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Precision medicine in pantothenate kinase-associated neurodegeneration

neural Regeneration Research 2019年第7期14卷 1177-1185页

作者： Mónica álvarez-Córdoba Marina Villanueva-Paz Irene Villalón-García Suleva Povea-Cabello Juan M.Suárez-Rivero Marta Talaverón-Rey Javier Abril-Jaramillo Ana Belén Vintimilla-Tosi José A.Sánchez-Alcázar Centro Andaluz de Biología del Desarrollo(CABD-CSIC-Universidad Pablo de Olavide) and Centro de Investigación Biomédica en Red:Enfermedades RarasInstituto de Salud Carlos Ⅲ Centro de neurología Avanzada Centro Civet

neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas,mainly the basal ganglia.The predominant clinical symptoms include spasticity,progressive dystonia,Parkinson's disease-like symptoms,neuropsychiatric alterations,and retinal degeneration.Among the neurodegeneration with brain iron accumulation disorders,the most frequent subtype is pantothenate kinase-associated neurodegeneration(PKAn) caused by defects in the gene encoding the enzyme pantothenate kinase 2(PAnK2)which catalyzed the first reaction of the coenzyme A biosynthesis pathway.Currently there is no effective treatment to prevent the inexorable course of these disorders.The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAn.Recently,we have described that dermal fibroblasts obtained from PKAn patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules,mitochondrial dysfunction and a pronounced increase of markers of oxidative stress.In addition,PKAn fibroblasts showed a morphological senescence-like phenotype.Interestingly,pantothenate supplementation,the substrate of the PAnK2 enzyme,corrected all pathophysiological alterations in responder PKAn fibroblasts with low/residual PAnK2 enzyme expression.However,pantothenate treatment had no favourable effect on PKAn fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein.The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAn fibroblasts.Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PAnK2 in specific mutations.Fibroblasts and induced neuron

关键词： neurodegeneration with brain iron accumulation pantothenate kinase-associated neurodegeneration pantothenate kinase 2 pantothenate induced neurons precision medicine induced neuron fibroblast

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Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration

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neural Regeneration Research 2023年第6期18卷 1196-1202页

作者： Instituto de Salud Carlos III Irene Villalón-García Suleva Povea-Cabello MónicaÁlvarez-Córdoba Marta Talaverón-Rey Juan MSuárez-Rivero Alejandra Suárez-Carrillo Manuel Munuera-Cabeza Diana Reche-López Paula Cilleros-Holgado Rocío Piñero-Pérez JoséA.Sánchez-Alcázar Centro Andaluz de Biología del Desarrollo(CABD-CSIC-Universidad Pablo de Olavide de Sevilla) and Centro de Investigación Biomédica en Red:Enfermedades RarasInstituto de Salud Carlos IIISevillaSpain

Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases,such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,or neurodegeneration with brain iron accumulation disorders.Mitochondrial dysfunction,lipofuscin accumulation,autophagy disruption,and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders.Currently,the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear.In this review,we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation,and the effect of iron overload on lipid peroxidation and cellular function.The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration.Therefore,the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration.In addition,we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration,particularly in PLA2G6-associated neurodegeneration,a rare neurodegenerative disease with autosomal recessive inheritance,which belongs to the group of neurodegeneration with brain iron accumulation disorders.

关键词： 4-hidroxynonenal ferroptosis iron lipid peroxidation lipofuscin neurodegeneration neurodegeneration with brain iron accumulation oxidative stress PLA2G6-associated neurodegeneration

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nutrient drink test: A promising new tool for irritable bowel syndrome diagnosis

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World Journal of Gastroenterology 2019年第7期25卷 837-847页

作者： Fermin Estremera-Arevalo marta Barcelo Blanca Serrano Enrique rey Department of Gastroenterology Complejo Hospitalario de Navarra Department of Gastroenterolgy Hospital Infanta Leonor Department of Digestive Diseases Hospital Clinico San Carlos Department of Digestive Diseases Hospital Clinico San Carlos and Complutense University

