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Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms

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Bioactive Materials 2023年第8期26卷 52-63页

作者： Nisakorn Yodsanit Takuro Shirasu Yitao Huang Li Yin Zain Husain Islam alexander christopher gregg Alessandra Marie Riccio Runze Tang Eric William Kent Yuyuan Wang Ruosen Xie Yi Zhao Mingzhou Ye Jingcheng Zhu Yi Huang Nicholas Hoyt Mengxue Zhang John A.Hossack Morgan Salmon K.Craig Kent Lian-Wang Guo Shaoqin Gong Bowen Wang Department of Biomedical Engineering Wisconsin Institute for DiscoveryUniversity of Wisconsin-MadisonMadisonWI53715USA Department of Ophthalmology and Visual Sciences University of Wisconsin-MadisonMadisonWI53715USA Department of Surgery School of MedicineUniversity of VirginiaCharlottesvilleVA22908USA The Biomedical Sciences Graduate Program(BIMS) School of MedicineUniversity of VirginiaCharlottesvilleVA22908USA Department of Biomedical Engineering School of EngineeringUniversity of VirginiaCharlottesvilleVA22908USA School of Medicine and Health Sciences George Washington UniversityWashingtonDC20052USA Department of Cardiac Surgery Michigan MedicineUniversity of MichiganAnn ArborMI48109USA

Abdominal aortic aneurysm(AAA)is a progressive aortic dilatation,causing~80%mortality upon rupture.Currently,there is no approved drug therapy for AAA.Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which,however,account for~90%of the newly diagnosed cases.It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression.We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods.There is substantial evidence that degenerative smooth muscle cells(SMCs)orchestrate AAA pathogenesis and progression.In this study,we made an exciting finding that PERK,the endoplasmic reticulum(ER)stress Protein Kinase R-like ER Kinase,is a potent driver of SMC degeneration and hence a potential therapeutic target.Indeed,local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo.In parallel,we also conceived a biomimetic nanocluster(NC)design uniquely tailored to AAA-targeting drug delivery.This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating;and when loaded with a selective PERK inhibitor(PERKi,GSK2656157),the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA.In summary,our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis,but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

关键词： Abdominal aortic aneurysm ER stress PERK Biomimetic nanomedicine Targeted delivery

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A new perspective on intervertebral disc calcification—from bench to bedside

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Bone Research 2024年第1期12卷 50-61页

作者： Emanuel J.Novais Rajkishen Narayanan Jose A.Canseco Koen van de Wetering christopher K.Kepler Alan S.Hilibrand alexander R.Vaccaro Makarand V.Risbud Department of Orthopaedic Surgery Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaPAUSA Unidade Local de Saúde do Litoral Alentejano Orthopedic DepartmentSantiago do CacémPortugal Rothman Orthopedic Institute at Thomas Jefferson University PhiladelphiaPAUSA

Disc degeneration primarily contributes to chronic low back and neck pain.Consequently,there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis,ectopic calcification,herniation,or mixed phenotypes.Amongst these phenotypes,disc calcification is the least studied.Ectopic calcification,by definition,is the pathological mineralization of soft tissues,widely studied in the context of conditions that afflict vasculature,skin,and cartilage.Clinically,disc calcification is associated with poor surgical outcomes and back pain refractory to conservative treatment.It is frequently seen as a consequence of disc aging and progressive degeneration but exhibits unique molecular and morphological characteristics:hypertrophic chondrocyte-like cell differentiation;TNAP,ENPP1,and ANK upregulation;cell death;altered Pi and PPi homeostasis;and local inflammation.Recent studies in mouse models have provided a better understanding of the mechanisms underlying this phenotype.It is essential to recognize that the presentation and nature of mineralization differ between AF,NP,and EP compartments.Moreover,the combination of anatomic location,genetics,and environmental stressors,such as aging or trauma,govern the predisposition to calcification.Lastly,the systemic regulation of calcium and Pi metabolism is less important than the local activity of PPi modulated by the ANK-ENPP1 axis,along with disc cell death and differentiation status.While there is limited understanding of this phenotype,understanding the molecular pathways governing local intervertebral disc calcification may lead to developing disease-modifying drugs and better clinical management of degeneration-related pathologies.

