Charge-switchable cell-penetrating peptides for rerouting nanoparticles to glioblastoma treatment.

Glioblastoma (GB) is one of the most lethal types of neoplasms with unique anatomic, physiologic, and pathologic features that usually persist after exposure to standard therapeutic modalities. It is biologically aggressive, and the existence of the blood-brain barrier (BBB) limits the efficacy of standard therapies. In this work, we hypothesize the potential of surface-functionalized ultra-small nanostructured lipid carriers (usNLCs) with charge-switchable cell-penetrating peptides (CPPs) to overcome this biological barrier and improve targeted delivery to brain tumor tissues. The big question is: what is the potential of CPPs in directing nanoparticles toward brain tumor tissue? To answer this question, the usNLCs were functionalized with distinct biomolecules [five CPPs, c(RGDfK) and transferrin, Tf] through electrostatic interaction and its ability as a targeting approach to BBB (HBMEC) and glioma cells (U87 cells) evaluated in terms of physicochemical properties, cellular uptake, permeability in a 2D-BBB model, and tumor growth inhibition. Monte Carlo simulations elucidated CPP adsorption patterns. The permeability studies revealed that targeted usNLCs, especially usNLCsTf and usNLCsCPP4, exhibited an increased permeability coefficient compared to the non-targeted usNLCs. Functionalized usNLCs evidenced enhanced uptake in BBB cells, with smaller CPPs showing higher internalization (CPP1 and CPP2). Similarly, functionalized usNLCs exhibited more significant cytotoxicity in glioma cells, with specific CPPs promoting favorable internalization. Analysis of the endocytic pathway indicated that usNLCsCPPs were mainly internalized by direct translocation and caveolae-mediated endocytosis. Optimal usNLCs with dual targeting capabilities to both BBB and GB cells provide a promising therapeutic strategy for GB.

Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer.

Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8 + T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.

Selective, broad-spectrum antiviral photodynamic disinfection with dicationic imidazolyl chlorin photosensitizers.

The COVID-19 pandemic exposes our vulnerability to viruses that acquire the ability to infect our cells. Classical disinfection methods are limited by toxicity. Existing medicines performed poorly against SARS-CoV-2 because of their specificity to targets in different organisms. We address the challenge of mitigating known and prospective viral infections with a new photosensitizer for antimicrobial photodynamic therapy (aPDT). Photodynamic inactivation is based on local oxidative stress, which is particularly damaging to enveloped viruses. We synthesized a cationic imidazolyl chlorin that reduced by > 99.999% of the percentage inhibition of amplification of SARS-CoV-2 collected from patients at 0.2 µM concentration and 4 J cm-2. Similar results were obtained in the prevention of infection of human ACE2-expressing HEK293T cells by a pseudotyped lentiviral vector exhibiting the S protein of SARS-CoV-2 at its surface. No toxicity to human epidermal keratinocytes (HaCaT) cells was found under similar conditions. aPDT with this chlorin offers fast and safe broad-spectrum photodisinfection and can be repeated with low risk of resistance.

Reactivity of ethyl nitrosoacrylate toward pyrrole, indole and pyrrolo[3,2-c]carbazole: an experimental and theoretical study.

Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2- and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMOheterodiene-HOMOdienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4',3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.

Fluorinated Mn(III)/(II)-Porphyrin with Redox-Responsive 1 H and 19 F Relaxation Properties.

