Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function

In terms of lipid nanoparticle (LNP) engineering, the relationship between particle composition, delivery efficacy, and the composition of the biocoronas that form around LNPs, is poorly understood. To explore this we analyze naturally efficacious biocorona compositions using an unbiased screening workflow. First, LNPs are complexed with plasma samples, from individual lean or obese male rats, and then functionally evaluated in vitro. Then, a fast, automated, and miniaturized method retrieves the LNPs with intact biocoronas, and multiomics analysis of the LNP-corona complexes reveals the particle corona content arising from each individual plasma sample. We find that the most efficacious LNP-corona complexes were enriched with high-density lipoprotein (HDL) and, compared to the commonly used corona-biomarker Apolipoprotein E, corona HDL content was a superior predictor of in-vivo activity. Using technically challenging and clinically relevant lipid nanoparticles, these methods reveal a previously unreported role for HDL as a source of ApoE and, form a framework for improving LNP therapeutic efficacy by controlling corona composition.</p

Criança e Delinquência - Fortalecer os Sistemas de Justiça

UID/SOC/04647/2019 SFRH/BPD/116119/2016publishersversionpublishe

Unidade de Internamento Psiquiátrico para Jovens dos 15 aos 25 Anos: Um Estudo de Follow-up

Introduction: Adolescence and early adulthood are life stages characterized by significant physical, psychological, and social transformations. The transitional age, between 15 and 25 years old, is considered a high-risk period for the development of psychopathology, representing a critical period of opportunities and challenges for mental health intervention. Our objective was to do 4-year follow-up study was conducted on young individuals who were hospitalized during the year 2018 in the acute psychiatric inpatient unit Unidade Partilhada, dedicated to individuals aged 15 to 25 years old. The aim was to assess the sociodemographic and clinical characteristics of the sample, inpatient characteristics, rehospitalization rate, psychopathological status, quality of life, satisfaction with the provided care, and maintenance of follow-up appointments; establishing relationships between the mentioned variables. Methods: Standardized telephone interviews were conducted using the reduced version of the Mental Health Inventory (MHI) and the World Health Organization’s Abbreviated Instrument for Quality of Life Assessment. Clinical records were also consulted. Results: There was a higher percentage of female patients (52.1%). The discharge diagnosis of mood disorders (54.3%) was significantly higher in females, while psychotic disorders (23.4%) were significantly higher in males (Fisher = 40; p&lt;0.001). The duration of hospitalization (average=16.1 days; SD=13.6 days) was significantly longer for psychotic disorders compared to mood disorders (p=0.009). A percentage of 41.5% of young individuals were readmitted, with 6.3% readmitted within 30 days and 35.2% readmitted within 365 days. At the time of the follow-up interview, 80.9% considered themselves “better,” and 62.7% reported being “satisfied” or “very satisfied” with their lives. A percentage of 74.5% continued to receive outpatient care, with significantly lower MHI scores observed among individuals without current follow‐up. A percentage of 37.2% reported being “very satisfied” or “extremely satisfied” with the care provided. Conclusion: Obtaining knowledge and data that allow for the characterization of psychiatric hospitalization during the transitional age is fundamental for the planning, organization, and optimization of care provided to this population. Valuing patient opinions and fostering closer relationships between healthcare professionals and young patients promotes treatment adherence.Introdução: A adolescência e início da idade adulta, são fases do ciclo de vida marcadas por grandes transformações físicas, psicológicas e sociais. A faixa etária de transição, entre os15 e 25 anos, é considerada uma idade de risco para o desenvolvimento de psicopatologia, representando um período crítico de oportunidades e desafios para a intervenção em saúde mental. O nosso objetivo foi realizar um estudo de follow-up a 4 anos dos jovens internados durante o ano de 2018 na unidade de internamento agudo psiquiátrico Unidade Partilhada, destinado a jovens dos 15 aos 25anos de idade; pretendeu‐se avaliar as características sociodemográficas e clínicas da amostra, as características do internamento, a taxa de reinternamento, o estado psicopatológico, qualidade de vida, grau de satisfação com os cuidados prestados e manutenção do seguimento em consulta; estabelecendo relações entre as variáveis mencionadasMétodos: Entrevista telefónica padronizada, com aplicação da versão reduzida do Mental Health Inventory (MHI) e o Instrumento Abreviado de Avaliação da Qualidade de Vida da Organização Mundial de Saúde; consulta de processo clínico.Resultados: Há uma maior percentagem de doentes do sexo feminino (52,1%). O diagnóstico de alta de perturbaçãodo humor (54,3%) foi significativamente superior no sexo feminino e o de perturbação psicótica (23,4%) foi significativamente superior no sexo masculino (Fisher= 40; p&lt;0,001). A duração do internamento (média=16,1 dias; DP=13,6 dias) foi significativamente superior para as perturbações psicóticas em comparação com as perturbações do humor (p=0,009). Dos jovens, 41,5% foram readmitidos, 6,3% num período inferior a 30 dias e 35,2% num período inferior a 365 dias. À data da entrevista de follow-up, 80,9% consideram estar “melhor”; e 62,7% estar “satisfeitos”ou “muito satisfeitos” com a sua vida. Mantêm acompanhamento em consulta 74,5%, sendo a pontuação do MHI significativamente inferior nos jovens sem seguimento atual. Referem estar “muito satisfeitos” ou “mais que muito” com o atendimento prestado, 37,2%.Conclusão: O conhecimento e obtenção de dados que permitam a caracterização do internamento psiquiátrico em idade de transição é fundamental para a planificação, organização e otimização dos cuidados prestados a esta população. A valorização da opinião do doente e a aproximação entre profissionais de saúde e doentes jovens, favorece a adesão ao tratamento

