invasion.Macrophages in particular have long been appreciated as potent antimicrobial immune cells equipped with several receptors that allow for rapid recognition,phagocytosis,and killing of pathogenic microbes,coupled to secretion of immunostimulatory cytokines to further orchestrate a robust multifaceted antibacterial immune response.To investigate the utility of macrophages as a cell therapy for MDR bacterial infections,we developed a therapeutically translatable process to generate,harvest,and cryopreserve monocyte-derived macrophages(ICONIMACTM).These cells effectively killed both Gram-positive and Gram-negative MDR pathogens in vitro,and conferred protection in vivo against experimental lethal peritonitis and lung infection.Our discoveries provide a proof-of-concept for a novel immunotherapeutic approach against MDR bacterial infections,urgently needed to supplement the diminishing antibiotic pipeline.

关键词： antibiotic resistance innate immunity bacterial infection macrophage cell therapy ICONIMACTM Staphylococcus aureus Pseudomonas aeruginosa Klebsiella pneumoniae

Site-Specific Conjugation of Cell Wall Polyrhamnose to Protein SpyAD Envisioning a Safe Universal Group A Streptococcal Vaccine

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Infectious Microbes & Diseases 2021年第2期3卷 87-100页

作者： Nina J.Gao satoshi uchiyama Lucy Pill Samira Dahesh Joshua Olson Leslie Bautista Shilpa Maroju Aym Berges Janet ZLiu Raymond HZurich Nina Mvan Sorge Jeff Fairman Neeraj Kapoor Victor Nizet Division of Host-Microbe Systems and Therapeutics Department of PediatricsUC San DiegoLa JollaCaliforniaUSA Vaxcyte Inc.Foster CityCaliforniaUSA Department of Medical Microbiology and Infection Prevention Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands Netherlands Reference Laboratory for Bacterial Meningitis Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands Skaggs School of Pharmacy and Pharmaceutical Sciences UC San DiegoLa JollaCaliforniaUSA

Development of an effective vaccine against the leading human bacterial pathogen group A Streptococcus(GAS)is a public health priority.The species defining group A cell wall carbohydrate(GAC,Lancefield antigen)can be engineered to remove its immunodominant N-acetylglucosamine(GlcNAc)side chain,implicated in provoking autoimmune cross-reactivity in rheumatic heart disease,leaving its polyrhamnose core(GACPR).Here we generate a novel protein conjugate of the GACPR and test the utility of this conjugate antigen in active immunization.Instead of conjugation to a standard carrier protein,we selected SpyAD,a highly conserved GAS surface protein containing both B-cell and T-cell epitopes relevant to the bacterium that itself shows promise as a vaccine antigen.SpyAD was synthesized using the XpressTM cell-free protein expression system,incorporating a non-natural amino acid to which GACpr was conjugated by site-specific click chemistry to yield high molecular mass SpyAD-GACPR conjugates and avoid disruption of important T-cell and B-cell immunological epitopes.The conjugated SpyAD-GACPR elicited antibodies that bound the surface of multiple GAS strains of diverse M types and promoted opsonophagocytic killing by human neutrophils.Active immunization of mice with a multivalent vaccine consisting of SpyAD-GACPR,together with candidate vaccine antigens streptolysin O and C5a peptidase,protected against GAS challenge in a systemic infection model and localized skin infection model,without evidence of cross reactivity to human heart or brain tissue epitopes.This general approach may allow GAC to be safely and effectively included in future GAS subunit vaccine formulations with the goal of broad protection without autoreactivity.

关键词： group A Streptococcus Streptococcus pyogenes group A carbohydrate Lancefield antigen conjugate vaccine XpressCFTM non-natural amino acids SpyAD Introduction

Simultaneous detection of the shuttling motion of liquid metal droplets in channels under alternating pressure and capacitive sensor signals

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Microsystems & Nanoengineering 2024年第2期10卷 83-90页

作者： Shinji Bono Ryotaro Nakai satoshi Konishi Research Organization of Science and Technology Ritsumeikan UniversityShigaJapan Ritsumeikan Advanced Research Academy KyotoJapan Ritsumeikan Global Innovation Research Organization Ritsumeikan UniversityShigaJapan Graduate School of Science and Engineering Ritsumeikan UniversityShigaJapan

Implementing a signal-switching mechanism for the selective use of integrated sensors and actuators plays a crucial role in streamlining the functionality of miniaturized devices.Here,a liquid metal droplet(LMD)-based signal-switching mechanism is introduced to achieve such functionality.Pressure modulation with a 100-μm spatial resolution enabled precise control of the position of the LMDs within a channel.After integrating the channel with asymmetrically structured electrodes,the effect of the shuttle-like movement of LMD on the temporal changes in the overall capacitance was investigated.Consequently,analysis of the capacitive peaks revealed the directional movement of the LMDs,enabling estimation of the position of the LMDs without direct observation.In addition,we achieved successful signal extraction from the capacitive sensor that was linked to the activated electrodes,thereby enabling selective data retrieval.The proposed signal-switching mechanism method achieved a detection accuracy of~0.1 pF.The sensor’s ability to simultaneously detect the LMD position and generate a signal underscores its significant potential for multiplexing in multisensing systems,particularly in concealed environments,such as in vivo settings.

