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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael s.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-stay-Trim,”“sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

Importance of defining the best treatment of a genital gunshot wound: A case report

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World Journal of Clinical Cases 2014年第10期2卷 587-590页

作者： Herney andrés García-Perdomo school of Medicine Faculty of Health University of Valle

Twenty percent of genital traumas are caused by penetrating injuries; accordingly gunshot and stab wounds have increased in the last couple of years around the globe, even in Colombia. A 67-year-old male patient was admitted to the emergency room because he received multiple gunshot wounds. On physical examination, multiple wounds on his penis with loss of tissue in the foreskin, glans, anterior urethra(distal third) and cavernous corpora were found. The urologist performed a partial penectomy with a penis reconstruction, he debrided the cutaneous flap of the dorsal foreskin and its glans, sutured the distal cavernous corpora and dissected the urethra. Penetrating genital injuries are extremely important due to their impact on the functional, psychological and the aesthetic consequences. It is necessary to define the best possible treatment to minimize the damage.

关键词： Genital Penile Injuries Trauma Amputation

soundscape Dynamics at Anuran Reproductive sites in Pannonian Biogeographical Region：Effects of Road Noise on Vocal Activity

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Asian Herpetological Research 2016年第1期7卷 34-40页

作者： andrás WEIPERTH Ed sMITH szilvia sIMIGLA Miklòs PUKY Yezhong TANG MTA Centre Jor Ecological Research Danube Research Institute H- 1113 Budapest Karolina ut 29 Hungary Department of Psychology University of Maryland College Park MD 20742 USA Chengdu Institute of Biology Chinese Academy of Sciences # 9 of Section 4 South Renmin Road Chengdu 610041 Sichuan China

The emerging field of soundscape ecology views ecosystems in terms of biophony, geophony and anthrophony. soundscape ecology considers the effects of sound on fauna, and this research focuses on anuran breeding lek soundscapes. The sensitivity of anuran breeding leks to acoustic disturbances makes breeding leks an important venue for a comparative soundscape study. We made long-term（〉 24 h） sound recordings in three representative wetlands and short-term（〈 30 min） recordings in ten sites in the Pannonian Biogeographical Region of Hungary and around the Hungary and slovakia border. Long-term soundscapes of the floodplain stretch, where there is relatively minor anthrophonical disturbance, showed an obvious circadian change in sound intensities. The site with moderate sound contamination exhibited a disturbed pattern of circadian sound variation, while the site with heavy traffic noise displayed an apparently random temporal soundscape. At different amphibian breeding sites during mating season, our short-term recordings were dominated by anuran calls, bird songs and wind noises, while insect calls and rain were present to a lesser degree. Our study indicates that vehicle traffic noise is a severe imposition to the natural soundscape, and suggests that soundscape monitoring can provide a reliable and sensitive index of environmental change for both short-term and long-term periods.

关键词： soundscape monitoring anuran breeding site biophony geophony anthrophony

Genetic differentiation of grain, fodder and pod vegetable type cowpeas (Vigna unguiculata L.) identified through single nucleotide polymorphisms from genotyping-by-sequencing

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Molecular Horticulture 2022年第1期2卷 101-115页

作者： Xingbo Wu andrés JCortés Matthew W.Blair Department of Agricultural and Environmental sciences Tennessee State UniversityNashvilleTN 37209USA Tropical Research and Education Center Department of Environmental HorticulturalUniversity of Florida18905 SW 280th StHomesteadFL 33031USA Corporación Colombiana de Investigación Agropecuaria AGROsAVIA C.I.La SelvaKm 7 vía Rionegro–Las PalmasRionegroColombia Universidad Nacional de Colombia–sede Medellín Facultad de Ciencias Agrarias–Departamento de Ciencias ForestalesMedellínColombia

The species Vigna unguiculata L.(Walp),commonly known as cowpea,is a multi-purpose legume that has been selected into three subspecies that are divided into grain,fodder and pod(yardlong bean)***,genetic bases for distinctions are not well *** purpose of this study was to apply genotyping-by-sequencing(GBs)and current reference genome for *** to distinguish three subspecies and identify signatures of *** collection of 130 accessions included 128 cultivated from:1)***,fodder type;2)***,pod vegetable type;and 3)***,grain *** wilds genotypes from *** and ***,were used to anchor phylogeny.A total of 11,083 highly informative single nucleotide polymorphisms(sNPs)were *** accessions showed distinct genetic fingerprints and were separated from cultivated *** component analysis showed closer relationship between *** and *** compared to *** differentiation of cultivated subspecies(with Fixation Index,FsT)indicated the existence of discrete signatures of *** work clarifies the population structure,phylogeny,and domestication of cultivated ***,significant genetic differences between grain and pod vegetable types can provide valuable information for future breeding in three cowpea groups.

