Diels–alder reactions of alkyl 2H-azirine-3-carboxylates with furans

Methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate 1 and furan give the aziridine 2 by a Diels–Alder cycloaddition reaction. The hydrolysis of compound 2 leads to a dihydrofuranol 11 by cleavage of a C–N bond. X-Ray crystal structures of compounds 2 and 11 have been determined. Compound 2 reacts with alcohols in a similar way to give 2-alkoxy-2,5-dihydrofurans as mixtures of cis and trans isomers. The structures of these compounds have been determined from an X-ray crystal structure of one of the methyl ethers, the trans isomer 13. The reaction of the azirine 1 with 1,3-diphenylisobenzofuran leads to the formation of two isomeric 1 : 1 adducts that have been identified as the products of endo and exo cycloaddition, 3 and 4. The endo isomer 3 is converted into the exo isomer 4 by heat. Similar Diels–Alder reactions have been carried out between furans and benzyl 2H-azirine-3-carboxylate 6. Hydrolysis of the adduct 7 formed with furan again produces a dihydrofuranol 25 as the major product together with three minor products, two of which are 1-azabicyclo[4.1.0]hept-3-ene-2,5-diols 27 and 28 that result from C–O bond cleavage. Protection of the mixture of alcohols with TBS triflate gives the bis(TBS) ether 31 of the trans-1-azabicyclo[4.1.0]hept-3-ene-2,5-diol as the major product, showing that this ring system can be produced from the dihydrofuranol 25. The bis(TBS) ether 30 of the cis-2,5-diol is a minor product and its structure has been established by independent synthesis through a Diels–Alder reaction between the azirine 6 and 1,4-bis(tert-butyldimethylsilyloxy)butadiene 32.Fundação para a Ciência e Tecnologia - POCTI/32723/QUI/2000. FEDER. EPSRC

Hallucinations in Large Multilingual Translation Models

Large-scale multilingual machine translation systems have demonstrated remarkable ability to translate directly between numerous languages, making them increasingly appealing for real-world applications. However, when deployed in the wild, these models may generate hallucinated translations which have the potential to severely undermine user trust and raise safety concerns. Existing research on hallucinations has primarily focused on small bilingual models trained on high-resource languages, leaving a gap in our understanding of hallucinations in massively multilingual models across diverse translation scenarios. In this work, we fill this gap by conducting a comprehensive analysis on both the M2M family of conventional neural machine translation models and ChatGPT, a general-purpose large language model~(LLM) that can be prompted for translation. Our investigation covers a broad spectrum of conditions, spanning over 100 translation directions across various resource levels and going beyond English-centric language pairs. We provide key insights regarding the prevalence, properties, and mitigation of hallucinations, paving the way towards more responsible and reliable machine translation systems

45S5 BAG-Ti6Al4V structures: The influence of the design on some of the physical and chemical interactions that drive cellular response

This work was supported by FCT (Fundação para a Ciência e Tecnologia) through the grants SFRH/BPD/112111/2015, SFRH/BD/128657/2017, PD/BDE/127836/2016, SFRH/BPD/97701/2013, SFRH/ BD/141056/2018, SFRH/BD/140191/2018 and the projects PTDC/EMSTEC/5422/2014 and NORTE-01-0145-FEDER-000018-HAMaBICo. Additionally, this work was supported by FCT with the reference project UID/EEA/04436/2013, by FEDER funds through the COMPETE 2020 – Programa Operacional Competitividade e Internacionalização (POCI) with the reference project POCI-01-0145-FEDER-006941.Multi-material Ti6Al4V cellular structures impregnated with 45S5 bioactive glass were designed and produced using Selective LaserMelting (SLM), an additive manufacturing technique, combinedwith Press and Sintering focusing on load bearing components like hip implants. These structures were designed to combine Ti6Al4V mechanical properties and promote bone ingrowth into the structure as the bioactive material (45S5) is being absorbed and replaced by newly formed bone. The influence of these structures design on some of the physical and chemical aspects that drive cellular response was assessed. Roughness, wettability, bioactive glass quantity and quality on the structures after processing and the pH measured during cell culture (as a consequence of bioactive glass dissolution) were evaluated and correlated with cellular viability, cellular distribution, morphology and proliferation on the surface and inside the structures.info:eu-repo/semantics/publishedVersio

iPSC-derived neurospheroids recapitulate development and pathological signatures of human brain microenvironment

