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Site-directed cysteine coupling of disulfide-containing non-antibody carrier proteins(THIOCAPs)

Science China Materials 2023年第10期66卷 4109-4120页

作者： Ariana Rueda Julian I.Mendoza lorena alba-castellon Eloi Parladé Eric Voltà-Durán David Paez Anna Avino Ramon Eritja Esther Vázquez Antonio Villaverde Ramón Mangues Ugutz Unzueta Institut d'Investigació Biomèdica Sant Pau(IIB Sant Pau) Sant Quintí 77-7908041 BarcelonaSpain Josep Carreras Leukaemia Research Institute(IJC Campus Sant Pau) 08041 BarcelonaSpain CIBER de Bioingeniería Biomateriales y NanomedicinaInstituto de Salud Carlos Ⅲ28029 MadridSpain Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona08193 BellaterraSpain Departament de Genètica i de Microbiologia Universitat Autònoma de Barcelona08193 BellaterraSpain Department of Medical Oncology Hospital de la Santa Creu i Sant Pau.Barcelona08025 BarcelonaSpain CIBER de Enfermedades Raras(CIBERER) Instituto de Salud Carlos Ⅲ28029 MadridSpain Institute for Advanced Chemistry of Catalonia(IQAC) CSIC08034 BarcelonaSpain

The development of a new generation of nonantibody protein drug delivery systems requires site-directed conjugation strategies to produce homogeneous,reproducible and scalable *** that,the genetic addition of cysteine residues into solvent-exposed positions allows the thiol-mediated cysteine coupling of therapeutic drugs into protein-based ***,the high reactivity of unpaired cysteine residues usually reduces protein stability,consequently imposing the use of more methodologically demanding purification *** is especially relevant for disulfide-containing nanocarriers,as previously observed in ***,although many protein scaffolds and targeting ligands are also rich in disulfide bridges,the use of these methodologies over emerging non-antibody carrier proteins has been completely ***,we report the development of a simple and straightforward procedure for a onestep production and site-directed cysteine conjugation of disulfide-containing non-antibody thiolated carrier proteins(THIOCAPs).This method is validated in a fluorescent C-X-C chemokine receptor 4(CXCR4)-targeted multivalent nanocarrier containing two intramolecular disulfide bridges and one reactive cysteine residue strategically placed into a solvent-exposed position(THIO-T22-GFP-H6)for drug conjugation and in a humanized alternative intended for clinical applications(T22-HSNBT-H6).Thus,we produce very stable,homogeneous and fully functional antitumoral nanoconjugates(THIO-T22-GFP-H6-MMAE and T22-HSNBT-H6-MMAE)that selectively eliminate target cancer cells via ***,the developed methodology appears as a powerful tool for the rational engineering of emerging non-antibody,cell-targeted protein nanocarriers that contain disulfide bridges together with a solvent-exposed reactive cysteine(THIOCAP).This should pave the way for the development of a new generation of stable,homogeneous and efficient nanomedicines.

关键词： disulfide directed bridges

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Cryptic exon inclusion in TDP-43 proteinopathies:opportunities and challenges

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Neural Regeneration Research 2025年第7期20卷 2003-2004页

作者： lorena Decker Sonja Menge Axel Freischmidt Department of Neurology Ulm UniversityUlmGermany

TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcription,splicing,transport,translation,and ***-43 shuttles between the nucleus and cytoplasm,but is predominantly localized in the *** diseases(NDs)may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and *** neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis(ALS),frontotemporal dementia(FTD)with TDP-43-immunoreactive pathology(FTD-TDP),limbic-predominant age-related TDP-43 encephalopathy(LATE)and Perry syndrome,but also coexists with the primary pathology in subsets of patients suffering from other NDs,such as Alzheimer’s disease,Lewy body dementias,or Huntington’s *** in the gene encoding TDP-43(TARDBP)are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging *** is still controversial if loss of nuclear,or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons(Nag and Schneider,2023).Recently,the role of nuclear TDP-43 in repressing the inclusion of intronic sequences,named cryptic exons(CEs),into mature mRNAs gained much attention.

