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s-Nitroso-N-acetyl-L-cysteine ethyl ester(sNACET) and N-acetyl-L-cysteine ethyl ester(NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H_2s and GsH suppliers and as antioxidants: Results and overview

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Journal of Pharmaceutical Analysis 2018年第1期8卷 1-9页

作者： Dimitrios Tsikas kathrin s.schwedhelm Andrzej surdacki Daniela Giustarini Ranieri Rossi Lea Kukoc-Modun George Kedia stefan ückert Institute of Toxicology Core Unit Proteomics Hannover Medical School second Department of Cardiology Jagiellonian University Medical College Department of Medicine Surgery and Neuroscience University of Siena Department of Life sciences Laboratory of Pharmacology and Toxicology University of Siena Department of Analytical Chemistry Faculty of Chemistry and Technology University of Split Department of Urology and Urological Oncology Hannover Medical School

s-Nitrosothiols or thionitrites with the general formula RsNO are formally composed of the nitrosyl cation(NOt) and a thiolate(Rsà), the base of the corresponding acids RsH. The smallest s-nitrosothiol is HsNO and derives from hydrogen sulfide(HsH, H_2s). The most common physiological s-nitrosothiols are derived from the amino acid L-cysteine(Cys sH). Thus, the simplest s-nitrosothiol is s-nitroso-L-cysteine(Cys sNO). Cys sNO is a spontaneous potent donor of nitric oxide(NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate(c GMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet *** NO, Cys sNO is a short-lived species and occurs physiologically at concentrations around 1 n M in human blood. Cys sNO can be formed from Cys sH and higher oxides of NO including nitrous acid(HONO)and its anhydride(N_2O_3). The most characteristic feature of RsNO is the s-transnitrosation reaction by which the NOtgroup is reversibly transferred to another thiolate. By this way numerous RsNO can be formed such as the low-molecular-mass s-nitroso-N-acetyl-L-cysteine(sNAC) and s-nitroso-glutathione(GsNO), and the high-molecular-mass s-nitrosol-L-cysteine hemoglobin(Hb Cys sNO) present in erythrocytes and s-nitrosol-L-cysteine albumin(Alb Cys sNO) present in plasma at concentrations of the order of 200 n M. All above mentioned RsNO exert NO-related biological activity, but they must be administered intravenously. This important drawback can be overcome by lipophilic charge-free ***, we prepared the ethyl ester of sNAC, the s-nitroso-N-acetyl-L-cysteine ethyl ester(sNACET), from synthetic N-acetyl-L-cysteine ethyl ester(NACET). Both NACET and sNACET have improved pharmacological features over N-acetyl-L-cysteine(NAC) and s-nitroso-N-acetyl-L-cysteine(sNAC), respectively,including higher oral bioavailability. sNACET exerts NO-related activities which can be

关键词： CGMP Nitric oxide s-Nitrosothiols Oxidative stress Pharmaceuticals

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Ca^(2+) binding to the C_(2)E domain of otoferlin is required for hair cell exocytosis and hearing

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Protein & Cell 2024年第4期15卷 305-312页

作者： Han Chen Mehar Monga Qinghua Fang Loujin slitin Jakob Neef shashank s.Chepurwar Regina Célia Mingroni Netto Karina Lezirovitz Alfredo Tabith,Jr. Fritz Benseler Nils Brose kathrin Kusch Carolin Wichmann Nicola strenzke Barbara Vona Julia Preobraschenski Tobias Moser Institute for Auditory Neuroscience and InnerEarLab University Medical Center Göttingen37075 GöttingenGermany Collaborative Research Center 889 University of Göttingen37075 GöttingenGermany Auditory Neuroscience and synaptic Nanophysiology Group Max Planck Institute for Multidisciplinary Sciences37075 GöttingenGermany Göttingen Graduate Center for Neurosciences Biophysics and Molecular BiosciencesUniversity of Göttingen37075 GöttingenGermany Biochemistry of Membrane Dynamics Group Institute for Auditory NeuroscienceUniversity Medical Center Göttingen37075 GöttingenGermany Molecular Architecture of synapses Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Center for Biostructural Imaging of Neurodegeneration University Medical Center Göttingen37075 GöttingenGermany Auditory systems Physiology Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Departamento de Genética e Biologia Evolutiva Centro de Pesquisas sobre o Genoma Humano e Células-TroncoInstituto de BiociênciasUniversidade de São PauloSão Paulo 05508-220Brazil Laboratório de Otorrinolaringologia/LIM32 Faculdade de MedicinaHospital das ClínicasUniversidade de São PauloSão PauloSP 05508-220Brazil DERDIC Pontifícia Universidade Católica de São PauloSão Paulo 05508-220Brazil Department of Molecular Neurobiology Max Planck Institute for Multidisciplinary Sciences37075 GöttingenGermany Multiscale Bioimaging Cluster of Excellence(MBExC) University of Göttingen37075 GöttingenGermany Functional Auditory Genomics Group Auditory Neuroscience and Optogenetics LaboratoryGerman Primate Center37077 GöttingenGermany Hearing Genomics Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Institute of Human Genetics University Medical Center Göttingen37075 GöttingenGermany