A new fluorinated manganese porphyrin, (Mn-TPP-p-CF3 ) is reported capable of providing, based on the Mn(III)/Mn(II) equilibrium, dual 1 H relaxivity and 19 F NMR response to redox changes. The physical-chemical characterization of both redox states in DMSO-d6 /H2 O evidenced that the 1 H relaxometric and 19 F NMR properties are appropriate for differential redox MRI detection. The Mn(III)-F distance (dMn-F =9.7-10 Å), as assessed by DFT calculations, is well tailored to allow for adequate paramagnetic effect of Mn(III) on 19 F T1 and T2 relaxation times. Mn-TPP-p-CF3 has a reversible Mn(II)/Mn(III) redox potential of 0.574 V vs. NHE in deoxygenated aqueous HEPES/ THF solution. The reduction of Mn(III)-TPP-p-CF3 in the presence of ascorbic acid is slowly, but fully reversed in the presence of air oxygen, as monitored by UV-Vis spectrometry and 19 F NMR. The broad 1 H and 19 F NMR signals of Mn(III)-TPP-p-CF3 disappear in the presence of 1 equivalent ascorbate replaced by a shifted and broadened 19 F NMR signal from Mn(II)-TPP-p-CF3 . Phantom 19 F MR images in DMSO show a MRI signal intensity decrease upon reduction of Mn(III)-TPP-p-CF3 , retrieved upon complete reoxidation in air within ~24 h. 1 H NMRD curves of the Mn(III)/(II)-TPP-p-CF3 chelates in mixed DMSO/water solvent have the typical shape of Mn(II)/Mn(III) porphyrins.

A descriptive analysis of hospitalized adolescents facing chronic illnesses with different durations of disease.

OBJECTIVES: To assess characteristics of hospitalized adolescents facing chronic diseases, correlating the perceptions of their illness, quality of life and the prevalence of risk behaviors, considering gender and the diseases' durations. METHODS: The sample consisted of 61 adolescents, aged between 10 and 19 years, with chronic diseases, hospitalized at the University Hospital of the State University of Londrina. They answered a questionnaire and the scales World Health Organization Quality of Life (WHOQOL-BREF) and Illness Perception Questionnaire (IPQ). They were divided in groups, according to the durations of the disease: group 1 (up to 4 years) and group 2 (5 years or more). RESULTS: Group 2 demonstrated higher leisure activity (p = 0.02) and more painful symptoms (p = 0.02). In WHOQOL-BREF, group 2 had a higher quality of life in the domain on environment (p = 0.02) and a higher total score (p = 0.04). Lower scores on the IPQ were associated with higher scores on the WHOQOL-BREF. Positive correlation was found between WHOQOL-BREF total score and years of disease, in which male presented higher scores. CONCLUSIONS: These findings may alert to the need for more knowledge about the diseases and the importance of encouraging ways to improve quality of life and care to reduce risky behaviors.

Preditores da satisfação com a vida entre universitários do Estado da Bahia, Brasil / Predictores de la satisfacción con la vida entre estudiantes universitarios del estado de Bahía, Brasil / Predictors of life satisfaction among university students in the state of Bahia, Brazil

A satisfação com a vida tem sido descrita como um constructo psicológico que se refere à avaliação global que o indivíduo faz em relação a sua vida. O presente estudo objetiva investigar se fatores individuais (gênero e idade), socioeconômico (classe social), de autoper-cepção (nível de estresse, estado de saúde e qualida-de do sono) e de percepção de qualidade de vida na universidade (oportunidade e motivação para aprendi-zagem, ambiente social para aprendizagem, ambiente físico e equipamentos para aprendizagem, autoava-liação de conhecimento e relevância da universidade) predizem a satisfação com a vida entre universitários de instituições públicas do Estado da Bahia, Brasil. Participaram do estudo 1.506 universitários dos cursos de graduação presenciais das Universidades Federais (ufs) localizados no Estado da Bahia, sendo 537 ho-mens (35.7 %), 968 mulheres (64.3 %) e um que não identificou seu gênero, com idades entre 18 a 24 anos (63.5 %) e sem companheiro(a) (86.0 %). Os resultados indicaram que o modelo que melhor predisse a satis-fação com a vida foi aquele que incluiu classe social, nível de estresse, estado de saúde, qualidade do sono, grau de motivação, ânimo para assistir as aulas do seu curso, relacionamento com os demais colegas do seu curso e oportunidade de participação em atividades de ensino, extensão e pesquisa. Juntas, essas variáveis foram responsáveis por explicar aproximadamente 27.5 % da variância em satisfação com a vida, o que é uma razoável capacidade explicativa, se considerarmos que satisfação com a vida é um constructo psicológico, complexo e multideterminado.