关键词： Huntington metabolism TDP

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Effect of intensity and duration of anthropic noises on European mink locomotor activity and fecal cortisol metabolite levels

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Current Zoology 2022年第6期68卷 688-699页

作者： lorena ORTIZ-JIMENEZ Carlos IGLESIAS-MERCHAN alba Itzel MARTıNEZ-SALAZAR Isabel BARJA Department of Biology Zoology UnitUniversidad Autonoma de MadridMadrid28049Spain Department of Forest and Environmental Engineering and Management Universidad Politecnica de MadridMadridSpain Geographic Information Systems Laboratory Institute of BiologyUniversidad Nacional Autonoma de MexicoMexico CityMexico Biodiversity and Global Change Research Centre(CIBC-UAM) Universidad Autonoma de MadridMadridSpain

Human activities involving noise emission can affect wild *** mink was exposed to road noise and human voice playbacks to analyze how sound intensity level and duration of both noises altered the time that individuals were active and if their fecal cortisol metabolite(FCM)levels varied.A Hierarchical Analysis Cluster was performed to establish 2 mink groups with respect to both noise source type:short duration/low intensity(SL)and long duration/high intensity(LH).We performed general linear mixed models to evaluate the variation in locomotor activity duration(s)and FCM(nanogram per gram)levels,*** results showed both road noise and human voices decreased locomotor activity duration in SL more sharply compared with LH,and human voices were the triggers that induced the most pronounced response to both exposure ***(ng/g)levels increased in SL compared with LH during road noise while the opposite happened during human *** based on sex and age of individuals were *** conclusion,noise characteristics given by the sound type determined the variations in locomotor activity duration while noise exposure level determined the variations in FCM(ng/g)*** should be paid to noisy activities(e.g.,recreational activities for visitors in protected natural areas)and loud groups of people to conserve wildlife,especially noise sensitive species.

关键词： anthropic disturbances European mink fecal cortisol metabolites noise exposure locomotor activity behavioral response

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Coseismic site response and slope instability using periodic boundary conditions in the material point method

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Journal of Rock Mechanics and Geotechnical Engineering 2023年第3期15卷 641-658页

作者： Abdelrahman Alsardi alba Yerro Department of Civil and Environmental Engineering Virginia TechBlacksburg24060VirginiaUSA

This paper proposed the explicit generalized-a time scheme and periodic boundary conditions in the material point method(MPM)for the simulation of coseismic site *** proposed boundary condition uses an intuitive particle-relocation algorithm ensuring material points always remain within the computational *** explicit generalized-a time scheme was implemented in MPM to enable the damping of spurious high frequency ***,the MPM was verified against finite element method(FEM).Secondly,ability of the MPM in capturing the analytical transfer function was ***,a symmetric embankment was adopted to investigate the effects of ground motion arias intensity(I_(a)),geometry dimensions,and constitutive *** results show that the larger the model size,the higher the crest runout and settlement for the same ground *** using a Mohr-Coulomb model,the crest runout increases with increasing I_(a).However,if the strain-softening law is activated,the results are less influenced by the ground ***,the MPM results were compared with the Newmark sliding block *** simplified analysis herein highlights the capabilities of MPM to capture the full deformation process for earthquake engineering applications,the importance of geometry characterization,and the selection of appropriate constitutive models when simulating coseismic site response and subsequent large deformations.

关键词： Coseismic site response Periodic conditions Time integration Material point method(MPM)

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Oil recovery tests with ionic liquids: A review and evaluation of 1-decyl-3-methylimidazolium triflate

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Petroleum Science 2022年第4期19卷 1877-1887页

作者： alba Somoza Alberto Arce Ana Soto CRETUS Department of Chemical EngineeringUniversidade de Santiago de CompostelaE-15782Santiago de CompostelaSpain School of Engineering Universidade de A CorunaE-15403FerrolSpain

