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Beyond monogenetic rare variants:tackling the low rate of genetic diagnoses in predominantly antibody deficiency

Cellular & Molecular Immunology 2021年第3期18卷 588-603页

作者： Emily S.j.Edwards julian j.bosco Samar Ojaimi Robyn E.O’Hehir Menno C.van Zelm Department of Immunology and Pathology Central Clinical SchoolMonash UniversityMelbourneVICAustralia The jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies MelbourneVICAustralia Department of Allergy Immunology and Respiratory MedicineCentral Clinical SchoolMonash University and AllergyAsthma and Clinical Immunology ServiceAlfred HospitalMelbourneVICAustralia Department of Infectious Diseases Monash HealthClaytonVICAustralia Centre for Inflammatory Diseases Monash HealthClaytonVICAustralia Department of Allergy and Immunology Monash HealthClaytonVICAustralia

Predominantly antibody deficiency(PAD)is the most prevalent form of primary immunodeficiency,and is characterized by broad clinical,immunological and genetic *** the current gold standard of whole exome sequencing for diagnosis,pathogenic gene variants are only identified in less than 20% of *** elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis,many other genes may remain as yet undefined to enable definitive diagnosis,prognostic monitoring and targeted therapy of *** that many patients display a relatively late onset of disease presentation in their 2^(nd) or 3^(rd) decade of life,it is questionable whether a single genetic lesion underlies disease in all ***,combined effects of other gene variants and/or non-genetic factors,including specific infections can drive disease *** this review,we define(1)the clinical and immunological variability of PAD,(2)consider how genetic defects identified in PAD have given insight into B-cell immunobiology,(3)address recent technological advances in genomics and the challenges associated with identifying causal variants,and(4)discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates,improved prognostic monitoring and personalized medicine for PAD patients.A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.

关键词： Predominantly antibody deficiency Genetic diagnosis Genomics Functional validation

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Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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Bone Research 2024年第1期12卷 199-214页

作者： Laura j.Brylka Assil-Ramin Alimy Miriam E.A.Tschaffon-Müller Shan jiang Tobias Malte Ballhause Anke Baranowsky Simon von Kroge julian Delsmann Eva Pawlus Kian Eghbalian Klaus Püschel Astrid Schoppa Melanie Haffner-Luntzer David j.Beech Frank Timo Beil Michael Amling johannes Keller Anita Ignatius Timur A.Yorgan Tim Rolvien Thorsten Schinke Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-Eppendorf20246 HamburgGermany Institute of Orthopedic Research and Biomechanics University Medical Center UlmBadenWürttemberg89081 UlmGermany Department Legal Medicine University Medical Center Hamburg-Eppendorf20246 HamburgGermany Leeds Institute of Cardiovascular and Metabolic Medicine School of MedicineUniversity of LeedsLS29JT LeedsUK

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell *** we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in *** we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)*** with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate ***,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth *** skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of ***,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage ***,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) *** further observed increased Piezo1 protein abundance in cartilaginous zones of human ***,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in ***,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

关键词： Piezo1 markedly ossification

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Traditional Healer’s Medicinal Practice Survey and Clinical Evidence Assessment of “YIKI”: An Antimalarial Phytomedicine Recipe from Bobo-Dioulasso, Burkina Faso

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Pharmacology & Pharmacy 2024年第7期15卷 248-267页

作者： Zachari Kabre Rakiswende Serge Yerbanga Aminata Fofana Roland Nâg-Tiero Meda Anyirekun Fabrice Some Alassane Haro Natacha A. j. A. Boro Fazhira B. Ye Benjamin Kouliga Koama Sami Eric Kam Eliasse Zongo Hadidjatou Belèm Windmi Kagambèga Florence Fournet Georges A. Ouedraogo jean-bosco Ouedraogo Institut de Recherche en Sciences de la Sant Direction Rgionale de lOuest Bobo-Dioulasso Burkina Faso Laboratoire de Recherche et dEnseignement en Sant et Biotechnologies Animales Universit Nazi BONI Bobo-Dioulasso Burkina Faso Institut des Sciences et Techniques Bobo-Dioulasso Burkina Faso Laboratoire de Recherche en Bactriologie INSP/Centre MURAZ Bobo-Dioulasso Burkina Faso Maladies Infectueuses et Vecteurs: Ecologie Gntique Evolution et Contrle (MIVEGEC) Institut de Recherche pour le Dveloppement Universit de Monpellier Montpellier France