La satisfacción con la vida ha sido descrita como un constructo psicológico que hace referencia a la valoración global que el individuo tiene en relación a su vida. El presente estudio tiene como objetivo investigar si factores individuales (género y edad), socioeconó-micos (clase social), autopercepción (nivel de estrés, estado de salud y calidad del sueño) y calidad de vida percibida en la universidad (oportunidad y motivación para el aprendizaje, ambiente social para el aprendizaje, ambiente físico y equipamiento para el aprendizaje, autoevaluación de conocimientos y pertinencia de la universidad) predicen la satisfacción con la vida en estudiantes universitarios de instituciones públicas del Estado de Bahía, Brasil. Participaron en el estudio 1.506 estudiantes universitarios de cursos de graduación presenciales en Universidades Federales (uf) ubicadas en el Estado de Bahía, 537 hombres (35.7 %), 968 mujeres (64.3 %) y uno que no identificó su género, edad entre 18 y 24 años (63.5 %) y sin pareja (86.0 %). Los resultados indicaron que el modelo que mejor predijo la satisfacción con la vida fue el que incluyó la clase social, el nivel de estrés, el estado de salud, la calidad del sueño, el grado de motivación, la disposición a asistir a las clases de su curso, la relación con los demás compañeros y la oportunidad de participar en actividades de docencia, extensión e investigación. En conjunto, estas variables fueron responsables de explicar aproximada-mente el 27.5 % de la varianza en la satisfacción con la vida, lo cual es una capacidad explicativa razonable, si consideramos que la satisfacción con la vida es un constructo psicológico, complejo y multideterminado.

Life satisfaction has been described as a psychological construct referring to the overall assessment the individ-ual makes regarding their life. The present study aims to investigate whether individual factors (gender and age), socioeconomic factors (social class), self-perception (level of stress, health status and quality of sleep), and perceived quaility of life at the university (opportu-nity and motivation for learning, social environment for learning, physical environment and equipment for learning, self-assessment of knowledge and relevance of the university) predict life satisfaction among university students from public institutions in the state of Bahia. In this study, 1.506 university students from undergraduate courses of the federal universities (ufs) participated in the study: 537 men (35.7 %), 969 women (64.3 %), and one student that did not identify their gender, with ages between 18 to 24 years (63.5 %) and without a partner (86.0 %). The results indicated that the model that best predicted life satisfaction was the one including social class, stress level, health status, quality of sleep, degree of motivation, willingness to attend classes in their degree, relationship with other colleagues in their degree, and opportunity to participate in teaching, ex-tension and research activities. Together these variables explained approximately 27.5 % of the variance in life satisfaction, which is a reasonable explanatory capacity if we consider that life satisfaction is a psychological, complex, and multidetermined construct.

Impact of ZNF804A rs1344706 or CACNA1C rs1006737 polymorphisms on cognition in patients with severe mental disorders: A systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis focussed on insights into the relationship between CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms and cognitive performance in schizophrenia (SCZ) spectrum and bipolar disorder (BD) and provide some contributions for clinical practice. METHODS: We searched the websites databases (PubMED, PsycINFO, Web of Science, EMBASE and Cochrane Library) using eligibility and exclusion criteria to capture all potential studies, based on PICO model and according to the PRISMA. RESULTS: Eight articles were included in this systematic review (five referring to CACNA1C-rs1006737 and three related to ZNF804A-rs1344706 polymorphisms), with a total of 5759 participants (1751 SCZ patients, 348 BD patients, 3626 controls and 34 first-degree relatives). The results demonstrated that the pooled effect of CACNA1C-rs1006737 (risk difference RD = 0.08; 95% CI 0.02-0.15) was associated with altered cognitive function in patients with severe mental disorders, but not ZNF804A-rs1344706 polymorphism (RD = 0.19; 95% CI 0.09-0.48. CONCLUSION: The present meta-analysis provides evidence regarding slight association between CACNA1C-rs1006737 polymorphisms and cognitive performance in severe mental disorders, indicating that cognitive impairment in severe mental disorders associated with the CACNA1C rs1006737 risk variants could only be expressed when interacting with environmental exposures. This study is registered with PROSPERO, number CRD42021246726.

