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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 ***,there is no approved drug therapy for *** repairs are invasive and risky and thus not recommended to patients with small AAAs which,however,account for~90%of the newly diagnosed *** is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA *** contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery *** is substantial evidence that degenerative smooth muscle cells(SMCs)orchestrate AAA pathogenesis and *** 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 ***,local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in *** parallel,we also conceived a biomimetic nanocluster(NC)design uniquely tailored to AAA-targeting drug *** 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 *** 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 ***,there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis,ectopic calcification,herniation,or mixed *** these phenotypes,disc calcification is the least *** calcification,by definition,is the pathological mineralization of soft tissues,widely studied in the context of conditions that afflict vasculature,skin,and ***,disc calcification is associated with poor surgical outcomes and back pain refractory to conservative *** 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 *** studies in mouse models have provided a better understanding of the mechanisms underlying this *** is essential to recognize that the presentation and nature of mineralization differ between AF,NP,and EP ***,the combination of anatomic location,genetics,and environmental stressors,such as aging or trauma,govern the predisposition to ***,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 *** 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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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 *** different nitrogen treatments of 0%,80%,100%and 120%BMP(best management practice)were *** component analysis-loading(PCA-loading)was used to identify the effective *** least squares(PLS)and multiple linear regression(MLR)models were built to predict different nitrogen *** indices(VIs)were calculated and then used to build more prediction *** full and selected wavelengths-based models showed similar prediction *** 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 *** selected wavelengths for overall MLR model obtained the R^(2) of 0.6735 and RMSE of 0.3457 in the prediction *** 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 *** vogelmann red edge index 2(VOG 2)performed the best among all *** 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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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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A critical examination of compound stability predictions from machine-learned formation energies

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npj Computational Materials 2020年第1期6卷 858-868页

作者： christopher J.Bartel Amalie Trewartha Qi Wang alexander Dunn Anubhav Jain Gerbrand Ceder Department of Materials Science&Engineering University of CaliforniaBerkeleyBerkeleyCA 94720USA Energy Technologies Area Lawrence Berkeley National LaboratoryBerkeleyCA 94720USA Materials Sciences Division Lawrence Berkeley National LaboratoryBerkeleyCA 94720USA

Machine learning has emerged as a novel tool for the efficient prediction of material properties,and claims have been made that machine-learned models for the formation energy of compounds can approach the accuracy of Density Functional Theory(DFT).The models tested in this work include five recently published compositional models,a baseline model using stoichiometry alone,and a structural *** testing seven machine learning models for formation energy on stability predictions using the Materials Project database of DFT calculations for 85,014 unique chemical compositions,we show that while formation energies can indeed be predicted well,all compositional models perform poorly on predicting the stability of compounds,making them considerably less useful than DFT for the discovery and design of new *** critically,in sparse chemical spaces where few stoichiometries have stable compounds,only the structural model is capable of efficiently detecting which materials are *** nonincremental improvement of structural models compared with compositional models is noteworthy and encourages the use of structural models for materials discovery,with the constraint that for any new composition,the ground-state structure is not known a *** work demonstrates that accurate predictions of formation energy do not imply accurate predictions of stability,emphasizing the importance of assessing model performance on stability predictions,for which we provide a set of publicly available tests.

关键词： stability critical solids

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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

The increasing population in older age will lead to greater numbers of them presenting with acute coronary syndromes （ACS）. This has implications on global healthcare resources and necessitates better management and selection for evidenced-based therapies. The elderly are a high risk group with more significant treatment benefits than younger ACS. Nevertheless, age related inequalities in ACS care are recognised and persist. This discrepancy in care, to some extent, is explained by the higher frequency of atypical and delayed presentations in the elderly, and less diagnostic electrocardiograms at presentation, potentiating a delay in ACS diagnosis. Under estimation of mortality risk in the elderly due to limited consideration for physiological tiailty, co-morbidity, cognitive/psychological impairment and physical disability, less input by cardiology specialists and lack of randomised, controlled trials data to guide management in the elderly may further confound the inequality of care. While these inequalities exist, there remains a substantial opportunity to improve age related ACS outcomes. The selection of elderly patients for specific therapies and medication regimens are unanswered. There is a growing need for randomised, controlled trial data to be more representative of the population and enroll those of advanced age with co-morbidity. A lack of reporting of adverse events, such as renal impairment post coronary angiography, in the elderly further limit risk benefit decisions. Substantial improvements in care of elderly ACS patients are required and should be advocated. Ultimately, these improvements are likely to lead to better outcomes post ACS. However, the improvement in outcome is not infinite and will be limited by non-modifiable factors of age-related risk.