YIKI is an antimalarial phytomedicine used by a traditional healer to treat malaria in Bobo-Dioulasso. However, there is no scientific evidence to support its use by local populations. The aim of this study was to identify the medicinal practices of the healer holder of YIKI and assess the clinical evidence of its phytomedicine in the uncomplicated malaria treatment. Ethnomedical survey based on a semi-structured and open questionnaire was conducted from October to December 2019 with the healer. Malaria knowledge and diagnosis methods, patient treatment and monitoring, and recipe formulation steps were surveyed. Moreover, thick and thin blood smears were taken, haemoglobin levels and temperature of consenting patients were measured before treatment, mid-treatment and at the end of treatment. The survey revealed that the healer has a good knowledge of malaria symptoms and his diagnosis is based on observation and physical examination of patients. The healer’s malaria diagnosis was rudimentary and had accuracy problems, with only 62.79% of malaria cases confirmed by microscopy. The formulation of YIKI and its use to treat malaria follow a standard process for plant harvesting, powder quantities and posology, but do not use any reproducible parameters for dose adjustment. Forty-three patients diagnosed and treated by the healer participated in the study. Laboratory results revealed 27 Plasmodium falciparum infection cases, including 2 with parasitaemia ≥ 200,000 p/µl blood. 25 patients were selected for therapeutic evidence assessment. There was a 48% elimination of parasites, a 28% parasitaemia decrease without complete cure, with gametocytogenesis in some patients, and a 24% parasitaemia increase. Haemoglobin and temperature results suggested that YIKI was not cytotoxic and reduced fever. Encouraging preliminary results have been obtained, but in view of the low number of patients, further YIKI efficacy and toxicity studies will be necessary for patient safety.

关键词： Antimalarial-Phytomedicine Efficacy Traditional Practices Bobo-Dioulasso

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Modeling and Control of Parallel Hybrid Electric Vehicle Using Sea-Lion Optimization

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Intelligent Automation & Soft Computing 2023年第2期35卷 1441-1454页

作者： j.Leon bosco Raj M.Marsaline Beno Department of EEE St.Xavier’s Catholic College of EngineeringChunkankadaiAnna UniversityChennaiIndia St.Xavier’s Catholic College of Engineering ChunkankadaiAnna UniversityChennaiIndia

This paper develops a parallel hybrid electric vehicle(PHEV)propor-tional integral controller with driving *** improve fuel efﬁciency and reduce hazardous emissions in hybrid electric vehicles(HEVs)combine an electric motor(EM),a battery and an internal combustion engine(ICE).The electric motor assists the engine when accelerating,driving longer highways or climbing *** enables the use of a smaller,more efﬁcient *** also makes use of the concept of regenerative braking to maximize energy efﬁ*** a Hybrid Electric Vehicle(HEV),energy dissipated while braking is utilized to charge the *** proportional integral controller was used in this paper to analyze engine,motor performance and the New European Driving Cycle(NEDC)was used in the vehicle driving test using Matlab/*** proportional integral controllers were designed to track the desired vehicle speed and manage the vehi-cle’s energyﬂ*** Sea Lion Optimization(SLnO)methods were created to reduce fuel consumption in a parallel hybrid electric vehicle and the results were obtained for the New European Driving Cycle.