BACKGROUnD Irritable bowel syndrome(IBS) is a highly prevalent condition. It is diagnosed on the basis of chronic symptoms after the clinical and/or investigative exclusion of organic diseases that can cause similar symptoms. There is no reproducible noninvasive test for the diagnosis of IBS, and this raises diagnostic uncertainty among physicians and hinders acceptance of the diagnosis by patients.Functional gastrointestinal(GI) syndromes often present with overlapping upper and lower GI tract symptoms, now believed to be generated by visceral hypersensitivity. This study examines the possibility that, in IBS, a nutrient drink test(nDT) provokes GI symptoms that allow a positive differentiation of these patients from healthy subjects.AIM To evaluate the nDT for the diagnosis of IBS.METHODS This prospective case-control study compared the effect of two different nutrient drinks on GI symptoms in 10 IBS patients(patients) and 10 healthy controls(controls). The 500 kcal high nutrient drink and the low nutrient 250 kcal drink were given in randomized order on separate days. Symptoms were assessed just before and at several time points after drink ingestion. Global dyspepsia and abdominal scores were derived from individual symptom data recorded by two questionnaires designed by our group, the upper and the general GI symptomquestionnaires, respectively. Psycho-social morbidity and quality of life were also formally assessed. The scores of patients and controls were compared using single factor analysis of variance test.RESULTS At baseline, IBS patients compared to controls had significantly higher levels of GI symptoms such as gastro-esophageal reflux(P = 0.05), abdominal pain(P =0.001), dyspepsia(P = 0.001), diarrhea(P = 0.001), and constipation(P = 0.001) as well as higher psycho-social morbidity and lower quality of life. The very low incidence of GI symptoms reported by control subjects did not differ significantly for the two test drinks. Compared with the low nutrient drink, IBS patients with the high nutrient

关键词： Irritable bowel syndrome nutrient drink test non-invasive Dyspepsia Screening

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Petrogenesis of Quebrada de la Mina and Altar north porphyries (Cordillera of San Juan, Argentina): Crustal assimilation and metallogenic implications

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Geoscience Frontiers 2017年第5期8卷 1135-1159页

作者： Laura Maydagán marta Franchini Massimo Chiaradia Verónica Bouhier noelia Di Giuseppe Roger rey Luis Dimieri Centro Patagónico de Estudios Metalogenéticos-COnICET Argentina InGEOSUR-COnICET Departamento de Geología Universidad Nacional del Sur San Juan 670 8000 Bahía Blanca Argentina Instituto de Investigación en Paleobiología y Geología Universidad Nacional de Río Negro Av. Roca 1242 8332 Roca Argentina Departamento de Geología y Petróleo Facultad de Ingeniería Universidad Nacional del Comahue Buenos Aires 1400 8300 Neuquén Argentina Section of Earth and Environmental Sciences University of Geneva Switzerland Minera Peregrine Argentina S.A Santa Fe (Oeste) 117 Piso 4B Edificio Derby Ciudad San Juan Argentina

We investigate the geology of Altar north(Cu-Au) and Quebrada de la Mina(Au) porphyry deposits located in San Juan Province(Argentina), close to the large Altar porphyry copper deposit(995 Mt,0.35% Cu, 0.083 g/t Au), to present constraints on the magmatic processes that occurred in the parental magma chambers of these magmatic-hydrothermal systems. Altar north deposit comprises a plagioclase-amphibole-phyric dacite intrusion(Altar north barren porphyry) and a plagioclaseamphibole-biotite-phyric dacite stock(Altar north mineralized porphyry, 11.98 ± 0.19 Ma). In Quebrada de la Mina, a plagioclase-amphibole-biotite-quartz-phyric dacite stock(QDM porphyry,11.91±0.33 Ma) crops out. High Sr/Y ratios(92-142) and amphibole compositions of Altar north barren and QDM porphyries reflect high magmatic oxidation states(fO_2= nnO+1.1 to+1.6) and high fH_2O conditions in their magmas. Zones and rims enriched in anorthite(An_(37-48))), SrO(0.22-0.33 wt.%)and FeO(0.21-0.37 wt.%) in plagioclase phenocrysts are evidences of magmatic recharge processes in the magma chambers. Altar north and Quebrada de la Mina intrusions have relatively homogeneous isotopic compositions(^(87)Sr/^(86)Sr_(t)= 0.70450-0.70466, ε_(nD)(t) = +0.2 to +1.2) consistent with mixed mantle and crust contributions in their magmas. Higher Pb isotopes ratios(^(207)Pb/^(204)Pb=15.6276-15.6294) of these intrusions compared to other porphyries of the district, reflect an increase in the assimilation of high radiogenic Pb components in the magmas. Ages of zircon xenocrysts(297,210,204,69 Ma) revealed that the magmas have experienced assimilation of Miocene, Cretaceous, Triassic and Carboniferous crustal rocks.Fluids that precipitated sulfides in the Altar deposit may have remobilized Pb from the host rocks, as indicated by the ore minerals being more radiogenic(207Pb/204 Pb = 15.6243-15.6269) than their host intrusions. Au/Cu ratio in Altar porphyries(average Au/Cu ratio of 0.14 ×10^(-4)by weight in Altar Central)is higher than in the giant Miocene porphyry deposits

