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Immunomodulatory oligonucleotide IMT504:Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

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World Journal of Stem Cells 2017年第3期9卷 45-67页

作者： Jorge Zorzopulos Steven M Opal Andrés Hernando-Insúa juan M Rodriguez Fernanda Elías juan fló Ricardo A López Norma A Chasseing Victoria A Lux-Lantos Maria F Coronel Raul Franco Alejandro D Montaner David L Horn Immunotech S.A. Ciudad de Buenos Aires C1440FFXArgentina Infectious Disease Division Memorial Hospital of Rhode Island and Alpert Medical SchoolProvidenceRI 02905United States Fundación Pablo Cassara Ciudad Autonoma de Buenos Aires C1440FFXArgentina Instituto de Biología y Medicina Experimental(IBYME-CONICET) Ciudad Autónoma de Buenos Aires C1428ADNArgentina Instituto de Ciencia y Tecnolog'DR.Cesar Milstein” Fundación Pablo CassaráCiudad Autonoma de Buenos Aires C1440FFXArgentina David Horn LLC DoylestownPA 18902United States

The immune responses of humans and animals to insults(i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged proinflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell(MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.

关键词： Immunohomeostasis Immunoprotection Immunoregeneration Inflammation Mesenchymal stem cells IMT504

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Quality assessment of the Topo-Iberia CGPS stations and data quality's effects on postfit ionosphere-free phase residuals

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Geodesy and Geodynamics 2024年第2期15卷 189-199页

作者： juan A.García-Armenteros Center for Advanced Studies in Earth Sciences Energy and Environment(CEACTEMA)University of Jaén23071 JaenSpain

This paper analyzed GPS data from the Topo-Iberia network spanning almost 12 years(2008-2020).The data quality information for all 26 Topo-Iberia stations is provided for the first time,complementing the Spanish Geological Survey’s storage *** analyses based on quality indicators obtained using TEQC have been carried *** guidelines and data quality information from the IGS stations have been considered as the quality references,with the stations ALJI,EPCU,and TIOU standing out as the worst stations,while on the contrary,FUEN,PALM,PILA,and TRIA meet the quality requirements to become an IGS *** relationship between the GPS data quality and their GAMIT-and Gipsy X-derived postfit ionosphere-free phase residuals has also been investigated,and the results reveal an inversely proportional *** has been found that the stations showing an increase in elevation of the horizon line,also show an increase in cycle slips and multipath,are among the poorest quality stations,and among those with the highest postfit RMS of phase ***,the evolution of the vegetation around the antenna should be considered as it could cause a progressive loss of quality,which is not complying with the IGS *** quality assessment shows that the Topo-Iberia stations are appropriate for geodetic purposes,but permanent monitoring would be necessary to avoid the least possible loss of data and *** addition,a method to characterize the GNSS data quality is proposed.

关键词： GPS dataquality's effects IGS quality standard Postfit LC phase residual Qualityassessment Topo-Iberia CGPS network

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Thermodynamic property of sandwich cylindrical shell structure with metallic wire mesh:Numerical modeling and experimental analysis

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Chinese Journal of Aeronautics 2024年第1期37卷 138-152页

作者： Xin XUE Guojian SHEN juan LIAO Institute of Metal Rubber&Vibration Noise School of Mechanical Engineering and AutomationFuzhou UniversityFuzhou 350116China Fujian Shuikou Power Generation Group Co. LTDFuzhou 350000China

As a new addition to lightweight composite structures,the sandwich cylindrical shell with a metallic wire mesh core has emerged as a promising solution for thermodynamic performance analysis at elevated *** intricate interwoven cellular formations within the metallic wire mesh pose difficulties for thermo-mechanical modeling and property ***,the constitutive models employed to characterize hysteresis phenomena were presented,comprising isotropic elasticity,Bergstrom-Boyce model,Ogden hyper-elasticity,and parameter identification through mechanical examinations at varying ***,the finite element modeling of cylindrical shell structures was determined for modal and steady-state dynamic ***,the experimental procedures were carried out,including the preparation of the sandwich cylindrical shell and the dynamic testing *** first-order natural frequency of the cylindrical shell structure is close to the resonance frequency of the dynamic test results,with a maximum error of 6.5%,demonstrating the accuracy of the simulation *** compared to the solid-core cylindrical shell,the average insertion loss of the sandwich cylindrical shell structure within the frequency range of 10–1000 Hz at room temperature is up to 11.09 ***,at elevated temperatures,the average insertion loss of the sandwich cylindrical shell decreases but fluctuates as the temperature changes.