关键词： Hybrid electric vehicle(HEV) proportional integral controller parallel HEV fuel efﬁciency new European driving cycle(NEDC) sea lion optimization(SLnO)

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Multiple forest structural elements are needed to promote beetle biomass, diversity and abundance

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Forest Ecosystems 2022年第5期9卷 585-595页

作者： Nolan j.Rappa Michael Staab julian Frey Nathalie Winiger Alexandra-Maria Klein Nature Conservation and Landscape Ecology University of FreiburgTennenbacherstrasse 479106Freiburg im BreisgauGermany Ecological Networks Technical University DarmstadtSchnittspahnstrasse 364287DarmstadtGermany Forest Growth and Dendroecology University of FreiburgTennenbacherstrasse 479106Freiburg im BreisgauGermany Wildlife Ecology and Management University of FreiburgTennenbacherstrasse 479106Freiburg im BreisgauGermany

Background:Retention forestry is a management strategy aiming to mitigate biodiversity loss by retaining structural elements such as dead trees that would otherwise be *** we analyze the biomass,diversity and abundance among forest beetles collected using window traps on 1281-ha forest sites reflecting gradients in the amount of structural elements in southwestern ***:We found that beetle biomass increased with mean diameter at breast height(a measure of tree size),and decreased with stand structural *** of individual feeding guilds responded differently to forest structural elements,namely lying deadwood,understory complexity,tree basal area and stand structural *** family diversity increased with the effective number of layers,i.e.1-m forest strata occupied by vegetation assessed via terrestrial laser *** of feeding guilds responded to only elevation and share of deciduous *** composition in terms of biomass was structured by forest elements similar to biomass of individual feeding guilds,with the addition of lying *** differed from community composition in terms of abundance of feeding guilds,which was structured by primarily standing deadwood volume and share of deciduous ***:Our results show that biomass,diversity and abundance respond differently to forest structural *** suggests that the concurrent prioritization of multiple forest elements is needed to promote forest beetles,with more focus placed on the differing resource needs among feeding *** addition,retention strategies should also consider the varying responses of beetle biodiversity metrics when assessing the importance of forest structural elements.

关键词： Allometry Biodiversity Coleoptera Forest management Terrestrial laser scanning Window trap

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Capillaric field effect transistors

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Microsystems & Nanoengineering 2022年第2期8卷 59-71页

作者： Claude Meffan julian Menges Fabian Dolamore Daniel Mak Conan Fee Renwick C.j.Dobson Volker Nock Department of Electrical and Computer Engineering University of CanterburyChristchurch 8041New Zealand Department of Microengineering Kyoto University615-8540 KyotoJapan School of Biological Sciences University of CanterburyChristchurch 8041New Zealand Biomolecular Interaction Centre School of Biological SciencesUniversity of CanterburyChristchurch 8041New Zealand School of Product Design University of CanterburyChristchurch 8041New Zealand Department of Biochemistry and Molecular Biology Bio21 Molecular Science and Biotechnology InstituteUniversity of MelbourneParkvilleVIC 3010Australia The MacDiarmid Institute for Advanced Materials and Nanotechnology Wellington 6140New Zealand

Controlling fluid flow in capillaric circuits is a key requirement to increase their uptake for assay *** action off-valves provide such functionality by pushing an occluding bubble into the channel using a difference in capillary ***,we utilized the binary switching mode of this structure to develop a powerful set of fundamental fluidic valving *** this work,we study the transistor-like qualities of the off-valve and provide evidence that these structures are in fact functionally complementary to electronic junction field effect *** view of this,we propose the new term capillaric field effect transistor to describe these types of *** support this conclusion,we present a theoretical description,experimental characterization,and practical application of analog flow resistance *** addition,we demonstrate that the valves can also be *** show modulation of the flow resistance from fully open to pinch-off,determine the flow rate-trigger channel volume relationship and demonstrate that the latter can be modeled using Shockley's equation for electronic ***,we provide a first example of how the valves can be opened and closed repeatedly.

关键词： transistors effect field

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An elliptical blade is not a true ellipse,but a superellipse–Evidence from two Michelia species

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journal of Forestry Research 2022年第4期33卷 1341-1348页

作者： Yuping Li Karl jNiklas johan Gielis Ülo Niinemets julian Schrader Rong Wang Peijian Shi College of Horticulture Jinling Institute of TechnologyNanjing 210038People’s Republic of China Bamboo Research Institute Nanjing Forestry UniversityNanjing 210037People’s Republic of China Plant Biology Section School of Integrative Plant ScienceCornell UniversityIthacaNY 14853USA Department of Biosciences Engineering University of AntwerpB-2020 AntwerpBelgium Institute of Agricultural and Environmental Sciences Estonian University of Life Sciences51006 TartuEstonia Estonian Academy of Sciences 10130 TallinnEstonia Department of Biological Sciences Macquarie UniversitySydneyNSW 2109Australia Biodiversity Macroecology and BiogeographyUniversity of Göttingen37077 GöttingenGermany