关键词： Porphyry High sulfidation epithermal Magmatic recharge Radiogenic isotopes Crustal assimilation Argentinian Andes

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Constructive thinking,rational intelligence and irritable bowel syndrome

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World Journal of Gastroenterology 2009年第25期15卷 3106-3113页

作者： Enrique rey marta Moreno Ortega Monica Olga Garcia Alonso Manuel Diaz-Rubio Department of Digestive Diseases Hospital Clinico San Carlos (IMSALUD)and Faculty of MedicineComplutense University

AIM:To evaluate rational and experiential intelligence in irritable bowel syndrome (IBS) sufferers.METHODS:We recruited 100 subjects with IBS as per Rome criteria(50 consulters and 50 non-consulters) and 100 healthy controls,matched by age,sex and educational level.Cases and controls completed a clinical questionnaire(including symptom characteristics and medical consultation)and the following tests:rational-intelligence(Wechsler Adult Intelligence Scale,3rd edition);experiential intelligence(Constructive Thinking Inventory);personality(nEO personality inventory); psychopathology(MMPI-2),anxiety(state-trait anxiety inventory)and life events(social readjustment rating scale).Analysis of variance was used to compare the test results of IBS-sufferers and controls,and a logistic regression model was then constructed and adjusted for age,sex and educational level to evaluate any possible association with IBS.RESULTS: no differences were found between IBS cases and controls in terms of IQ (102.0 ±10.8 vs 102.8±12.6), but IBS sufferers scored significantly lower in global constructive thinking (43.7±9.4 vs 49.6±9.7). In the logistic regression model, global constructive thinking score was independently linked to suffering from IBS [OR 0.92 (0.87-0.97)], without significant OR for total IQ.COnCLUSIOn: IBS subjects do not show lower rational intelligence than controls, but lower experiential intelligence is nevertheless associated with IBS.

关键词：综合征智慧理性逻辑回归模型肠教育水平 IBS 症状特点

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Security Threats to Business Information Systems Using nFC Read/Write Mode

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Computers, Materials & Continua 2021年第6期67卷 2955-2969页

作者： Sergio Rios-Aguilar marta Beltrán González-Crespo Rubén Department of Organization Engineering Business Administration and StatisticsETSI InformáticosUniversidad Politécnica de Madrid(UPM)Boadilla del Monte(Madrid)28660Spain Department of Computing ETSIIUniversidad Rey Juan CarlosMóstoles(Madrid)28933Spain ESIT Universidad Internacional de La Rioja(UNIR)Logroño(La Rioja)26006Spain

Radio Frequency IDentification(RFID)and related technologies such as near Field Communication(nFC)are becoming essential in industrial contexts thanks to their ability to perform contactless data exchange,either device-to-device or tag-to-device.One of the three main operation modes of nFC,called read/write mode,makes use of the latter type of interaction.It is extensively used in business information systems that make use of nFC tags to provide the end-user with augmented information in one of several available nFC data exchange formats,such as plain text,simple URLs or enriched URLs.Using a wide variety of physical form factors,nFC-compatible tags(wireless transponders)are currently available in many locations with applications going from smart posters,contactless tokens,tap-and-go payments or transport ticketing to automated device configuration,patient identification at hospitals or inventory management within supply chains.Most of these applications handle sensitive processes or data.This paper proposes a complete security threat model for the read/write operation mode of nFC used in next Generation Industrial IoT(nx-IIoT)contexts.This model,based on a wellknown methodology,STRIDE,allows developers and users to identify nFC applications vulnerabilities or weaknesses,analyze potential threats,propose risk management strategies,and design mitigation mechanisms to mention only some significant examples.