The main advantages of the use of ionic liquids in enhanced oil recovery are their tunability and stability in harsh environmental conditions. In this work, a comprehensive review of ionic liquids proposed to improve current chemical oil recovery methods has been presented, focusing on core flooding experiments. With an almost infinite number of possible ionic liquids, the amount of experiments carried out up to now has been very limited. However, results are promising, with additional recovery after secondary flooding of up to 32% of the original oil in place. Most formulations with ionic liquids have been proposed for sandstone reservoirs, the number of studies with carbonate cores being very scarce. The possibilities of a new room temperature surface active ionic liquid, 1-decyl-3-methylimidazolium triflate,for this application were analyzed. It was shown that it is able to drastically reduce the water/oil interfacial tension. An optimized formulation was proposed for carbonate reservoirs. After secondary flooding with brine, an additional recovery of 10.5% of original oil in place was achieved at room conditions. A combination of the proposed method followed by a polymer flooding step with polyacrylamide led to a lesser but still significant recovery, reducing the costs associated to the ionic liquid.

关键词： Enhanced oil recovery(EOR) Ionic liquids Core flooding Interfacial tension 1-Decyl-3-methylimidazolium triflate

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The transcription factor ZEB1 promotes chemoresistance in prostate cancer cell lines

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Asian Journal of Andrology 2019年第5期21卷 460-467页

作者： Octavio Orellana-Serradell Daniela Herrera Enrique A castellon Hector R Contreras Department of Basic and Clinical Oncology Faculty of MedicineUniversity of ChileIndependenciaSantiago 8380453Chile

One of the factors promoting tumoral progress is the abnormal activation of the epithelial-mesenchymal transition(EMT)program which has been associated with chemoresistance in tumoral *** transcription factor zinc finger E-box-binding homeobox 1(ZEB1),a key EMT activator,has recently been related to docetaxel resistance,the main chemotherapeutic used in advanced prostate cancer *** mechanisms involved in this protective effect are still *** a previous work,we demonstrated that ZEB1 expression induced an EMT-like phenotype in prostate cancer cell *** this work,we used prostate cancer cell lines 22Rvl and DU145 to study the effect of ZEB1 modulation on docetaxel resistance and its possible *** results showed that ZEB1 overexpression conferred to 22Rvl cell resistance to docetaxel while its silencing made DU145 cells more sensitive to *** of resistance markers showed no presenee of ATP-binding cassette subfamily B member 1(MDR1)and no changes in breast cancer resistance protein(BCRP)or ATP-binding cassette subfamily C member 10(MRP7).However,a correlation between ZEB1,multidrug resistance-associated protein 1(MRP1),and ATP-binding cassette subfamily C member 4(MRP4)expression was ***4 inhibition,using MK571,resensitized cells with ZEB1 overexpression to docetaxel *** addition,modulation of ZEB1 and subsequent change in MRP4 expression correlated with a lower apoptotic response to docetaxel,characterized by lower B-cell lymphoma 2(Bcl2),high BCL2-associated X protein(Bax),and high active caspase 3 *** response to docetaxel in our model seems to be mediated mainly by activation of the apoptotic death *** results showed that modulation of MRP4 could be a mediator of ZEBl-related resistance to docetaxel in prostate cancer,making it a possible marker for chemotherapy response in patients who do not express MDR1.

关键词： chemoresistance prostate cancer ZEB1

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The transcription factor ZEB1 promotes an aggressive phenotype in prostate cancer cell lines

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Asian Journal of Andrology 2018年第3期20卷 294-299页

作者： Octavio Orellana-Serradell Daniela Herrera Enrique A castellon Hector R Contreras Department of Basic and Clinical Oncology Faculty of Medicine University of Chile Independencia Santiago 8380453 Chile.