The shape of leaf laminae exhibits considerable diversity and complexity that reflects adaptations to environmental factors such as ambient light and precipitation as well as phyletic *** leaves appear to be elliptical which may represent a‘default’developmental ***,whether their geometry truly conforms to the ellipse equation(EE),i.e.,(x/a)^(2)+(y/b)^(2)=1,remains *** alternative is described by the superellipse equation(SE),a generalized version of EE,i.e.,|x/a|^(n)+|y/b|^(n)=*** test the efficacy of EE versus SE to describe leaf geometry,the leaf shapes of two Michelia species(i.e.,*** ***,and ***),were investigated using 60 leaves from each *** shows that the majority of leaves(118 out of 120)had adjusted root-mean-square errors of<0.05 for the nonlinear fitting of SE to leaf geometry,i.e.,the mean absolute deviation from the polar point to leaf marginal points was smaller than 5%of the radius of a hypothesized circle with its area equaling leaf *** estimates of n for the two species were<2,indicating that all sampled leaves conformed to SE and not to *** study confirms the existence of SE in leaves,linking this to its potential functional advantages,particularly the possible influence of leaf shape on hydraulic conductance.

关键词： Bilateral symmetry Leaf ellipticalness index Leaf laminae Leaf roundness index Magnoliaceae

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Rotational stability of plate haptic toric intraocular lenses after combined 25-gauge vitrectomy and cataract surgery

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International journal of Ophthalmology(English edition) 2023年第8期16卷 1231-1236页

作者： Lara Buhl julian Langer Stefan Kassumeh Thomas C.Kreutzer Wolfgang j.Mayer Siegfried G.Priglinger Department of Ophthalmology University HospitalLMU MunichMunich 80336Germany

AIM:To evaluate the postoperative intraocular lens(IOL)rotational stability and residual refractive astigmatism following combined 25-gauge vitrectomy and cataract surgery with implantation of a plate haptic toric ***:In this retrospective case series,32 eyes of 32 patients underwent a combined 25-gauge vitrectomy and phacoemulsification for vitreoretinal diseases and cataract with regular corneal astigmatism of at least 1 diopter(D).A plate haptic toric IOL(AT Torbi 709M,Carl Zeiss Meditec AG)was implanted in all *** outcome measures were rotational stability and refractive astigmatism up to 6mo postoperatively as well as the best corrected visual acuity(BCVA).RESULTS:Preoperative refractive astigmatism was 2.14±1.17 D,which was significantly reduced to 0.77±0.37 D six to eight weeks postoperatively and remained stable throughout the observation period(0.67±0.44 D at three months and 0.75±0.25 D at six months;for all groups:P<0.0001 compared to baseline).BCVA improved significantly from 0.36±0.33 logMAR preoperatively to 0.10±0.15 logMAR following surgery(P=0.02).Mean IOL axis deviation from the target axis was 3.4°±2.9°after six to eight weeks and significantly decreased over time(2.4°±2.6°six months after surgery;P=0.04).In one patient IOL,re-alignment was ***:Corneal astigmatism is significantly reduced following combined 25-gauge vitrectomy and cataract *** plate haptic toric IOL position and axis remain stable during the observation period of six months.