关键词： near field communications read/write nFC security threat modelling STRIDE nx-IIoT

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Advantages of early cholecystectomy in clinical practice of a terciary care center

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Hepatobiliary & Pancreatic Diseases International 2013年第1期12卷 87-93页

作者： marta Barceló Dulce María Cruz-Santamaría Cristina Alba-López María José Devesa-Medina Manuel Díaz-Rubio Enrique rey Health Research Institute San Carlos Clinical HospitalDepartment of MedicineSchool of MedicineComplutense University

BACKGROUnD:Despite a number of studies show the superiority of early over delayed cholecystectomy in the treatment of acute cholecystitis,there is still controversy over the time for intervention.This study aimed to assess the use of early versus delayed cholecystectomy for the treatment of acute cholecystitis in terms of complications,conversion to open surgery and mean hospital stay.METHOD:We collected patients with acute cholecystitis treated at a referral center for a year,and retrospectively analyzed the chosen therapeutic approach,the percentage of conversion of early cholecystectomy to open surgery,appearance of surgical complications,and mean hospital stay.RESULTS:The study included 117 patients,44 women and 73 men,who had a mean age of 67.36±15.74 years.Early cholecystectomy was chosen in 31(26.5%) and delayed cholecystectomy in 74 patients(63.2%).Of the 74 patients,28(37.8%) required emergency performance of delayed cholecystectomy,and 19(25.7%) had not undergone surgery by the end of the study.While no differences were observed between early and delayed cholecystectomy in terms of surgical complications and conversion to open surgery,mean hospital stay was nevertheless significantly shorter in the early versus the delayed cholecystectomy group(8.32±4.98 vs 15.96±8.89 days).COnCLUSIOn:Under the routine working conditions of a hospital that is neither specially dedicated to the surgical treatment of acute cholecystitis nor provided with specific management guidelines,early cholecystectomy can reduce the hospital stay without increase of the conversion rate or complications.

关键词： acute cholecystitis cholecystectomy complications

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Promotion of structural plasticity in area V2 of visual cortex prevents against object recognition memory deficits in aging and Alzheimer's disease rodents

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neural Regeneration Research 2024年第8期19卷 1835-1841页

作者： Irene navarro-Lobato Mariam Masmudi-Martín Manuel F.López-Aranda Juan F.López-Téllez Gloria Delgado Pablo Granados-Durán Celia Gaona-Romero marta Carretero-rey Sinforiano Posadas María E.Quiros-Ortega Zafar U.Khan Laboratory of neurobiology Centro de Investigaciones Médico Sanitarias(CIMES)University of MalagaMalagaSpain Department of Medicine Faculty of MedicineUniversity of MalagaMalagaSpain Centro de Investigación Biomédica en Red de Enfermedades neurodegenerativas(CIBERnED) Institute of Health Carlos IIIMadridSpain the Donders Institute for Brain Cognition and Behaviour Radboud UniversityNijmegenThe Netherlands the Brain Metastasis Group National Cancer Research Centre(CNIO)MadridSpain the Department of neurobiology University of California-Los AngelesLos AngelesCAUSA

Memory deficit,which is often associated with aging and many psychiatric,neurological,and neurodegenerative diseases,has been a challenging issue for treatment.Up till now,all potential drug candidates have failed to produce satisfa ctory effects.Therefore,in the search for a solution,we found that a treatment with the gene corresponding to the RGS14414protein in visual area V2,a brain area connected with brain circuits of the ventral stream and the medial temporal lobe,which is crucial for object recognition memory(ORM),can induce enhancement of ORM.In this study,we demonstrated that the same treatment with RGS14414in visual area V2,which is relatively unaffected in neurodegenerative diseases such as Alzheimer s disease,produced longlasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer’s disease.Furthermore,we found that the prevention of memory deficits was mediated through the upregulation of neuronal arbo rization and spine density,as well as an increase in brain-derived neurotrophic factor(BDnF).A knockdown of BDnF gene in RGS14414-treated aging rats and Alzheimer s disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits.These findings suggest that BDnF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer’s disease.Therefore,our findings of RGS14414gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.

关键词： behavioral performance brain-derived neurotrophic factor cognitive dysfunction episodic memory memory circuit activation memory deficits memory enhancement object recognition memory prevention of memory loss regulator of G protein signaling

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S-adenosyl-L-methionine modifies antioxidant-enzymes,glutathione-biosynthesis and methionine adenosyltransferases-1/2 in hepatitis C virus-expressing cells

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World Journal of Gastroenterology 2016年第14期22卷 3746-3757页