关键词： Energy dissipation Metallic matrix composites Numerical analysis Sandwich structure Thermodynamic properties

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Interface property of dissimilar Ti-6Al-4V/AA1050 composite laminate made by non-equal channel lateral co-extrusion and heat treatment

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Defence Technology（防务技术） 2024年第3期33卷 197-208页

作者： juan Liao Mengmeng Tian Xin Xue School of Mechanical Engineering and Automation Fuzhou UniversityFuzhou 350116China

The purpose of this paper is to examine the effect of processing parameters and subsequent heat treatments on the microstructures and bonding strengths of Ti-6Al-4V/AA1050 laminations formed via a non-equal channel lateral co-extrusion *** microstructural evolution and growth mechanism in the diffusion layer were discussed further to optimize the bonding quality by appropriately adjusting process *** electron microscopes(SEM),energy dispersive spectrometer(EDS),and X-ray diffraction(XRD)were used to characterize interfacial diffusion *** shear test was used to determine the mechanical properties of the interfacial diffusion *** experimental results indicate that it is possible to co-extrusion Ti-6Al-4V/AA1050 compound profiles using non-equal channel lateral *** heat treatment processes affect the thickness of the diffusion *** the temperature and time of heat treatment increase,the thickness of the reaction layers increases ***,the shear strength of the Ti-6Al-4V/AA1050 composite interface is proportional to the diffusion layer *** is observed that a medium interface thickness results in superior mechanical performance when compared to neither a greater nor a lesser interface *** characterization of all heat treatments reveals that the only intermetallic compound observed in the diffusion layers is TiAl_(3).Due to the inter-diffusion of Ti and Al atoms,the TiAl_(3) layer grows primarily at AA1050/TiAl_(3) interfaces.

关键词： Shear strength Co-extrusion Heat treatment Microstructure Intermetallic compounds

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Single-neuron neurodegeneration as a degenerative model for Parkinson’s disease

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Neural Regeneration Research 2024年第3期19卷 529-535页

作者： Sandro Huenchuguala juan Segura-Aguilar Escuela de Tecnología Médica Facultad de SaludUniversidad Santo TomásLos CarrerasOsornoChile Molecular&Clinical Pharmacology Instituto de Ciencias Biomedicas(ICBM)Faculty of medicineUniversity of ChileIndependenciaSantiagoChile

The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal *** preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical ***,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic *** lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big *** our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic *** exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic *** endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in t

关键词： 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 6-hydroxydopamine aminochrome dopaminergic neurons DT-diaphorase exogenous neurotoxins glutathione transferase M2-2

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Presynaptic endoplasmic reticulum architecture and hereditary spastic paraplegia

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Neural Regeneration Research 2024年第3期19卷 485-486页

作者： juan JoséPérez-Moreno Instituto de Biomedicina de Sevilla(IBiS) Hospital Universitario Virgen Del Rocío/CSIC/Universidad de Sevillaand Departamento de Biología CelularFacultad de BiologíaUniversidad de SevillaSevilleSpain

Hereditary spastic paraplegia(HSP)is a clinically and genetically heterogeneous neurodegenerative disorder,characterized primarily by progressive spasticity and weakness in the lower *** ients can also experience peripheral neuropathy,cognitive impairment,and other neurological *** date,more than 80 genes have been implicated in HSP,encompassing various cellular components,although mutations in genes encoding endoplasmic reticulum(ER)-shaping proteins are the most prevalent(Parodi et al.,2017).ER-shaping proteins are generally known for regulating the tubulation and curvation of the ER,but most of them show additional functions,including fusion of ER tubules,microtubule-severing,ER autophagy,lipid droplet synthesis,contact sites with other organelles(Öztürk et al.,2020).This highlights the complexity of studying the role of these proteins and the link between ER function and HSP.

关键词： reticulum endoplasmic

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Attractor for the Extensible Beam Equation with Nonlocal Weak Damping on Time–Dependent Space

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Acta Mathematica Sinica,English Series 2024年第4期40卷 1115-1126页

作者： Chun Xiang ZHAO Feng juan MENG Institute of Applied System Analysis Jiangsu UniversityZhenjiang 212013P.R.China School of Mathematics and Physics Jiangsu University of TechnologyChangzhou 213001P.R.China

In this article,we consider the long-time behavior of extensible beams with nonlocal weak damping:ε(t)u_(tt)+Δ^(2)u-m(‖▽u‖^(2))Δu+‖u_(t)‖^(p_(u_(t)))+f(u)=h,whereε(t)is a decreasing function vanishing at *** the theory of process on time-dependent spaces,we investigate the existence of the time-dependent attractor by using the Condition(C_(t))method and more detailed *** results obtained essentially improve and complete some previous works.