关键词： combined phaco-vitrectomy toric intraocular lens rotational stability corneal astigmatism cataract vitreoretinal disease

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Versus—A tool for evaluating visualizations and image quality using a 2AFC methodology

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Visual Informatics 2018年第4期2卷 225-234页

作者： jenny Vuong Sandeep Kaur julian Heinrich bosco K.Ho Christopher j.Hammang Benedetta F.Baldi Seán I.O’Donoghue CSIRO Data61Australia Garvan Institute of Medical Research Australia University of New South Wales Australia University of Tübingen Germany University of Sydney Australia

Novel visualization methods and strategies are necessary to cope with the deluge of datasets present in any scientific field to make discoveries and find answers to previously unanswered *** methods and strategies should not only present scientific findings as images in a concise way but also need to be effective and expressive,which often remain ***,we present Versus,a tool to enable easy image quality assessment and image ranking,utilizing a two-alternative forced choice methodology(2AFC)and an efficient ranking algorithm based on a binary *** tool provides a systematic way of setting up evaluation experiments via the web without the necessity to install any additional software or require any programming ***,Versus can easily interface with crowdsourcing platforms,such as Amazon’s Mechanical Turk,or can be used as a stand-alone system to carry out evaluations with *** demonstrate the use of Versus by means of an image evaluation study,aiming to determine if hue,saturation,brightness,and texture are good indicators of uncertainty in three-dimensional protein *** from the power of crowdsourcing,we argue that there is demand and also great potential for this tool to become a standard for simple and fast image evaluations,with the aim to test the effectiveness and expressiveness of scientific visualizations.

关键词： Evaluation Visualization Visual analytics Image comparison Crowdsourcing Evaluation methods 2AFC Image evaluation Tool Visualization evaluation

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Genome and clonal hematopoiesis stability contrasts with immune,cfDNA,mitochondrial,and telomere length changes during short duration spaceflight

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Precision Clinical Medicine 2024年第1期7卷 1-13页

作者： j.Sebastian Garcia-Medina Karolina Sienkiewicz S.Anand Narayanan Eliah G.Overbey Kirill Grigorev Krista A.Ryon Marissa Burke jacqueline Proszynski Braden Tierney Caleb M.Schmidt Nuria Mencia-Trinchant Remi Klotz Veronica Ortiz jonathan Foox Christopher Chin Deena Najjar Irina Matei Irenaeus Chan Carlos Cruchaga Ashley Kleinman jangKeun Kim Alexander Lucaci Conor Loy Omary Mzava Iwijn De Vlaminck Anvita Singaraju Lynn E.Taylor julian C.Schmidt Michael A.Schmidt Kelly Blease juan Moreno Andrew Boddicker junhua Zhao Bryan Lajoie Andrew Altomare Semyon Kruglyak Shawn Levy Min Yu Duane C.Hassane Susan M.Bailey Kelly Bolton jaime Mateus Christopher E.Mason Department of Physiology and Biophysics Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine Weill Cornell MedicineNew YorkNY 10021USA Department of Immunology Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA Department of Stem Cell Biology and Regenerative Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Space Exploration Technologies Corporation HawthomeCA 90250USA Sovaris Aerospace BoulderCO 80302USA Advanced Pattern Analysis&Human Performance Group BoulderCO 80302USA Children's Cancer and Blood Foundation Laboratories Departments of Pediatrics and Cell and Developmental BiologyDrukier Institute for Children's HealthMeyer Cancer CenterWeill Cornell MedicineNew YorkNY 10021USA Meyer Cancer Center Weill Cornell MedicineNew YorkNY 10065USA Department of Nutrition and Integrative Physiology Florida State UniversityTallahasseeFL 32306USA Department of Systems Engineering Colorado State UniversityFort CollinsCO 80523USA Element Biosciences San DiegoCA 10055USA Department of Environmental and Radiological Health Sciences Colorado State UniversityFort CollinsCO 80523USA Cell and Molecular Biology Program Colorado State UniversityFort CollinsCO 80523USA BioAstra Inc New YorkNYUSA Washington University St Louis Oncology Division St.LouisMO 63100USA Meinig School of Biomedical Engineering Cornell UniversityIthacaNY 14853USA The Feil Family Brain and Mind Research Institute Weill Cornell MedicineNY 10021USA WorldQuant Initiative for Quantitative Prediction Weill Cornell MedicineNew YorkNY 10021USA

Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic *** advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation *** To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA *** length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational *** Telomere elongation occurred during spaceflight and shortened after return to ***-free DNA analysis revealed increased immune cell signatures *** significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was *** long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months *** Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to *** sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career *** study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.

关键词： genomes clonal hematopoiesis stability immune mitochondria ribosomes spaceflight

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