关键词： degeneration metabolism intervertebral

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Quantifying Kinematic Tremor in an NGLY1-Deficient Individual: A Case Study

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Case Reports in Clinical Medicine 2024年第1期13卷 25-36页

作者： Brock Futrell christopher alexander Malaya Dacia Martinez Diaz Christian Alfaro Hannah Elizabeth Gustafson Subhalakshmi Chandrasekaran Rhea Mohan Phatak Bernhard Suter Charles Shannon Layne Department of Health and Human Performance University of Houston Houston USA Center for Neuromotor and Biomechanics Research University of Houston Houston USA Department of Computer Science and Engineering Texas A&M University College Station USA Blue Bird Circle Rett Center Texas Children’s Hospital Houston USA Baylor College of Medicine Houston USA Center for NeuroEngineering and Cognitive Science University of Houston Houston USA

NGLY1 Deficiency is an autosomal recessive congenital disorder that has been identified in less than 100 individuals. Most individuals with NGLY1 Deficiency display hyperkinetic movement disorders, including choreiform, athetoid, dystonic myoclonic, dyskinetic, and dysmetric movements. Developing a consistent and concise consensus on the classification and evaluation of tremors is essential to forward the research and treatment of tremors. It has also been reported that some individuals with NGLY1 Deficiency demonstrate tremor, but such tremor has never been formally investigated. The primary objective of this study is to determine if an individual with NGLY1 Deficiency demonstrates an identifiable tremor during a series of arm movements and, if so, describe the frequency and power characteristics of that tremor. Arm movement kinematics were obtained using a 16-camera Vicon system, and time series trajectory waveforms for three planes of a marker placed on the hand were developed. Custom MATLAB scripts were utilized to compute Fast Fourier Transformations of the data within the identified waveform segments. A mean frequency of 2.30 Hz (SD = 1.05) with a mean power of 5.02 |P1(f)| (SD = 4.63) suggests that our participant’s kinematic data did display a persistent tremor in both hands across all tasks and movement planes. Analyses of the reaching hand and the non-reaching hand suggest the participant displayed an action tremor in both postural and intention (kinetic) tremors. Future directions should include assessing additional individuals with NGLY1 Deficiency to determine if the tremor is a distinguishable disorder behavior. Additionally, evaluating other anatomical sites, such as the elbow, head, and lower limbs, would provide further insights into the characteristics of this tremor.

关键词： Tremor NGLY Fast Fourier Transformation Reaching Hyperkinetic Movement

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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 approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere 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 burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion 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 Earth.CHIP 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 astronauts.This 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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Electrochemically Grown Ultrathin Platinum Nanosheet Electrodes with Ultralow Loadings for Energy-Saving and Industrial-Level Hydrogen Evolution

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Nano-Micro Letters 2023年第9期15卷 257-274页

作者： Lei Ding Zhiqiang Xie Shule Yu Weitian Wang alexander Y.Terekhov Brian K.Canfield christopher B.Capuano Alex Keane Kathy Ayers David A.Cullen Feng-Yuan Zhang Nanodynamics and High-Efficiency Lab for Propulsion and Power Department of MechanicalAerospace&Biomedical EngineeringUT Space Institute(University of Tennessee-Knoxville)TullahomaTN 37388USA Center for Laser Applications UT Space Institute(University of Tennessee-Knoxville)TullahomaTN 37388USA Nel Hydrogen WallingfordCT 06492USA Oak Ridge National Laboratory Center for Nanophase Materials SciencesOak RidgeTN 37831USA

Nanostructured catalyst-integrated electrodes with remarkably reduced catalyst loadings,high catalyst utilization and facile fabrication are urgently needed to enable cost-effective,green hydrogen production via proton exchange membrane electrolyzer cells(PEMECs).Herein,benefitting from a thin seeding layer,bottom-up grown ultrathin Pt nanosheets(Pt-NSs)were first deposited on thin Ti substrates for PEMECs via a fast,template-and surfactant-free electrochemical growth process at room temperature,showing highly uniform Pt surface coverage with ultralow loadings and vertically well-aligned nanosheet morphologies.Combined with an anode-only Nafion 117 catalyst-coated membrane(CCM),the Pt-NS electrode with an ultralow loading of 0.015 mgPt cm−2 demonstrates superior cell performance to the commercial CCM(3.0 mgPt cm^(−2)),achieving 99.5%catalyst savings and more than 237-fold higher catalyst utilization.The remarkable performance with high catalyst utilization is mainly due to the vertically well-aligned ultrathin nanosheets with good surface coverage exposing abundant active sites for the electrochemical reaction.Overall,this study not only paves a new way for optimizing the catalyst uniformity and surface coverage with ultralow loadings but also provides new insights into nanostructured electrode design and facile fabrication for highly efficient and low-cost PEMECs and other energy storage/conversion devices.