Research and Diagnostic Algorithmic Rules (RADAR) for mood disorders, recurrence of illness, suicidal behaviours, and the patient's lifetime trajectory.

The top-down Diagnostic and Statistical Manual/International Statistical Classification of Diseases categories of mood disorders are inaccurate, and their dogmatic nature precludes both deductive (as indisputable) and inductive (as top-down) remodelling of case definitions. In trials, psychiatric rating scale scores employed as outcome variables are invalid and rely on folk psychology-like narratives. Using machine learning techniques, we developed a new precision nomothetic model of mood disorders with a recurrence of illness (ROI) index, a new endophenotype class, namely Major Dysmood Disorder (MDMD), characterised by increased ROI, a more severe phenome, and more disabilities. Nonetheless, our previous studies did not compute Research and Diagnostic Algorithmic Rules (RADAR) to diagnose MDMD and score ROI, lifetime (LT), and current suicidal behaviours, as well as the phenome of mood disorders. Here, we provide rules to compute bottom-up RADAR scores for MDMD, ROI, LT and current suicidal ideation and attempts, the phenome of mood disorders, and the lifetime trajectory of mood disorder patients from a family history of mood disorders and substance abuse to adverse childhood experiences, ROI, and the phenome. We also demonstrate how to plot the 12 major scores in a single RADAR graph, which displays all features in a two-dimensional plot. These graphs allow the characteristics of a patient to be displayed as an idiomatic fingerprint, allowing one to estimate the key traits and severity of the illness at a glance. Consequently, biomarker research into mood disorders should use our RADAR scores to examine pan-omics data, which should be used to enlarge our precision models and RADAR graph.

Cognitive impairment, childhood trauma, sedentary behaviour, and elevated C-reactive protein levels in major affective disorders.

Elevated C-reactive protein (CRP) levels were associated with cognitive decline, sedentary behaviour, and childhood trauma in patients with major affective disorders. This study aims to examine the association of peripheral CRP levels, cognitive function, childhood trauma, sedentary behaviour, and quality of life in individuals with major affective disorders, including bipolar disorder (BD), major depressive disorder (MDD), and individuals without mood disorders (controls). We included outpatients with BD (n = 42), MDD (n = 27), and healthy controls (n = 40). All participants were assessed by a questionnaire, structured clinical interview, and the following scales: international physical activity questionnaire, childhood trauma questionnaire, 17-item Hamilton Depression Rating Scale (HDRS17), and World Health Organization Quality of Life instrument, brief version (WHOQOL-BREF). Other measures were included: hs-CRP levels, anthropometric measures, and cognitive tests (Trail-making test part A and part B, Stroop test, phonemic verbal fluency test, and semantic verbal fluency test). Our results indicated that BD outpatients were less significantly physically active on leisure domain than controls. Levels of hs-CRP ≥ 5 mg/L were significantly linked with a history of childhood sexual abuse and childhood physical abuse, as well as worse neurocognitive performance in major depressive disorders, mainly in BD. There was a significant negative correlation between Trail-making part B score and WHOQOL-BREF total score. The findings support the hypothesis that levels of hs-CRP ≥ 5 mg/L may be a possible predictor of cognitive dysfunction, childhood sexual abuse and sedentary behaviour in major affective disorders.