关键词： liquid thereby integrating

Molecular biomarkers for vascular cognitive impairment and dementia:the current status and directions for the future

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Neural Regeneration Research 2024年第12期19卷 2579-2580页

作者： satoshi Hosoki Perminder SSachdev Centre for Healthy Brain Ageing Discipline of Psychiatry and Mental HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesSydneyAustralia Department of Neurology National Cerebral and Cardiovascular CenterOsakaJapan

Dementia is a syndrome with various underlying pathologies acting independently or in concert to cause cognitive dysfunction.The development of disease-specific treatments and targeted prevention strategies requires precise clinical sub-typing via etiology and pathophysiological processes.Furthermore,recent research advances in biomarkers,especially for Alzheimer's disease(AD)diagnosis,have improved diagnostic precision for dementia.

关键词： prevention diagnosis impairment

Controllable multi-domain semantic artwork synthesis

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Computational Visual Media 2024年第2期10卷 355-373页

作者： Yuantian Huang satoshi Iizuka Edgar Simo-Serra Kazuhiro Fukui Department of Computer Science University of TsukubaTsukuba 305-8577Japan Department of Computer Science and Engineering Waseda UniversityTokyo 169-8050Japan

We present a novel framework for the multidomain synthesis of artworks from semantic layouts.One of the main limitations of this challenging task is the lack of publicly available segmentation datasets for art synthesis.To address this problem,we propose a dataset called ArtSem that contains 40,000 images of artwork from four different domains,with their corresponding semantic label maps.We first extracted semantic maps from landscape photography and used a conditional generative adversarial network(GAN)-based approach for generating high-quality artwork from semantic maps without requiring paired training data.Furthermore,we propose an artwork-synthesis model using domain-dependent variational encoders for high-quality multi-domain synthesis.Subsequently,the model was improved and complemented with a simple but effective normalization method based on jointly normalizing semantics and style,which we call spatially style-adaptive normalization(SSTAN).Compared to the previous methods,which only take semantic layout as the input,our model jointly learns style and semantic information representation,improving the generation quality of artistic images.These results indicate that our model learned to separate the domains in the latent space.Thus,we can perform fine-grained control of the synthesized artwork by identifying hyperplanes that separate the different domains.Moreover,by combining the proposed dataset and approach,we generated user-controllable artworks of higher quality than that of existing approaches,as corroborated by quantitative metrics and a user study.

关键词： semantic artwork synthesis generative adversarial network(GAN) datasets non-photorealistic rendering

Evaluation of mitral chordae tendineae length using four-dimensional computed

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World Journal of Cardiology 2024年第5期16卷 274-281页

作者： Takuya Mori satoshi Matsushita Terumasa Morita Abulaiti Abudurezake Junji Mochizuki Atsushi Amano Department of Cardiovascular Surgery Juntendo University Faculty of MedicineTokyo 113-8421Japan Department of Cardiovascular Surgery JACCT Japan Animal Cardiovascular Care TeamOsaka 533-0033Japan Department of Radiology Minamino Cardiovascular HospitalTokyo 192-0918Japan

BACKGROUND Mitral valvuloplasty using artificial chordae tendineae represents an effective surgical approach for treating mitral regurgitation.Achieving precise measurements of artificial chordae tendineae length(CL)is an important factor in the procedure;however,no objective index currently exists to facilitate this measurement.Therefore,preoperative assessment of CL is critical for surgical planning and support.Four-dimensional x-ray micro-computed tomography(4D-CT)may be useful for accurate CL measurement considering that it allows for dynamic three-dimensional(3D)evaluation compared to that with transthoracic echocardiography,a conventional inspection method.AIM To investigate the behavior and length of mitral chordae tendineae during systole using 4D-CT.METHODS Eleven adults aged>70 years without mitral valve disease were evaluated.A 64-slice CT scanner was used to capture 20 phases in the cardiac cycle in electrocardiographic synchronization.The length of the primary chordae tendineae was measured from early systole to early diastole using the 3D image.The primary chordae tendineae originating from the anterior papillary muscle and attached to the A1-2 region and those from the posterior papillary muscle and attached to the A2-3 region were designated as cA and cP,respectively.The behavior and maximum lengths[cA(ma),cP(max)]were compared,and the correlation with body surface area(BSA)was evaluated.RESULTS In all cases,the mitral anterior leaflet chordae tendineae could be measured.In most cases,the cA and cP chordae tendineae could be measured visually.The mean cA(max)and cP(max)were 20.2 mm±1.95 mm and 23.5 mm±4.06 mm,respectively.cP(max)was significantly longer.The correlation coefficients(r)with BSA were 0.60 and 0.78 for cA(max)and cP(max),respectively.Both cA and cP exhibited constant variation in CL during systole,with a maximum 1.16-fold increase in cA and a 1.23-fold increase in cP from early to mid-systole.For cP,CL reached a plateau at 15%and remained elongated until end-systole,whereas for cA,aft

关键词： Mitral valve Chordae tendineae Computed tomography Four-dimensional Cardiac cycle

Bi-predual spaces of generalized Campanato spaces with variable growth condition

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Acta Mathematica Sinica,English Series 2024年

作者： satoshi YAMAGUCHI Eiichi NAKAI Katsunori SHIMOMURA Department of Mathematics Ibaraki University

In this paper we extend the duality(■)*= H1(Rd) to generalized Campanato spaces with variable growth condition Lp,φ(Rd) instead of BMO(Rd). We also extend the characterization of Cc∞omp(Rd)BMO(Rd)by uchiyama(1978) to ■. Moreover, using this characterization, we prove the boundedness of singular and fractional integral operators on ■.The function space Lp,φ(Rd) treated in this paper covers the case that it is coincide with Lipαon one area, with BMO on another area and with the Morrey space on the other area, for example.

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