关键词： Acute coronary syndromes Elderly patients Inequalities of care Evidenced-based treatments

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Applying reticular synthesis to the design of Cu-based MOFs with mechanically interlocked linkers

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Nano Research 2021年第2期14卷 417-422页

作者： alexander J.Stirk Benjamin H.Wilson christopher A.O’Keefe Hazem Amame Kelong Zhu Robert W.Schurko Stephen J.Loeb Department of Chemistry and Biochemistry University of WindsorWindsorOntarioN9B 3B4Canada Department of Chemistry The University of JordanAmman11942Jordan School of Chemistry Sun Yat-Sen UniversityGuangzhou 510275China Department of Chemistry and Biochemistry Florida State UniversityTallahasseeFlorida 32306-4390USA

The concept of“robust dynamics”describes the incorporation of mechanically interlocked molecules(MIMs)into metal-organic framework(MOF)materials such that large amplitude motions(e.g.,rotation or translation of a macrocycle)can occur inside the free volume pore of the *** aid in the preparation of such materials,reticular synthesis was used herein to design rigid molecular building blocks with predetermined ordered structures starting from the well-known MOF *** linkers were synthesized that have a T-shape,based on a triphenylene tetra-carboxylate strut,and their incorporation into Cu(II)-based MOFs was *** single-crystal structures of three new MOFs,UWCM-12(fof),β-UWCM-13(loz),UWCM-14(lil),with naked T-shaped linkers were determined;β-UWCM-13 is the first reported example of the loz topology.A fourth MOF,UWDM-14(lil)is analogous to UWCM-14(lil)but contains a[2]rotaxane ***-temperature,^(2)H solid-state NMR was used to probe the dynamics of a 24-membered macrocycle threaded onto the MOF skeleton.

关键词： reticular chemistry metal-organic frameworks mechanically interlocked molecules rotaxane

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Combinations of Feature Descriptors for Texture Image Classification

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Journal of Data Analysis and Information Processing 2014年第3期2卷 67-76页

作者： alexander Barley christopher Town University of Cambridge Computer Laboratory Cambridge UK

Texture recognition and classification is a widely applicable task in computer vision. A key stage in performing this task is feature extraction, which identifies sets of features that describe the visual texture of an image. Many descriptors can be used to perform texture classification;among the more common of these are the grey level co-occurrence matrix, Gabor wavelets, steerable pyramids and SIFT. We analyse and compare the effectiveness of these methods on the Brodatz, UIUCTex and KTH-TIPS texture image datasets. The efficacy of the descriptors is evaluated both in isolation and by combining several of them by means of machine learning approaches such as Bayesian networks, support vector machines, and nearest-neighbour approaches. We demonstrate that using a combination of features improves reliability over using a single feature type when multiple datasets are to be classified. We determine optimal combinations for each dataset and achieve high classification rates, demonstrating that relatively simple descriptors can be made to perform close to the very best published results. We also demonstrate the importance of selecting the optimal descriptor set and analysis techniques for a given dataset.

关键词： Image Processing Texture Analysis Computer Vision Image Classification

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Reactive and non-reactive transport modelling in partially water saturated argillaceous porous media around the ventilation experiment,Mont Terri

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Journal of Rock Mechanics and Geotechnical Engineering 2013年第1期5卷 44-57页

作者： alexander Bond Steven Benbow James Wilson Alain Millard Shigeo Nakama Myles English christopher McDermott Benoit Garitte Quintessa Ltd. Chadwick House Birchwood Park Warrington Cheshire WA3 6AE UK Commissariat à l'Energie Atomique Japan Atomic Energy Agency (JAEA) University of Edinburgh Universidad Politécnica de Catalunya

At Mont Terri Underground Research Laboratory （URL） Switzerland, a specific experiment has been per- formed in a tunnel, in order to investigate the hydro-mechano-chemical （HMC） perturbations induced in the argillaceous formation by forced ventilation. This experiment has been selected in the international project DECOVALEX to be used for process model development and validation. The numerical simula- tion of the geochemical response to the ventilation experiment （VE） is the object of the present paper, focusing on the transport of chloride as a conservative species and sulphate as a reactive species. Uti- lising the validated hydro-mechanical （HM） results from earlier steps of the DECOVALEX task, reactive and non-reactive transport models, incorporating the current understanding of the geochemistry at the site, were successfully constructed for the whole experimental period. The associated parametric and process uncertainty analyses clearly demonstrate that the basic HM understanding must be sound. How- ever, to demonstrate this degree of robustness, the explicit inclusion of process representations of water desaturation, liquid vaporisation, species exclusion porosity, and redox processes, is required.

关键词： Reactive transportHydro-mechanical (HM) couplingNumerical modellingMont Terri Underground ResearchLaboratory (URL)Ventilation experiment (VE)ArgilliteChlorideSulphate

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