Pilot project. Resveratrol intake by physical active and sedentary older adult women and blood pressure.

OBJECTIVE: Although the use of resveratrol is widespread, there is a lack of studies concerning its use in older adults who practice regular physical activity. The present study aimed to evaluate how resveratrol influenced anthropometric parameters, heart measures, blood analytes in women participants, aged 60 to 80 years old, distributed in four groups consisting of those who regularly exercise or not, and those who were under resveratrol treatment or not. The older adult women exercised in a Community Center. METHODS: A prospective, comparative clinical pilot study was carried out based on convenience non-probability sampling. Resveratrol 300 mg/daily/60 days was orally-administered to 43 participants that were regularly accompanied and checked for anthropometrical parameters, heart measures, blood analytes, leukogram, and plaquetogram indices. RESULTS: The effect of resveratrol and exercise was not significant in most of the parameters evaluated in the study. Nonetheless, both systolic (p = 0.0120) and diastolic (p = 0.0241) blood pressures (BP) were elevated in sedentary older adult women in comparison with older women that regularly exercised. However, they remained within the normal BP range considered for the age. Mean corpuscular volume (MCH; p = 0.0198) and red blood cell distribution width (RDW; p < 0.0001) were improved in the groups receiving resveratrol and exercises compared to the sedentary group receiving resveratrol. The sedentary group receiving resveratrol showed diminished segmented cells (p = 0.0459), basophils (p < 0.0001), and lymphocytes (p < 0.0001). CONCLUSIONS: Present findings showed that resveratrol consumption for sedentary older women could lead to dysregulated blood pressure. Although resveratrol consumption is indicated to treat inflammation, its use must be discussed with a health professional and not be inadvertently self-administered due to significant alterations in blood pressure in older adult women, primarily if not related to exercise practice.

Hybrid and Remote Psychosocial Interventions Focused on Weight and Sedentary Behavior Management Among Patients with Severe Mental Illnesses: a Systematic Review.

Severe mental illness could be defined through its diagnosis, disability, and duration, and one of their main characteristics is the high prevalence of some clinical conditions such as obesity and metabolic syndrome. Although the promotion of a healthier lifestyle has been demonstrated as an effective strategy to reduce both body mass index and abdominal circumference in this population, there is a lack of studies focusing on digital intervention in this population. The aim of this systematic review was to evaluate the efficacy of studies that used digital technologies to reduce weight, body mass index (BMI) and abdominal circumference in individuals with severe mental illness. This current review also compared remote and hybrid interventions, the effects of those interventions in metabolic biomarkers as well as in the development of a healthier lifestyle. The main findings included the following: (a) the use of digital devices or strategies might be feasible and useful to reduce sedentary behavior among individuals with severe mental illnesses, 2) most interventions used digital pedometers and mobile phone communication (either text messages or phone calls) as main strategies, 3) all remote interventions and six of nine hybrid interventions found significant outcomes in favor of their interventions. In conclusion, even with a limited number of studies promoting healthier lifestyle through digital interventions among individuals with severe mental illnesses, evidence from studies included in this review showed that they might be useful to improve a healthier lifestyle and increase the frequency of physical activity behavior.

Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells' Pluripotency in Bladder Cancer.

Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette-Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1ß. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid-tumoral hybrid population (CD11b+EPCAM+) was detected after 48 h, which indicates BC cell-macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers (SOX2, NANOG, miR-302) as compared with non-fused (CD11b-EPCAM+) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10. Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.

Cognition-immune interactions between executive function and working memory, tumour necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNFR1 and sTNFR2) in bipolar disorder.