Dear Editor,Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in supplementary Materials).Otoferlin is a key player in this machinery and its defects cause human auditory synaptopathy(Moser and starr,2016).Otoferlin,a tail-anchored(Vogl et al.,2016)multi-C_(2)-domain protein(Fig.1Ai)specific to hair cells(Roux et al.,2006),is a member of the ferlin protein family involved in membrane trafficking and repair that are of major disease relevance(Pangršičet al.,2012),also see supplementary *** is distributed broadly within IHCs(Fig.2Ai-Aiii;Pangrsic et al.,2010;Roux et al.,2006).

关键词： auditory hair

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Effect of Eu3+,Bi3+,and Li+ doping on luminescent property of GdNbO4

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Journal of Rare Earths 2024年第1期42卷 66-75页

作者： s.W.Wi Y.s.Lee Department of Physics and Integrative Institute of Basic sciences Soongsil University

We investigated the emission properties of Eu3+-doped GdNbO4-based oxide phosphors,aiming at improving the Eu3+emission by codoping of Bi3+and Li+.Eu3+singly doped,Eu3+and Bi3+doubly doped,and Eu3+,Bi3+,and Li+triply doped GdNbO4were prepared using a high-temperature solid-state reaction *** red-orange emissions from Eu3+in the singly doped samples are significantly improved by the codoping of Bi3+,mainly due to the energy transfer from Bi3+to Eu3+.The additional codoping of Li+is found to increase the Eu3+emission *** improvement might be attributed to the increase in the photoluminescent quantum yield originating from larger grain sizes and better crystallinity.A detailed analysis of the X-ray diffraction pattern and the asymmetric ratio estimated from the photoluminescence spectra show that the local lattice environment around Eu3+in GdNbO4does not change significantly with the codoping of Bi3+and Li+.Our results indicate that Li+doping is a promising way to improve the emission properties of rare-earth ion-doped GdNbO4phosphors.

关键词： Eu3+ GdNbO4 Codoping of Li+ Photoluminescence sensitizer Rare earths

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First evidence for chiral wobbling of triaxial nuclei

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Nuclear science and Techniques 2024年第7期35卷 4-7页

作者： s.Frauendorf Department of Physics and Astronomy University of Notre DameNotre DameIN 46556USA

Chirality(Greek“handiness”)is a property of many com-plex *** molecules exist in two forms,one being the mirror image of the *** for our hands,it is impossible to make the images identical by a suitable *** two forms are called left-handed and *** have the same binding energy,because the electro-magnetic interaction,which holds the molecule together,does not change under a *** properties that are insensitive to the geometry are also the *** different geometry is the reason why the left-handed form turns the polarization plane of transmitted light in one direction by some angle while the right-handed form turns it in the oppo-site direction by the same ***,the geometrical differences between the two species may have other *** two species of the carvon molecule shown in Fig.1 taste quite differently.

关键词： turns Chiral mirror

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Tribological behavior of lubricant-impregnated porous polyimide

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Friction 2024年第4期12卷 711-725页

作者： Jinbang LI Ningning ZHOU Janet s.s.WONG school of Mechanical Engineering and Mechanics Ningbo UniversityNingbo 315211China Beijing Key Laboratory of Long-life Technology of Precise Rotation and Transmission Mechanisms Beijing Institute of Control EngineeringBeijing 100029China Department of Mechanical Engineering Imperial College LondonLondon SW72AZUK