关键词： Seeding layer Electrochemically grown Pt nanosheet Ultralow loadings High catalyst utilization Hydrogen evolution

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Spectral reflectance response to nitrogen fertilization in field grown corn

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International Journal of Agricultural and Biological Engineering 2018年第4期11卷 118-126页

作者： Chuanqi Xie Ce Yang alexander Hummel Jr gregg A Johnson Forrest T Izuno Department of Bioproducts and Biosystems Engineering University of MinnesotaSaint PaulMN 55108United States Farm Nutrients Inc. 4949 Hwy 71RembrandtIA 50576United States Department of Agronomy and Plant Genetics University of MinnesotaSaint PaulMN 55108United States Southern Research and Outreach Center University of MinnesotaWasecaMN 56093United States

This study was carried out to analyze the spectral reflectance response of different nitrogen levels for corn crops.Four different nitrogen treatments of 0%,80%,100%and 120%BMP(best management practice)were studied.Principal component analysis-loading(PCA-loading)was used to identify the effective wavelengths.Partial least squares(PLS)and multiple linear regression(MLR)models were built to predict different nitrogen values.Vegetation indices(VIs)were calculated and then used to build more prediction models.Both full and selected wavelengths-based models showed similar prediction trends.The overall PLS model obtained the coefficient of determination(R^(2))of 0.6535 with a root mean square error(RMSE)of 0.2681 in the prediction set.The selected wavelengths for overall MLR model obtained the R^(2) of 0.6735 and RMSE of 0.3457 in the prediction set.The results showed that the wavelengths in visible and near infrared region(350-1000 nm)performed better than the two either spectral regions(1001-1350/1425-1800 nm and 2000-2400 nm).For each data set,the wavelengths around 555 nm and 730 nm were identified to be the most important to predict nitrogen rates.The vogelmann red edge index 2(VOG 2)performed the best among all VIs.It demonstrated that spectral reflectance has the potential to be used for analyzing nitrogen response in corn.

关键词： spectrum effective wavelengths principal component analysis-loading(PCA-loading) prediction vegetation indices(VIs) corn

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Closed-loop superconducting materials discovery

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npj Computational Materials 2023年第1期9卷 471-478页

作者： Elizabeth A.Pogue alexander New Kyle McElroy Nam Q.Le Michael J.Pekala Ian McCue Eddie Gienger Janna Domenico Elizabeth Hedrick Tyrel M.McQueen Brandon Wilfong Christine D.Piatko christopher R.Ratto Andrew Lennon Christine Chung Timothy Montalbano Gregory Bassen christopher D.Stiles Research and Exploratory Development Department Johns Hopkins University Applied Physics Laboratory11100 Johns Hopkins RoadLaurel 20723 MDUSA Department of Materials Science and Engineering Northwestern University2220 Campus DriveEvanston 60208 ILUSA Department of Materials Science and Engineering Johns Hopkins University3400 N.Charles StreetBaltimore 21218 MDUSA Department of Chemistry Johns Hopkins University3400 N.Charles StreetBaltimore 21218 MDUSA Institute for Quantum Matter William H.Miller III Department of Physics and AstronomyJohns Hopkins University3400 N.Charles StreetBaltimore 21218 MDUSA

Discovery of novel materials is slow but necessary for societal progress.Here,we demonstrate a closed-loop machine learning(ML)approach to rapidly explore a large materials search space,accelerating the intentional discovery of superconducting compounds.By experimentally validating the results of the ML-generated superconductivity predictions and feeding those data back into the ML model to refine,we demonstrate that success rates for superconductor discovery can be more than doubled.Through four closed-loop cycles,we report discovery of a superconductor in the Zr-In-Ni system,re-discovery of five superconductors unknown in the training datasets,and identification of two additional phase diagrams of interest for new superconducting materials.Our work demonstrates the critical role experimental feedback provides in ML-driven discovery,and provides a blueprint for how to accelerate materials progress.

关键词： discovery materials loop

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Acute coronary syndromes： an old age problem

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Journal of Geriatric Cardiology 2012年第2期9卷 192-196页

作者： alexander D Simms Philip D Batin John Kurian Nigel Durham christopher P Gale Centre for Epidemiology and Biostatistics Level 8 Worsley Building University of Leeds Clarendon Way West Yorkshire Leeds LS2 9JT UK Hull and York Medical School York Teaching Hospital NHS Foundation Trust York Y031 8HE UK Department of Cardiology York Teaching Hospital NHS Foundation Trust York Y031 8HE UK Department of Cardiology Mid Yorkshire NHS Trust Wakefield WF1 4DG UK Department of Cardiology Bradford Teaching Hospital NHS Foundation Trust Bradford UK

在老年的增加的人口将导致他们的更大的数字与急性冠的症候群(交流) 介绍。这在全球保健资源上有含意并且为基于证据的治疗要求更好的管理和选择。老比更年轻的交流是有更重要的治疗好处的一个高风险组。不过，在交流的相关不平等在乎... 详细信息