关键词： Genomic landscape of divergence Relative differentiation FsT GBs-derived sNP markers

Eosinophilic esophagitis: Current concepts in diagnosis and treatment

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World Journal of Gastroenterology 2019年第32期25卷 4598-4613页

作者： andrés Gómez-Aldana Mario Jaramillo-santos andrés Delgado Carlos Jaramillo Adán Lúquez-Mindiola Departament of Internal Medicine Section of GastroenterologySanta Fe Foundation of Bogotá(Fundación Santa Fe de Bogotá)Bogotá220246Colombia University of Los Andes Bogotá111711Colombia Department of Endoscopy Caldas UniversityManizales 275Colombia Department of Endoscopy Surgeons’Union SAS(Joint stock company)(Union de cirujanos SAS)Manizales 170001661Colombia Department of Gastroenterology Gut MédicaBogotá110221001Colombia

Eosinophilic esophagitis is an immune-allergic pathology of multifactorial etiology(genetic and environmental)that affects both pediatric and adult *** symptoms,which include heartburn,regurgitation,and esophageal stenosis(with dysphagia being more frequent in eosinophilic esophagitis in young adults and children),are similar to those of gastroesophageal reflux disease,causing delays in diagnosis and *** endoscopic findings such as furrows,esophageal mucosa trachealization,and whitish exudates may suggest its presence,this diagnosis should be confirmed histologically based on the presence of more than 15 eosinophils per high-power field and the exclusion of other causes of eosinophilia(parasitic infections,hypereosinophilic syndrome,inflammatory bowel disease,among others)for which treatment could be ***,the 3“D”s(“Drugs,Diet,and Dilation”)are considered the fundamental components of *** first 2 components,which involve the use of proton pump inhibitors,corticosteroids,immunosuppressants and empirical diets or guided food elimination based on allergy tests,are more useful in the initial phases,whereas endoscopic dilation is reserved for esophageal ***,the most important aspects of eosinophilic esophagitis pathophysiology will be reviewed,in addition to evidence for the various treatments.

关键词： Eosinophilic esophagitis Corticoid Esophageal stenosis Diet Dilation Proton pump inhibitor

Aquaculture solids Management Using A Combination of sand/Gravel or Unwoven Fabric Bed With Lolium perenne Lam as A Plant Biofilter

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Biomedical and Environmental sciences 2007年第6期20卷 439-444页

作者： andr NDUWIMANA Institute of Agricultural and Bio-Environmental Engineering College of Biosystems Engineering and Food Sciences Zhejiang University

Objective This work is an evaluation of the efficiency of a sand-gravel or unwoven fabric bed system and Lolium perenne Lam as plant biofilter in the reduction of solids and nutrients removal from aquaculture discharge water. Methods The fzrst step consisted of the collection of wastewater in the tank and the distribution at three different hydraulic loading regimes （0.5, 1, 1.5 L/hour） to the different experimental systems. The second step was to evaluate the performance of the different systems. The fzrst system consisted of a bucket filled with a substrate of sand/gravel （20 cm in depth）, on the bottom of which was a 80 mesh/inch2 of nylon （s1）; the second was similar, but was planted with Lolium perenne lam （s2）; the third was planted with a grass plate consisting of 7 layers of unwoven fabric planted with L. perenne （s3）. Results The second system showed the best performance in reducing solids as well as in nutrients （TN, TP, and COD） reduction. The removal rates for Ts, TN, and TP were negatively correlated with the loading regimes, with 0.5 L/hour being the most efficient and thus taken as the reference. Conclusions solids management using a sand/gravel substrate as bed culture and Lolium perenne L. as plant biofilter has proved to be an efficient technique for solids reduction with low operating cost. This grass plays an important role in wastewater eco-treatment by absorbing dissolved pollutants （TAN） as nutrients for its growth.