Enhanced neuronal differentiation by dynamic piezoelectric stimulation

Abstract Electroactive smart materials play an important role for tissue regenerative applications. Poly(vinylidene fluoride) (PVDF) is a specific subtype of piezoelectric electroactive material that generates electrical potential upon mechanical stimulation. This work focuses on the application of piezoelectric PVDF films for neural differentiation. Human neural precursor cells (hNPCs) are cultured on piezoelectric poled and non-poled -PVDF films with or without a pre-coating step of poly-d-lysine and laminin (PDL/L). Subsequently, hNPCs differentiation into the neuronal lineage is assessed (MAP2+ and DCX+) under static or dynamic (piezoelectric stimulation) culture conditions. The results demonstrate that poled and coated -PVDF films induce neuronal differentiation under static culture conditions which is further enhanced with mechanical stimulation. In silico calculations of the electrostatic potential of different domains of laminin, highlight the high polarity of those domains, which shows a clear preference to interact with the varying surface electric field of the piezoelectric material under mechanical stimulation. These interactions might explain the higher neuronal differentiation induced by poled -PVDF films pre-coated with PDL/L under dynamic conditions. Our results suggest that electromechanical stimuli, such as the ones induced by piezoelectric -PVDF films, are suitable to promote neuronal differentiation and hold great promise for the development of neuroregenerative therapies.Fundação para a Ciência e a Tecnologia, Grant/Award Numbers: POCI-01-0145-FEDER-029206, POCI-01-0145-FEDER-031392, PTDC/MED-NEU/31417/2017, UIDB/50026/2020, UIDP/50026/2020, NORTE-01-0145-FEDER-029968, POCI-01-0145-FEDER-029751, POCI-01-0145-FEDER-032619, UID/FIS/04650/2020, PTDC/EMD-EMD/28159/2017, PTDC/BTM-MAT/28237/2017, PTDC/QUI-OUT/32243/2017, LA/P/0058/2020, UIDB/04539/2020, UIDP/04539/2020, POCI-01-0145-FEDER-031356, DSAIPA/DS/0118/2020; Santa Casa da Misericórdia de Lisboa, Grant/Award Numbers: MC-04-17, MC-18-21; Basque Government Industry Departments; Spanish State Research Agency; European Regional Development Fund, Grant/Award Number: PID2019-106099RB-C43/AEI; Northern Portugal Regional Operational Program, Grant/Award Numbers: NORTE-01-0145-FEDER-000023, NORTE-01-0145-FEDER-000013; Portuguese Platform of Bioimaging, Grant/Award Number: PPBI-POCI-01-0145-FEDER-022122; ICVS Scientific Microscopy Platform; Portuguese Foundation for Science and Technology, Grant/Award Number: PD/BDE/143150/2019info:eu-repo/semantics/publishedVersio

miRNome Expression Analysis Reveals New Players on Leprosy Immune Physiopathology