OBJECTIVES: This study examined cognition-immune interactions, specifically executive function, working memory, peripheral levels of tumour necrosis factor-alpha (TNF-α), and soluble tumour necrosis factor receptors-1 and -2 (sTNFR1 and 2) levels in bipolar disorder (BD) patients in comparison with controls. METHODS: Thirty-one BD participants and twenty-seven controls participated in the study. The neurocognitive assessment was performed through three of CogState Research BatteryTM tasks for executive function and working memory. Plasma levels of TNF-α, sTNFR1, and sTNFR2 were measured after overnight fasting. Sociodemographic data and symptom severity of depression and mania were assessed. RESULTS: BD presented a significantly worse performance in the working memory task (p = .005) and higher levels of TNF-α (p = .043) in comparison to controls. A trend level of significance was found for sTNFR1 between groups (p = .082). Among BD participants, there were significant correlations between sTNFR2 and neurocognitive tasks (Groton Maze Learning Task: ρ = .54, p = .002; Set-Shifting Task: ρ = .37, p = .042; and the Two-Back Task: ρ = -.49, p = .005), and between sTNFR1 and mania, depression and anxiety symptoms (respectively ρ = .37, p = .038; ρ = -.38, p = .037; and ρ = .42, p = .002). CONCLUSION: TNF-α and its receptors might be an important variable in cognitive impairment in BD. Future studies might focus on the development of anti-inflammatory therapeutic targets for cognitive dysfunction in BD.

Cognitive Profile and Relationship with Quality of Life and Psychosocial Functioning in Mood Disorders.

BACKGROUND: Comparisons between healthy controls (HCs) and individuals with mood disorders have shown more cognitive dysfunction among the latter group, in particular in bipolar disorder (BD). This study aimed to characterize the pattern of cognitive function of BD and major depressive disorder (MDD) and compare them to HC using the (CogState Research Battery) CSRB™. METHOD: Participants were tested, comprising the following domains: processing speed, attention, working memory, visual memory, executive functions, and verbal memory. Quality of life and functionality were also assessed. Multiple linear regression models were performed to examine the effect of demographic characteristics and functionality on cognitive outcomes separately for BD and MDD. RESULTS: Ninety individuals participated in the study, of which 32 had BD, 30 had MDD, and 28 were HC. Differences were found between both BD and MDD and HC for the composite cognitive score, with significant differences between BD and HC (Diff = -5.5, 95% CI = [-9.5, -1.5], p = 0.005), and MDD and HC (Diff = -4.6, 95% CI = [-8.6, -0.5], p = 0.025). There were overall significant differences in five cognitive domains: processing speed (p = 0.001 and p = 0.004), attention (p = 0.002), working memory (p = 0.02), visual memory (p = 0.021), and verbal memory (p = 0.007). BD also presented worse performance than both MDD and HC, and MDD presented better performance than BD but worse than HC in quality of life and functionality. Multiple linear regression models were significative for education (p < 0.001) and age (p = 0.004) for BD and education (p < 0.001) for MDD. CONCLUSION: In general, cognition is more affected in BD than MDD, which could be associated with functional and quality of life impairment.

Artificial Intelligence and Quantum Computing as the Next Pharma Disruptors.