作者： Sonia Amelia Lozano-Sepulveda Eduardo Bautista-Osorio Jose Angel Merino-Mascorro marta Varela-rey Linda Elsa Munoz-Espinosa Paula Cordero-Perez María Luz Martinez-Chantar Ana Maria Rivas-Estilla Department of Biochemistry and Molecular Medicine School of Medicine Autonomous University of Nuevo Leon Monterrey Metabolomic Unit CIC bio GUNE CIBERehd Parque Tecnológico de Bizkaia Liver Unit School of Medicine and Hospital Universitario Autonomous University of Nuevo Leon

AIM: To elucidate the mechanism(s) by which S-adenosyl-L-methionine(SAM) decreases hepatitis C virus(HCV) expression.METHODS: We examined the effects of SAM on viral expression using an HCV subgenomic replicon cell culture system. Huh7 HCV-replicon cells were treated with 1 mmol/L SAM for different times(24-72 h), then total RnA and proteins were isolated. c DnA was synthesized and real time-PCR was achieved to quantify HCV-RnA, superoxide dismutase 1 and 2(SOD-1, SOD-2) catalase, thioredoxin 1, methionine adenosyltransferase 1A and 2A(MAT1A, MAT2A) expression, and GAPDH and RPS18 as endogenous genes. Expression of cellular and viral protein was evaluated by western-blot analysis using antibodies vs HCV-nS5 A, SOD-1, SOD-2, catalase, thioredoxin-1, MAT1 A, MAT2 A, GAPDH and actin. Total glutathione levels were measured at different times by Ellman's recycling method(0-24 h). Reactive oxidative species(ROS) levels were quantified by the dichlorofluorescein assay(0-48 h); Pyrrolidin dithiocarbamate(PDTC) was tested as an antioxidant control and H2O2 as a positive oxidant agent.RESULTS: SAM exposition decreased HCV-RnA levels 50%-70% compared to non-treated controls(24-72 h). SAM induced a synergic antiviral effect with standard IFn treatment but it was independent of IFn signaling. In addition, 1 mmol/L SAM exposition did not modify viral RnA stability, but it needs cellular translation machinery in order to decrease HCV expression. Total glutathione levels increased upon SAM treatment in HCV-replicon cells. Transcriptional antioxidant enzyme expression(SOD-1, SOD-2 and thioredoxin-1) was increased at different times but interestingly, there was no significant change in ROS levels upon SAM treatment, contrary to what was detected with PDTC treatment, where an average 40% reduction was observed in exposed cells. There was a turnover from MAT1A/MAT2 A, since MAT1 A expression was increased(2.5 fold-times at 48 h) and MAT2 A was diminished(from 24 h) upon SAM treatment at both the transcriptional and translational lev

关键词： Hepatitis C virus S-adenosyl-L-methionine Superoxide dismutase 1 Superoxide dismutase 2 Replication Hepatitis C virus-RnA nS5A Oxidative stress Antioxidants Viral proteins Reactive oxygen species Pyrrolidine dithiocarbamate

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磺酸多相催化剂用于二甲基亚砜中C_6-单糖脱水制5-羟甲基糠醛(英)

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催化学报 2014年第5期35卷 644-655页

作者： Gabriel Morales Juan A.Melero marta Paniagua Jose Iglesias Blanca Hernandez Maria Sanz Department of Chemical and Environmental Technology Universidad Rey Juan Carlos. C/Tulipan s/n. Mostoles. E28933Madrid Spain Department of Chemical and Energy Technology Universidad Rey Juan Carlos. C/Tulipan s/n. Mostoles. E28933 Madrid Spain

Sulfonic acid-functionalized heterogeneous catalysts have been evaluated in the catalytic dehydration of C(,monosaccharides into 5-hydroxymethylfurfural(HMF) using dimethyl sulfoxide(DMSO)as solvent.Sulfonic commercial resin Amberlyst-70 was the most active catalyst,which was ascribed to its higher concentration of sulfonic acid sites as compared with the other catalysts,and it gave 93 mol%yield of HMF from fructose in 1 h.With glucose as the starting material,which is a much more difficult reaction,the reaction conditions(time,temperature,and catalyst loading) were optimized for Amberlyst-70 by a response surface methodology,which gave a maximum HMF yield of 33 mol%at 147 °C with 23 wt%catalyst loading based on glucose and 24 h reaction time.DMSO promotes the dehydration of glucose into anhydroglucose,which acts as a reservoir of the substrate to facilitate the production of HMF by reducing side reactions.Catalyst reuse without a regeneration treatment showed a gradual but not very significant decay in catalytic activity.

关键词：非均相催化剂羟甲基糠醛二甲基亚砜磺酸脱水单糖响应面分析法 DMSO

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