Leprosy remains as a public health problem and its physiopathology is still not fully understood. MicroRNAs (miRNA) are small RNA non-coding that can interfere with mRNA to regulate gene expression. A few studies using DNA chip microarrays have explored the expression of miRNA in leprosy patients using a predetermined set of genes as targets, providing interesting findings regarding the regulation of immune genes. However, using a predetermined set of genes restricted the possibility of finding new miRNAs that might be involved in different mechanisms of disease. Thus, we examined the miRNome of tuberculoid (TT) and lepromatous (LL) patients using both blood and lesional biopsies from classical leprosy patients (LP) who visited the Dr. Marcello Candia Reference Unit in Sanitary Dermatology in the State of Pará and compared them with healthy subjects. Using a set of tools to correlate significantly differentially expressed miRNAs with their gene targets, we identified possible interactions and networks of miRNAs that might be involved in leprosy immunophysiopathology. Using this approach, we showed that the leprosy miRNA profile in blood is distinct from that in lesional skin as well as that four main groups of genes are the targets of leprosy miRNA: (1) recognition and phagocytosis, with activation of immune effector cells, where the immunosuppressant profile of LL and immunoresponsive profile of TT are clearly affected by miRNA expression; (2) apoptosis, with supportive data for an antiapoptotic leprosy profile based on BCL2, MCL1, and CASP8 expression; (3) Schwann cells (SCs), demyelination and epithelial–mesenchymal transition (EMT), supporting a role for different developmental or differentiation gene families, such as Sox, Zeb, and Hox; and (4) loss of sensation and neuropathic pain, revealing that RHOA, ROCK1, SIGMAR1, and aquaporin-1 (AQP1) may be involved in the loss of sensation or leprosy pain, indicating possible new therapeutic targets. Additionally, AQP1 may also be involved in skin dryness and loss of elasticity, which are well known signs of leprosy but with unrecognized physiopathology. In sum, miRNA expression reveals new aspects of leprosy immunophysiopathology, especially on the regulation of the immune system, apoptosis, SC demyelination, EMT, and neuropathic pain

data_sheet_1.xlsx

<p>Leprosy remains as a public health problem and its physiopathology is still not fully understood. MicroRNAs (miRNA) are small RNA non-coding that can interfere with mRNA to regulate gene expression. A few studies using DNA chip microarrays have explored the expression of miRNA in leprosy patients using a predetermined set of genes as targets, providing interesting findings regarding the regulation of immune genes. However, using a predetermined set of genes restricted the possibility of finding new miRNAs that might be involved in different mechanisms of disease. Thus, we examined the miRNome of tuberculoid (TT) and lepromatous (LL) patients using both blood and lesional biopsies from classical leprosy patients (LP) who visited the Dr. Marcello Candia Reference Unit in Sanitary Dermatology in the State of Pará and compared them with healthy subjects. Using a set of tools to correlate significantly differentially expressed miRNAs with their gene targets, we identified possible interactions and networks of miRNAs that might be involved in leprosy immunophysiopathology. Using this approach, we showed that the leprosy miRNA profile in blood is distinct from that in lesional skin as well as that four main groups of genes are the targets of leprosy miRNA: (1) recognition and phagocytosis, with activation of immune effector cells, where the immunosuppressant profile of LL and immunoresponsive profile of TT are clearly affected by miRNA expression; (2) apoptosis, with supportive data for an antiapoptotic leprosy profile based on BCL2, MCL1, and CASP8 expression; (3) Schwann cells (SCs), demyelination and epithelial–mesenchymal transition (EMT), supporting a role for different developmental or differentiation gene families, such as Sox, Zeb, and Hox; and (4) loss of sensation and neuropathic pain, revealing that RHOA, ROCK1, SIGMAR1, and aquaporin-1 (AQP1) may be involved in the loss of sensation or leprosy pain, indicating possible new therapeutic targets. Additionally, AQP1 may also be involved in skin dryness and loss of elasticity, which are well known signs of leprosy but with unrecognized physiopathology. In sum, miRNA expression reveals new aspects of leprosy immunophysiopathology, especially on the regulation of the immune system, apoptosis, SC demyelination, EMT, and neuropathic pain.</p