Porous materials impregnated with lubricants can be used in conditions where limited lubricant is *** this work,three porous polyimides(PPI)with different densities were ***(PAO)impregnated PPI(iPPI)discs were rubbed against steel and sapphire *** operando observations of the iPPI-sapphire contacts show that oil is released under an applied load,forming a meniscus around *** at the outlet is created at high sliding *** amount of released oil increases with increasing PPI *** moduli,E*,estimated based on the actual contact size show that trapped oil in iPPIs contributes to load *** higher speeds,tribological rehydration of the contact occurs in low density iPPI,with that E*rises with *** high density PPIs,high speeds give a constantly high E*which is limited by the viscoelastic properties of the PPI network and possibly the rate of oil *** of iPPI-steel contacts is governed by the mechanical properties of the PPI,the flow of the lubricant,and the roughness of the PPI *** low-and medium-density(highly porous,high roughness)PPIs,large amount of oil is released,and lubrication is mainly via lubricant restricted in the contact in the pores and possibly tribological *** high density(low porosity)PPI,with lower roughness,hydrodynamic lubrication is achieved which gives the lowest *** results show that polymeric porous materials for effective lubrication require the optimization of its surface roughness,stiffness,oil flow,and oil retentions.

关键词： polyimide porous material friction mechanism polymer limited lubrication

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Enhancing fatigue performance of AZ31 magnesium alloy components fabricated by cold metal transfer-based wire arc directed energy deposition through LPB

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Journal of Magnesium and Alloys 2024年第4期12卷 1638-1662页

作者： shambhu Kumar Manjhi srikanth Bontha A.s.s.Balan Department of Mechanical Engineering National Institute of Technology KarnatakaSurathkalSrinivasanagarMangaloreKarnataka 575025India

Cold Metal Transfer-Based Wire Arc Directed Energy Deposition(CMT-WA-DED)presents a promising avenue for the rapid fabrication of components crucial to automotive,shipbuilding,and aerospace ***,the susceptibility to fatigue of CMT-WA-DED-produced AZ31 Mg alloy components has impeded their widespread adoption for critical load-bearing *** this study,a comprehensive investigation into the fatigue behaviour of WA-DED-fabricated AZ31 Mg alloy has been carried out and compared to commercially available wrought AZ31 *** findings indicate that the as-deposited parts exhibit a lower fatigue life than wrought Mg alloy,primarily due to poor surface finish,tensile residual stress,porosity,and coarse grain microstructure inherent in the WA-DED *** Plasticity Burnishing(LPB)treatment is applied to mitigate these issues,which induce significant plastic deformation on the *** treatment resulted in a remarkable improvement of fatigue life by 42%,accompanied by a reduction in surface roughness,grain refinement and enhancement of compressive residual stress ***,during cyclic deformation,WA-DED specimens exhibited higher plasticity and dislocation density compared to both wrought and WA-DED+LPB specimens.A higher fraction of Low Angle Grain Boundaries(LAGBs)in WA-DED specimens contributed to multiple crack initiation sites and convoluted crack paths,ultimately leading to premature *** contrast,wrought and WA-DED+LPB specimens displayed a higher percentage of High Angle Grain Boundaries(HAGBs),which hindered dislocation movement and resulted in fewer crack initiation sites and less complex crack paths,thereby extending fatigue *** findings underscore the effectiveness of LPB as a post-processing technique to enhance the fatigue performance of WA-DED-fabricated AZ31 Mg alloy *** study highlights the importance of LPB surface treatment on AZ31 Mg components produced by CMT-WA-DED to remove surface d

关键词： Wire arc additive manufacturing AZ31 Mg alloy Low plasticity burnishing Low cycle fatigue test strain amplitude

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Ren-integrable and ren-symmetric integrable systems

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Communications in Theoretical Physics 2024年第3期76卷 62-69页

作者： s Y Lou school of Physical science and Technology Ningbo UniversityNingbo315211China

A new type of symmetry,ren-symmetry,describing anyon physics and corresponding topological physics,is ***-symmetry is a generalization of super-symmetry which is widely applied in super-symmetric physics such as super-symmetric quantum mechanics,super-symmetric gravity,super-symmetric string theory,super-symmetric integrable systems and so *** and Grassmann numbers are,in some sense,dual conceptions,and it turns out that these conceptions coincide for the ren situation,that is,a similar conception of ren-number(R-number)is devised for *** particular,some basic results of the R-number and ren-symmetry are exposed which allow one to derive,in principle,some new types of integrable systems including ren-integrable models and ren-symmetric integrable *** examples of ren-integrable KdV-type systems and ren-symmetric KdV equations are explicitly given.