Artificial intelligence (AI) consists of a synergistic assembly of enhanced optimization strategies with wide application in drug discovery and development, providing advanced tools for promoting cost-effectiveness throughout drug life cycle. Specifically, AI brings together the potential to improve drug approval rates, reduce development costs, get medications to patients faster, and help patients complying with their treatments. Accelerated pharmaceutical development and drug product approval rates can further benefit from the quantum computing (QC) technology, which will ultimately enable larger profits from patent-protected market exclusivity.Key pharma stakeholders are endorsing cutting-edge technologies based on AI and QC , covering drug discovery, preclinical and clinical development, and postapproval activities. Indeed, AI-QC applications are expected to become standard in the pharma operating model over the next 5-10 years. Generalizing scalability to larger pharmaceutical problems instead of specialization is now the main principle for transforming pharmaceutical tasks on multiple fronts, for which systematic and cost-effective solutions have benefited in areas such as molecular screening, synthetic pathway design, and drug discovery and development.The information generated by coupling the life cycle of drugs and AI and/or QC through data-driven analysis, neural network prediction, and chemical system monitoring will enable (1) better understanding of the complexity of process data, (2) streamlining the design of experiments, (3) discovering new molecular targets and materials, and also (4) planning or rethinking upcoming pharmaceutical challenges The power of AI-QC makes accessible a range of different pharmaceutical problems and their rationalization that have not been previously addressed due to a lack of appropriate analytical tools, demonstrating the breadth of potential applications of these emerging multidimensional approaches. In this context, creating the right AI-QC strategy often involves a steep learning path, especially given the embryonic stage of the industry development and the relative lack of case studies documenting success. As such, a comprehensive knowledge of the underlying pillars is imperative to extend the landscape of applications across the drug life cycle.The topics enclosed in this chapter will focus on AI-QC methods applied to drug discovery and development, with emphasis on the most recent advances in this field.

Análise da realocação do tempo sentado, sono e em atividades físicas sob a autoavaliação de saúde negativa de universitários / Analysis of the reallocation of time spent sitting, sleeping, and performing physical activities under negative self-rated heath of university students

O objetivo deste estudo foi examinar o efeito da substituição isotemporal da atividade física, do tempo sedentário e horas de sono em relação à autoavaliação de saúde (AAS) negativa em universitários de uma universidade pública do ensino superior do estado de Minas Gerais, MG, Brasil. Foi realizado um estudo de delineamento transversal, no qual os dados foram obtidos via questionário e a AAS negativa foi o desfecho deste estudo. O tempo por dia despendido em atividade física, tempo sentado e sono foram padronizados por constantes de 10, 30 e 60 minutos. O modelo de substituição isotemporal foi empregado por meio da estimativa do Odds Ratio, via regressão logística binária. O nível de significância foi de 5%. Participaram deste estudo 1.110 estudantes. Observou-se que a substituição de 10, 30 ou 60 minutos por dia de tempo sentado pela mesma quantidade de tempo em atividade física reduz as chances de AAS negativa entre os universitários. De modo geral, maiores chances de AAS negativa foram observadas ao substituir os mesmos tempos de atividade física por tempo sentado. Nenhuma associação foi observada com a realocação do tempo de sono. Conclui-se que a substituição de pelo menos 10 minutos de tempo sentado por atividade física pode reduzir progressivamente as chances de AAS negativa entre os universitários.

The aim of this study was to examine the effect of isotemporal substitution of physical activity, sedentary, and sleep time in relation to negative self-rated health (SRH) in university students from a public university in the state of Minas Gerais, Brazil. A cross-sectional study was carried out, in which data were obtained via a questionnaire and the study's outcome was the negative SRH. The time per day spent on physical activity, sitting, and sleeping were standardized by constants of 10, 30, and 60 minutes. The isotemporal substitution model was used through the estimation of the Odds Ratio via binary logistic regression. The significance level was 5%. A total of 1,110 students participated in this study. It was observed that replacing 10, 30, or 60 minutes per day of sitting time for the same amount of time in physical activity reduces the probability of negative SRH among university students. In general, greater probability of negative SRH were observed when replacing the same times of physical activity with sitting time. No association was observed with sleep time reallocation. It is concluded that replacing at least 10 minutes of sitting time with physical activity can progressively reduce chances of negative SRH among university students.