关键词： Lolium perenne lam Hydraulic loading regimes Microcosm

Trabectedin therapy as an emerging treatment strategy for recurrent platinum-sensitive ovarian cancer

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Chinese Journal of Cancer 2015年第1期34卷 41-49页

作者： José Antonio López-Guerrero Ignacio Romero andrés Poveda Laboratory of Molecular Biology Fundación Instituto Valenciano de Oncología Clinical Area of Gynecological Cancer Fundación Instituto Valenciano de Oncología

Epithelial ovarian cancer(OC) is a common gynecologic malignancy in women. The standard treatment for OC is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. Despite the high response rate to primary therapy, approximately 85% of patients will develop recurrent ovarian cancer(ROC). This review identifies the clinical use of trabectedin in the treatment algorithm for ROC, with specific emphasis on platinum-sensitive ROC, for which trabectedin in combination with pegylated liposomal doxorubicin has been approved as a treatment protocol. The main mechanisms of action of trabectedin at the cellular level and in the tumor microenvironment is also discussed as bases for identifying biomarkers for selecting patients who may largely benefit from trabectedin-based therapies.

关键词：治疗方案卵巢癌敏感复发铂疗法恶性肿瘤聚乙二醇化

Affinity-Based Network Interfaces for Efficient Communication on Multicore Architectures

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Journal of Computer science & Technology 2013年第3期28卷 508-524页

作者： andrés Ortiz Julio Ortega Antonio F.Díaz Alberto Prieto Department of Communications Engineering University of Málaga Department of Computer Architecture and Technology/CITIC University of Granada

Improving the network interface performance is needed by the demand of applications with high communication requirements （for example, some multimedia, real-time, and high-performance computing applications）, and the availability of network links providing multiple gigabits per second bandwidths that could require many processor cycles for communication tasks. Multicore architectures, the current trend in the microprocessor development to cope with the difficulties to further increase clock frequencies and microarchitecture efficiencies, provide new opportunities to exploit the parallelism available in the nodes for designing efficient communication architectures. Nevertheless, although present Os network stacks include multiple threads that make it possible to execute network tasks concurrently in the kernel, the implementations of packet-based or connection-based parallelism are not trivial as they have to take into account issues related with the cost of synchronization in the access to shared resources and the efficient use of caches. Therefore, a common trend in many recent researches on this topic is to assign network interrupts and the corresponding protocol and network application processing to the same core, as with this affinity scheduling it would be possible to reduce the contention for shared resources and the cache misses. In this paper we propose and analyze several configurations to distribute the network interface among the different cores available in the server. These alternatives have been devised according to the affinity of the corresponding communication tasks with the location （proximity to the memories where the different data structures are stored） and characteristics of the processing core. As this approach uses several cores to accelerate the communication path of a given connection, it can be seen as complementary to those that consider several cores to simultaneously process packets belonging to either the same or different connections.

关键词： interrupt affinity processor affinity network interface offioading, sIMICs

Modeling slow deformation of polygonal particles using DEM

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Particuology 2008年第6期6卷 506-514页

作者： andrés A. Pea Pedro G. Lind Hans J. Herrmann Institute for Computational Physics Universitt Stuttgart Computational Physics IfB HIF E12 ETH Hnggerberg CH-8093 Zrich Switzerland Departamento de Física Universidade Federal do Ceará

We introduce two improvements in the numerical scheme to simulate collision and slow shearing of irregular particles. First, we propose an alternative approach based on simple relations to compute the frictional contact forces. The approach improves efficiency and accuracy of the Discrete Element Method （DEM） when modeling the dynamics of the granular packing. We determine the proper upper limit for the integration step in the standard numerical scheme using a wide range of material parameters. To this end, we study the kinetic energy decay in a stress controlled test between two particles. second, we show that the usual way of defining the contact plane between two polygonal particles is, in general, not unique which leads to discontinuities in the direction of the contact plane while particles move. To solve this drawback, we introduce an accurate definition for the contact plane based on the shape of the overlap area between touching particles, which evolves continuously in time.

关键词： Granular media Discrete element method slow deformation Contact forces