关键词： symmetries integrable systems anyon physics extended supersymmetry ren-symmetry

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AutoRhythmAI: A Hybrid Machine and Deep Learning Approach for Automated Diagnosis of Arrhythmias

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Computers, Materials & Continua 2024年第2期78卷 2137-2158页

作者： s.Jayanthi s.Prasanna Devi Department of Computer science and Engineering SRM Institute of Science and Technology-Vadapalani CampusChennaiTamil NaduIndia

In healthcare,the persistent challenge of arrhythmias,a leading cause of global mortality,has sparked extensive research into the automation of detection using machine learning(ML)***,traditional ML and AutoML approaches have revealed their limitations,notably regarding feature generalization and automation *** glaring research gap has motivated the development of AutoRhythmAI,an innovative solution that integrates both machine and deep learning to revolutionize the diagnosis of *** approach encompasses two distinct pipelines tailored for binary-class and multi-class arrhythmia detection,effectively bridging the gap between data preprocessing and model *** validate our system,we have rigorously tested AutoRhythmAI using a multimodal dataset,surpassing the accuracy achieved using a single dataset and underscoring the robustness of our *** the first pipeline,we employ signal filtering and ML algorithms for preprocessing,followed by data balancing and split for *** second pipeline is dedicated to feature extraction and classification,utilizing deep learning ***,we introduce the‘RRI-convoluted trans-former model’as a novel addition for binary-class *** ensemble-based approach then amalgamates all models,considering their respective weights,resulting in an optimal model *** our study,the VGGRes Model achieved impressive results in multi-class arrhythmia detection,with an accuracy of 97.39%and firm performance in precision(82.13%),recall(31.91%),and F1-score(82.61%).In the binary-class task,the proposed model achieved an outstanding accuracy of 96.60%.These results highlight the effectiveness of our approach in improving arrhythmia detection,with notably high accuracy and well-balanced performance metrics.

关键词： Automated machine learning neural networks deep learning arrhythmias

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Machine learning-enhanced Monte Carlo and subset simulations for advanced risk assessment in transportation infrastructure

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Journal of Mountain science 2024年第2期21卷 690-717页

作者： Furquan AHMAD Pijush sAMUI s.s.MIsHRA Department of Civil Engineering National Institute of TechnologyPatna 800006India

The maintenance of safety and dependability in rail and road embankments is of utmost importance in order to facilitate the smooth operation of transportation *** study introduces a comprehensive methodology for soil slope stability evaluation,employing Monte Carlo simulation(MCs)and subset simulation(ss)with the"UPss 3.0 Add-in"in *** on an 11.693-meter embankment with a soil slope(inclination ratio of 2H:1V),the investigation considers earthquake coefficients(kh)and pore water pressure ratios(ru)following Indian zoning *** chance of slope failure showed a considerable increase as the Coefficient of Variation(COV),seismic coefficients(kh),and pore water pressure ratios(ru)experienced an *** ss approach showed exceptional efficacy in calculating odds of failure that are notably *** computational modeling,the study optimized the worst-case scenario using ANFIs-GA,ANFIs-GWO,ANFIs-PsO,and ANFIs-BBO *** ANFIs-PsO model exhibits exceptional accuracy(training R2=0.9011,RMsE=0.0549;testing R2=0.8968,RMsE=0.0615),emerging as the most *** study highlights the significance of conducting thorough risk assessments and offers practical insights into evaluating and improving the stability of soil slopes in transportation *** findings contribute to the enhancement of safety and reliability in real-world situations.

关键词： Monte Carlo simulation subset simulation Machine Learning seismic coefficient

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Detection and clearance in Alzheimer’s disease: leading with illusive chemical, structural and morphological features of the targets

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Neural Regeneration Research 2024年第3期19卷 497-498页

作者： Luís Gales i3s−Instituto de Investigação e Inovação em saúde Rua Alfredo AllenPortoPortugal(Gales L)IBMC−Instituto de Biologia Molecular e CelularUniversidade do PortoRua Alfredo AllenPortoPortugal ICBAs−Instituto de Ciências Biomédicas Abel salazar Rua de Jorge Viterbo FerreiraPortoPortugal

Highly specific interactions between biomolecules,such as antigen-antibody,protein-ligand,or nucleic acid base pair complementary are on the basis of the organization of complex *** same principles may be tentatively used in molecular medicine for diagnosis and therapeutics.A molecule can be designed to selectively bind a protease and thereby inhibit the production of a peptide that forms toxic aggregates in the brain or an antibody may be produced to bind specifically to that peptide for detection or clearance ***,interference in biological systems is not that *** a start there is the inhibition of the physiological role of the protease;moreover,several cleavage fragments may be produced,which may continue to diverge due to putative post-translational modification and self-assembly processes,hiding the toxic target in a“soup”of peptide species varying in size,structure and chemical composition.A perspective of the current status and challenges in targeting peptide species for diagnosis and treatment in the context of Alzheimer’s disease is given.

关键词： Alzheimer diagnosis thereby

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