Prevalence of negative self-rated health in university students and its relationship with the co-occurrence of risk behaviors / Prevalência da autoavaliação de saúde negativa em universitários e sua relação com a concorrência de comportamentos de risco

ABSTRACT The present study estimate the prevalence of negative self-rated health and to analyze its association with simultaneous risk behaviors (insufficient levels of physical activity, greater exposure to sedentary time and inappropriate sleep time) in students at a public university in the state from Minas Gerais, Brazil. It consists of cross-sectional study, with data collected through a questionnaire. The outcome variable was negative self-rated health. The independent variables were estimated by the questions related to the time spent on physical activity, sitting and sleep time, and these three behaviors were considered according to the risk criteria (none, one, two and three risk behaviors). The association was estimated by the Prevalence Ratios (PR), via Poisson regression. 1,110 students participated in the study. The prevalence of negative self-rated health among university students was 47.3%, and the prevalence of two risk behaviors and three risk behaviors were 41.3% and 11.3%, respectively. The simultaneous occurrence of three risk behaviors was associated with negative self-rated health in university students. The information in this study makes it possible to characterize the need for actions to promote health in the university environment.

RESUMO O presente estudo estimou a prevalência da autoavaliação de saúde negativa e analisou a sua associação com comportamentos de risco simultâneos (níveis insuficientes de atividade física, maior exposição ao tempo sedentário e tempo de sono não apropriado) em estudantes de uma universidade pública do ensino superior do estado de Minas Gerais, Brasil. Consiste de um estudo transversal, com informações mensuradas via questionário e a variável desfecho foi a autoavaliação de saúde negativa. As variáveis independentes foram estimadas pelas perguntas referentes ao tempo despendido em: atividade física, tempo sentado e tempo de sono, e esses três comportamentos foram somados conforme os critérios de risco (nenhum, um, dois e três fatores de risco). A associação foi estimada pelas Razões de Prevalências (RP), via regressão de Poisson. Participaram do estudo 1.110 estudantes. A prevalência da autoavaliação de saúde negativa entre os universitários foi de 47,3%, e as prevalências de dois fatores de risco e de três fatores de risco foram de 41,3% e 11,3%, respectivamente. A ocorrência de forma simultânea de três fatores de risco mostrou-se associada com a autoavaliação de saúde negativa em universitários. As informações deste estudo possibilitam caracterizar a necessidade de ações na promoção de saúde no ambiente universitário.

Key Factors for Implementing Magnetic NDT Method on Thin UHPFRC Bridge Elements.

This paper provides an overview of the use of the magnetic NDT method for estimating the fibre content, and fibre orientation and efficiency factors in thin UHPFRC elements/layers, along any two orthogonal directions. These parameters are of utmost importance for predicting the post-cracking tensile strength in the directions of interest. After establishing meaningful correlations at the lab-specimen scale, this NDT method can be effectively implemented into quality control protocols at the industrial production scale. The current study critically addresses the influence of key factors associated with using this NDT method in practice and provides recommendations for its efficient implementation.

BDNF in antipsychotic naive first episode psychosis: Effects of risperidone and the immune-inflammatory response system.

Brain-derived neurotrophic factor (BDNF) and the immune-inflammatory response system (IRS) have been implicated in the pathophysiology of schizophrenia. However, no research examined the associations between BDNF and immune activation both before and after treatment in antipsychotic-naïve first episode psychosis (AN-FEP). This study aims to examine serum BDNF levels and their association with IRS and the compensatory immune-regulatory reflex system (CIRS) in AN-FEP before and after risperidone treatment. We included 31 AN-FEP and 22 healthy controls. AN-FEP showed reduced levels of BDNF as compared to controls, and BDNF levels normalized after treatment with risperidone. BDNF levels were inversely correlated with a greater IRS response. Higher levels of IRS/CIRS biomarkers were associated with lower levels of BDNF including M1 macrophage, T-helper (Th)-1, Th-2, and Th-17, and T-regulatory (Treg) cell responses. Our findings indicate that AN-FEP is characterized by decreased levels of BDNF, which are normalized after treatment with risperidone. BDNF levels were inversely associated with activated immune-inflammatory pathways. The findings support the hypothesis that, increased IRS is linked to neurotoxicity, and that a decrease in BDNF may be part of the IRS/CIRS responses in FEP and, thus, be involved in the development of psychosis.