Brain microenvironment plays an important role in neurodevelopment and pathology, where extracellular matrix (ECM) and soluble factors modulate multiple cellular processes. Neural cell culture typically relies on the use of heterologous matrices that poorly resemble the brain ECM or reflect its pathological features. We have previously demonstrated that perfusion stirred-tank bioreactor-based 3D differentiation of human neural stem cells (NSC) - pSTR-neurospheroids, sustains the concomitant differentiation of the three neural cell lineages (neurons, astrocytes and oligodendrocytes) and the establishment of physiologically relevant cell-cell interactions. Here, we hypothesized that if the pSTR-neurospheroid strategy would also allow the deposition of native neural ECM components and diffusion of secreted factors, it would be possible to: (i) mimic the cellular and microenvironment remodeling occurring during neural differentiation without the confounding effects of exogenous matrices; (ii) recapitulate the pathological phenotypes of diseases in which alteration of homotypic and heterotypic cell-cell interactions and ECM components are relevant. To demonstrate the first point, we analyzed pSTR-neurospheroid differentiation by quantitative transcriptome (NGS) and proteome (SWATH-MS). Data showed that neurogenic developmental pathways were recapitulated, with significant changes at cell membrane and ECM composition, diverging from the 2D differentiation profile. A significant enrichment in structural proteoglycans typical of brain ECM, along with downregulation of basement membrane constituents was observed. Moreover, higher expression of synaptic and ion transport machinery in pSTR-neurospheroids suggest higher neuronal maturation than in 2D. Having shown recapitulation of neural microenvironmental dynamics in pSTR-neurospheroids, we used Mucopolysaccharidosis VII (MPSVII) as a disease case study. MPS VII is a lysosomal storage disease caused by deficient β-glucuronidase (β-gluc) activity, which leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. In pSTR-neurospheroids generated from hiPSC of a MPS VII patient, the main molecular disease hallmarks were recapitulated, namely accumulation of GAGs. Notably, MPS VII neurospheroids showed reduced neuronal activity and a disturbance in network functionality, with alterations both in connectivity and synchronization, not observed in 2D cultures. These data provide insight into the interplay between reduced β-gluc activity, GAG accumulation, alterations in the neural network, and its impact on MPS VII-associated cognitive defects. Overall we demonstrate that neural cellular and extracellular developmental and pathological features are recapitulated in healthy and diseased pSTR-neurospheroids, respectively. These can be valuable in vitro models to address molecular defects associated with neurological disorders that affect neural microenvironment homeostasis. Moreover, the 3D neuronal connectivity assay developed is a new tool with potential to assess other lysosomal storage diseases and neurodegenerative diseases that have variable phenotypes. Acknowledgements: SFRH/BD/78308/2011, SFRH/BD/52202/2013 and SFRH/BD/52473/2014 PhD fellowships from FCT, Portugal and iNOVA4Health-UID/Multi/04462/2013, supported by FCT/ MEC, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement

Sustained remission from depressive-like behavior depends on hippocampal neurogenesis

Impairment of hippocampal neurogenesis has been associated with the expression of depressive-like symptoms and some studies have suggested neurogenesis as a critical factor in the normalization of behavior by antidepressant (AD) drugs. This study provides robust evidence that ongoing neurogenesis is essential for the maintenance of behavioral homeostasis and that its pharmacological arrest precipitates symptoms commonly found in depressed patients. Further, the incorporation of newly born neurons and astrocytes into the preexisting hippocampal neurocircuitry is shown to be necessary for the spontaneous recovery from the adverse effects of stress and for long-term benefits of AD treatments.We thank M Carneiro and L Martins for technical assistance. AM-P, LP, MM and SM received fellowships from the Portuguese Foundation for Science and Technology (FCT). This work was supported by FCT (PTDC/SAU-NEU/105180/2008) and the ICVS

PRICHAIN: A Partially Decentralized Implementation of UbiPri Middleware Using Blockchain