在老年的增加的人口将导致他们的更大的数字与急性冠的症候群(交流) 介绍。这在全球保健资源上有含意并且为基于证据的治疗要求更好的管理和选择。老比更年轻的交流是有更重要的治疗好处的一个高风险组。不过，在交流的相关不平等在乎的年龄被认出并且坚持。到某程度，在照顾的这差异被不正常、推迟的演讲的更高的频率在表示在老、不太诊断的心电图解释，加强在交流的延期诊断。在死亡风险在的评价下面由于为生理的脆弱，合作病态，认知 / 心理的缺陷和物理残疾的有限考虑老，由心病学专家和 randomised 的缺乏的更少的输入，指导管理在的控制试用数据老可以进一步使照顾的不平等惊讶。当这些不平等存在时，在那里仍然是一个实质的机会改进年龄相关交流结果。为特定的治疗和药政体的老病人的选择是未答复的。对 randomised 有成长需要，人口更代表性并且与合作病态先进年龄注册那些的控制试用数据。不利事件报导的缺乏，张贴冠的 angiography 例如肾的缺陷，在老进一步的限制风险利益决定。在老交流病人的照顾的实质的改进被要求并且应该被倡导。最终，这些改进是可能的导致更好的结果柱子交流。然而，在结果的改进不是无限的并且将由年龄相关的风险的非可修改的因素有限。

关键词：急性冠脉综合征年龄急性冠状动脉综合征中老年人冠状动脉造影风险估计 ACS 肾功能不全

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Particle-Mediated Histotripsy for the Targeted Treatment of Intraluminal Biofilms in Catheter-Based Medical Devices

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Biomedical Engineering Frontiers 2022年第1期3卷 367-380页

作者： christopher Childers Connor Edsall Isabelle Mehochko Waleed Mustafa Yasemin Yuksel Durmaz alexander L.Klibanov Jayasimha Rao Eli Vlaisavljevich Virginia Tech Carilion School of Medicine USA Department of Biomedical Engineering and Mechanics Virginia TechUSA Department of Biomedical Engineering Istanbul Medipol UniversityTurkey Division of Cardiovascular Medicine(Department of Medicine)and Robert M.Berne Cardiovascular Research Center at University of Virginia School of Medicine University of VirginiaUSA Department of Medicine Division of Infectious DiseasesVirginia Tech Carilion School of MedicineUSA ICTAS Center for Engineered Health Virginia Polytechnic Institute and State UniversityUSA

Objective.This paper is an initial work towards developing particle-mediated histotripsy(PMH)as a novel method of treating catheter-based medical device(CBMD)intraluminal biofilms.Impact Statement.CBMDs commonly become infected with bacterial biofilms leading to medical device failure,infection,and adverse patient outcomes.Introduction.Histotripsy is a noninvasive focused ultrasound ablation method that was recently proposed as a novel method to remove intraluminal biofilms.Here,we explore the potential of combining histotripsy with acoustically active particles to develop a PMH approach that can noninvasively remove biofilms without the need for high acoustic pressures or real-time image guidance for targeting.Methods.Histotripsy cavitation thresholds in catheters containing either gas-filled microbubbles(MBs)or fluid-filled nanocones(NCs)were determined.The ability of these particles to sustain cavitation over multiple ultrasound pulses was tested after a series of histotripsy exposures.Next,the ability of PMH to generate selective intraluminal cavitation without generating extraluminal cavitation was tested.Finally,the biofilm ablation and bactericidal capabilities of PMH were tested using both MBs and NCs.Results.PMH significantly reduced the histotripsy cavitation threshold,allowing for selective luminal cavitation for both MBs and NCs.Results further showed PMH successfully removed intraluminal biofilms in Tygon catheters.Finally,results from bactericidal experiments showed minimal reduction in bacteria viability.Conclusion.The results of this study demonstrate the potential for PMH to provide a new modality for removing bacterial biofilms from CBMDs and suggest that additional work is warranted to develop histotripsy and PMH for treatment of CBMD intraluminal biofilms.

关键词： cavitation remove filled

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Improved bridge pier collar for reducing scour

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International Journal of Sediment Research 2022年第1期37卷 37-46页

作者： christopher Valela Colin David Rennie Ioan Nistor Department of Civil Engineering University of Ottawa

This study performed a bridge pier collar comparison for the purpose of reducing scour,while introducing a new collar design.The new collar,referred to as Collar Prototype Number 3,was designed based on an equilibrium scour hole and provides a method of controlling the horseshoe vortex.Numerical modelling was utilized to show the flow field and bed shear stress as a result of using Collar Prototype Number 3.A prototype model of Collar Prototype Number 3 and a flat plate collar were constructed for the purpose of comparing both experimentally under different flow conditions.Collar Prototype Number 3 proved to be an effective device as it reduced scour in terms of the maximum depth downstream of the pier and overall volume,in some instances,by up to 69.7%and 75.7%,respectively.Furthermore,Collar Prototype Number 3 outperformed the flat plate collar,especially because,unlike the flat plate collar,Collar Prototype Number 3 did not experience undermining.

关键词： Bridge pier Scour Horseshoe vortex Pier collar Scour countermeasure

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