关键词： Time-dependent attractor extensible beams equation nonlocal weak damping

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Temporal stability and directional change in a color cline of a marine snail from NW Spain

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Current Zoology 2024年第2期70卷 163-173页

作者： juan Gefaell Ramon Vigo A.Honorato Gonzalez-Vazquez juan Galindo Emilio Rolan-Alvarez Centro de Investigacion Marina Universidade de VigoDepartamento de BioquimicaGenetica e Inmunologia36310 VigoSpain

The evolution and maintenance of color clines is a classic topic of research in evolutionary ***,studies analyzing the temporal dynamics of such clines are much less frequent,due to the difficulty of obtaining reliable data about past color distributions along environmen-tal *** this article,we describe a case of decades-long temporal stability and directional change in a color cline of the marine snail Littorina saxatilis along the coastal inlet of the Ria de Vigo(NW Spain).*** from this area shows a clear color cline with 3 distinct areas from the innermost to the more wave-exposed localities of the Ria:the inner,protected localities show an abundance of fawn-like individuals;the intermediate localities show a high diversity of colors;and the outer,wave-exposed localities show populations with a high frequency of a black and lineated *** compare data from the 1970s and 2022 in the same localities,showing that the cline has kept relatively stable for at least over half a century,except for some directional change and local variability in the frequency of certain *** regression analyses and biodiversity measures are presented to provide clues into the selective pressures that might be involved in the maintenance of this color *** research avenues to properly test the explanatory power of these selective agents as well as the possible origins of the cline are discussed.

关键词： clinal variation color polymorphism ecological gradient Littorina saxatilis natural selection wave exposure.

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Distributed Region Tracking and Perimeter Surveillance for Second-Order Multi-Agent Systems in Star-Shaped Sets

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Journal of Systems Science & Complexity 2024年第5期37卷 1995-2020页

作者： SHANG juan MO Lipo MI Rongxin CAO Xianbing School of Mathematics and Statistics Beijing Technology and Business University The Department of Foundation Shijiazhuang Institute of Railway Technology School of Computer and Artificial Intelligence Beijing Technology and Business University Research Centre for Agri-Product Quality Traceability Beijing Technology and Business University Coordination Center of China National Computer Network Emergency Response Technical Team

This paper investigates region tracking and perimeter surveillance of second-order multi-agent systems, where all agents move within a star-shaped set. First, by coordination transformations,the region tracking problem is converted from the star-shaped sets to a circular region. The authors employ communication and collaboration to complete region tracking and perimeter surveillance tasks,and then revert back to the star-shaped set by using inverse transformations. Second, the authors propose a distributed control strategy based on attractive and interaction potential functions, under which all agents can quickly track a given circular region and move around the perimeter. Finally,the authors validate the effectiveness and performance advantages of the proposed method through simulation experiments.

关键词： Distributed control multi-agent systems star-shaped sets target tracking

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IMT504: A New and Potent Adjuvant for Rabies Vaccines Permitting Significant Dose Sparing

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World Journal of Vaccines 2012年第4期2卷 182-188页

作者： Alejandro D. Montaner Analia De Nichilo juan M. Rodriguez Andres Hernando-Insua juan fló Ricardo A. Lopez Verónica Sierra Claudio Paolazzi Oscar Larghi David L. Horn Jorge Zorzopulos Fernanda Elias David Horn LLC Doylestown PA USA. Immunotech S.A. Buenos Aires Argentina Instituto de Investigaciones Biomédicas Fundación Pablo Cassará Buenos Aires Argentina Instituto San Jorge Bagó Buenos Aires Argentina Instituto San Jorge Bagó Buenos Aires Argentina. nstituto de Investigaciones Biomédicas Fundación Pablo Cassará Buenos Aires Argentina

Background: Rabies virus infection causes encephalitis, which is almost always fatal. Vaccination can be extremely effective at preventing disease but is prohibitively costly. Vaccine formulations allowing dose-sparing and fewer inoculations with faster antibody response would be extremely desirable. IMT504, an immunostimulatory non-CpG oligo-deoxynucleotide, is a highly potent vaccine adjuvant. Methods: Human and rat antibody measurements, and rat chal-lenge studies were performed. Results: In rats, highly effective immune responses with IMT504 were observed even after diluting vaccine up to 1/625. In highly lethal, live intracerebral rabies challenge studies, protection occurred even with extremely dilute vaccine plus IMT504. In humans, antibody titers developed faster and were significantly higher with IMT504-adjuvanted diluted vaccine vs non-adjuvanted vaccine (full strength or diluted). All five administered IMT504-adjuvanted diluted vaccine reached protective antibodies (≥0.5 IU/ml) after the second injection. After the third injection, individuals receiving IMT504-adjuvanted diluted vaccine reached levels approximately 10 times higher than controls (M ± SEM: 31.0 ± 10.9 vs 3.40 ± 0.99 IU/ml). Conclusions: These data suggest that IMT504 may allow fewer inoculations, highly significant dose-sparing of vaccine, rapid antibody production and protection from rabies. Extensive clinical studies are necessary to confirm if the use of IMT504 will permit significantly greater access to highly effective life-saving rabies vaccines.

关键词： IMT504 Adjuvant Rabies Vaccine Human Animal

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