With the popularization of the Internet-of-Things, various applications have emerged to make life easier. These applications generate a large amount of user data. Analyzing the data obtained from these applications, one can infer personal information about each user. Considering this, it is clear that ensuring privacy in this type of application is essential. To guarantee privacy various solutions exist, one of them is UbiPri middleware. This paper presents a decentralized implementation of UbiPri middleware using the Ethereum blockchain. Smart contracts were used in conjunction with a communication gateway and a distributed storage service to ensure users privacy. The results obtained show that the implementation of this work ensures privacy at different levels, data storage security, and performance regarding scalability in the Internet of Things environments.info:eu-repo/semantics/publishedVersio

Mineralization of Sialoliths Investigated by Ex Vivo and In Vivo X-ray Computed Tomography

The fraction of organic matter present affects the fragmentation behavior of sialoliths; thus, pretherapeutic information on the degree of mineralization is relevant for a correct selection of lithotripsy procedures. This work proposes a methodology for in vivo characterization of salivary calculi in the pretherapeutic context. Sialoliths were characterized in detail by X-ray computed microtomography (μCT) in combination with atomic emission spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. Correlative analysis of the same specimens was performed by in vivo and ex vivo helical computed tomography (HCT) and ex vivo μCT. The mineral matter in the sialoliths consisted essentially of apatite (89 vol%) and whitlockite (11 vol%) with average density of 1.8 g/cm3. In hydrated conditions, the mineral mass prevailed with 53 ± 13 wt%, whereas the organic matter, with a density of 1.2 g/cm3, occupied 65 ± 10% of the sialoliths' volume. A quantitative relation between sialoliths mineral density and X-ray attenuation is proposed for both HCT and μCT.info:eu-repo/semantics/publishedVersio

Optimization of Au:CuO thin films by plasma surface modification for high-resolution LSPR gas sensing at room temperature

In this study, thin films composed of gold nanoparticles embedded in a copper oxide matrix (Au:CuO), manifesting Localized Surface Plasmon Resonance (LSPR) behavior, were produced by reactive DC magnetron sputtering and post-deposition in-air annealing. The effect of low-power Ar plasma etching on the surface properties of the plasmonic thin films was studied, envisaging its optimization as gas sensors. Thus, this work pretends to attain the maximum sensing response of the thin film system and to demonstrate its potential as a gas sensor. The results show that as Ar plasma treatment time increases, the host CuO matrix is etched while Au nanoparticles are uncovered, which leads to an enhancement of the sensitivity until a certain limit. Above such a time limit for plasma treatment, the CuO bonds are broken, and oxygen is removed from the film’s surface, resulting in a decrease in the gas sensing capabilities. Hence, the importance of the host matrix for the design of the LSPR sensor is also demonstrated. CuO not only provides stability and protection to the Au NPs but also promotes interactions between the thin film’s surface and the tested gases, thereby improving the nanocomposite film’s sensitivity. The optimized sensor sensitivity was estimated at 849 nm/RIU, which demonstrates that the Au-CuO thin films have the potential to be used as an LSPR platform for gas sensors.This research was sponsored by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UIDB/04650/2020 and by the project CO2Plasmon with reference EXPL/CTM-REF/0750/2021. M.P. acknowledges her Ph.D. Scholarship from FCT, with reference SFRH/BD/137076/2018. Diana I. Meira acknowledges her Ph.D. Scholarship from FCT, with reference SFRH/BD/143262/2019

Expanding the potential of self-assembled silk fibroin as aerogel particles for tissue regeneration

A newly produced silk fibroin (SF) aerogel particulate system using a supercritical carbon dioxide (scCO2)-assisted drying technology is herein proposed for biomedical applications. Different concentrations of silk fibroin (3%, 5%, and 7% (w/v)) were explored to investigate the potential of this technology to produce size- and porosity-controlled particles. Laser diffraction, helium pycnometry, nitrogen adsorption–desorption analysis and Fourier Transform Infrared with Attenuated Total Reflectance (FTIR-ATR) spectroscopy were performed to characterize the physicochemical properties of the material. The enzymatic degradation profile of the SF aerogel particles was evaluated by immersion in protease XIV solution, and the biological properties by cell viability and cell proliferation assays. The obtained aerogel particles were mesoporous with high and concentration dependent specific surface area (203–326 m2/g). They displayed significant antioxidant activity and sustained degradation in the presence of protease XIV enzyme. The in vitro assessment using human dermal fibroblasts (HDF) confirm the particles’ biocompatibility, as well as the enhancement in cell viability and proliferation.info:eu-repo/semantics/publishedVersio