It has been reported that one of the factors that promotes tumoral progression is the abnormal activation of the epithelial-mesenchymal transition program. This process is associated with tumoral cells acquiring invasive and malignant properties and has the transcription factor zinc finger E-box-binding homeobox 1 （ZEB1） as one of its main activators. However, the role of ZEB1 in promoting malignancy in prostate cancer （PC, a） is still unclear. Here, we report that ZEB1 expression correlates with Gleason score in PCa samples and that expression of ZEB1 regulates epithelial-mesenchymal transition and malignant characteristics in PCa cell lines. The results showed that ZEB1 expression is higher in samples of higher malignancy and that overexpression of ZEB1 was able to induce epithelial-mesenchymal transition by upregulating the mesenchymal marker Vimentin and downregulating the epithelial marker E-Cadherin. On the contrary, ZEB 1 silencing repressed Vimentin expression and upregulated E-Cadherin. ZEB1 expression conferred enhanced motility and invasiveness and a higher colony formation capacity to 22Rvl cells whereas DU145 cells with ZEB1 silencing showed a decrease in those same properties. The results showed that ZEB1 could be a key promoter of tumoral progression toward advanced stages of PC, a.

关键词： epithelial-mesenchymal transition prostate cancer transcriptional repression ZEB1

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Bowel function and inflammation: Is motility the other side of the coin?

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World Journal of Gastroenterology 2024年第14期30卷 1963-1967页

作者： alba Panarese Division of Gastroenterology and Digestive Endoscopy Department of Medical SciencesCentral Hospital-Azienda OspedalieraTaranto 74123Italy

Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the *** the flip side,functions also arise from its role as an interface with the ***,the gut houses microorganisms,collectively known as the gut microbiota,which interact with the host,and is the site of complex immune *** role in human pathology is complex and scientific evidence is progressively elucidating the functions of the gut,especially regarding the pathogenesis of chronic intestinal diseases and inflammatory conditions affecting various organs and *** editorial aims to highlight and relate the factors involved in the pathogenesis of intestinal and systemic inflammation.

关键词： Motility Inflammation Pathogenesis Vitamin D Microbiota Gut Chronic intestinal pseudo-obstruction

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Phosphorylation-driven aggregative proteins in neurodegenerative diseases:implications and therapeutics

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Neural Regeneration Research 2024年第5期19卷 966-968页

作者： alba Espargaró Raimon Sabate Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry School of PharmacyUniversity of BarcelonaBarcelonaSpain Institute of Nanoscience and Nanotechnology(IN2UB) University of BarcelonaBarcelonaSpain

Protein aggregation is related to a large number of neurodegenerative *** in some cases,aggregation is induced by hyperphosphorylation of a given *** is the case of tau,TAR DNA-binding protein 43(TDP-43),amyloid-beta peptides(Aβ)and alpha-synuclein(α-syn),which play a key pathogenic role in Alzheimer’s disease(AD),Parkinson’s disease(PD)and amyotrophic lateral sclerosis,among others(Tenreiro et al.,2014;Chiti and Dobson,2017).In this perspective,we will discuss both the relationship between phosphorylation and amyloid aggregation as well as current and future therapeutic strategies aimed at inhibiting specific kinases involved in the phosphorylation step or inhibiting subsequent protein aggregation.

关键词： tau Aβ Alzheimer

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Endoscopic resection for early gastric cancer:Towards a global understanding

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World Journal of Gastroenterology 2022年第13期28卷 1377-1379页

作者： alba Panarese Department of Gastroenterology and Digestive Endoscopy Central HospitalTaranto 74123Italy

Gastric cancer is widespread globally,and disease diagnosis is accompanied by high mortality and morbidity ***,prognoses and survivability have improved following implementation of surveillance and screening programs,which have led to earlier ***,early diagnosis itself supports increased surgical curability,which is the main treatment goal and guides therapeutic *** most recent Japanese guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer consider the degree of endoscopic curability in relation to the characteristics of the gastric *** clinical practice,the management approach for both prevention and treatment should be similar to that of colon lesions;however,unlike the established practices for colorectal cancer,the diagnostic and therapeutic pathways are not shared nor widespread for gastric ***,this negatively impacts the opportunity to perform an endoscopic resection with curative intent.

关键词： Early gastric cancer Artificial intelligence Malignancy Helicobacter pylori Autoimmune gastritis Dysplasia

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