Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities

Funding Information: We acknowledge Diogo Vila Vi?osa for valuable discussions. We acknowledge financial support from Funda??o para a Ci?ncia e a Tecnologia, Portugal through projects PTDC/MED-QUI/29036/2017, PTDC/BIA-MIC-30692/2017, UIDB/00100/2020, UIDP/00100/2020, UIDB/04046/2020, UIDP/04046/2020, and UID/Multi/04413/2020, and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017. Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation, USA (MCB 1616059). Funding Information: We acknowledge Diogo Vila Viçosa for valuable discussions. We acknowledge financial support from Fundação para a Ciência e a Tecnologia , Portugal through projects PTDC/MED-QUI/29036/2017 , PTDC/BIA-MIC-30692/2017 , UIDB/00100/2020 , UIDP/00100/2020 , UIDB/04046/2020 , UIDP/04046/2020 , and UID/Multi/04413/2020 , and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017 . Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation , USA ( MCB 1616059 ). Publisher Copyright: © 2021 The AuthorsIsoniazid (INH) is one of the two most effective first-line antitubercular drugs and is still used at the present time as a scaffold for developing new compounds to fight TB. In a previous study, we have observed that an INH derivative, an hydrazide N′-substituted with a C10acyl chain, was able to counterbalance its smaller reactivity with a higher membrane permeability. This resulted in an improved performance against the most prevalent Mycobacterium tuberculosis (Mtb) resistant strain (S315T), compared to INH. In this work, we have designed two new series of INH derivatives (alkyl hydrazides and hydrazones) with promising in silico properties, namely membrane permeabilities and spontaneous IN* radical formation. The kinetics, cytotoxicity, and biological activity evaluations confirmed the in silico predictions regarding the very high reactivity of the alkyl hydrazides. The hydrazones, on the other hand, showed very similar behavior compared to INH, particularly in biological tests that take longer to complete, indicating that these compounds are being hydrolyzed back to INH. Despite their improved membrane permeabilities, the reactivities of these two series are too high, impairing their overall performance. Nevertheless, the systematic data gathered about these compounds have showed us the need to find a balance between lipophilicity and reactivity, which is paramount to devise better INH-based derivatives aimed at circumventing Mtb resistance.publishersversionpublishe

Spatial Factors Play a Major Role as Determinants of Endemic Ground Beetle Beta Diversity of Madeira Island Laurisilva

The development in recent years of new beta diversity analytical approaches highlighted valuable information on the different processes structuring ecological communities. A crucial development for the understanding of beta diversity patterns was also its differentiation in two components: species turnover and richness differences. In this study, we evaluate beta diversity patterns of ground beetles from 26 sites in Madeira Island distributed throughout Laurisilva – a relict forest restricted to the Macaronesian archipelagos. We assess how the two components of ground beetle beta diversity (βrepl – species turnover and βrich - species richness differences) relate with differences in climate, geography, landscape composition matrix, woody plant species richness and soil characteristics and the relative importance of the effects of these variables at different spatial scales. We sampled 1025 specimens from 31 species, most of which are endemic to Madeira Island. A spatially explicit analysis was used to evaluate the contribution of pure environmental, pure spatial and environmental spatially structured effects on variation in ground beetle species richness and composition. Variation partitioning showed that 31.9% of species turnover (βrepl) and 40.7% of species richness variation (βrich) could be explained by the environmental and spatial variables. However, different environmental variables controlled the two types of beta diversity: βrepl was influenced by climate, disturbance and soil organic matter content whilst βrich was controlled by altitude and slope. Furthermore, spatial variables, represented through Moran’s eigenvector maps, played a significant role in explaining both βrepl and βrich, suggesting that both dispersal ability and Madeira Island complex orography are crucial for the understanding of beta diversity patterns in this group of beetles.Peer reviewe

Opsoclonus-myoclonus-ataxia syndrome associated with chikungunya and dengue virus co-infection

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-09-19T16:55:58Z No. of bitstreams: 1 Rosario MS Opsoclonus-Myoclonus-Ataxia Syndrome....pdf: 514736 bytes, checksum: 2d645cdbe4121ce8c8d637e1a2c7ed2d (MD5) Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-09-19T17:27:26Z (GMT) No. of bitstreams: 1 Rosario MS Opsoclonus-Myoclonus-Ataxia Syndrome....pdf: 514736 bytes, checksum: 2d645cdbe4121ce8c8d637e1a2c7ed2d (MD5) Made available in DSpace on 2018-09-19T17:27:26Z (GMT). No. of bitstreams: 1 Rosario MS Opsoclonus-Myoclonus-Ataxia Syndrome....pdf: 514736 bytes, checksum: 2d645cdbe4121ce8c8d637e1a2c7ed2d (MD5) Previous issue date: 2018 CNPq-National Council for Scientific and Technological Development (302584/2015-3) and MCTI-Ministry of Science, Technology, Innovation/FINEP–Funding Authority for Studies and Projects/FNDCT–National Fund for the Development of Science and Technology (04160060-00/2016) Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Secretaria Estadual da Saúde da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / University of Rome Tor Vergata. Rome, Italy Secretaria Estadual da Saúde da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil Secretaria Estadual da Saúde da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil University of Oxford. Department of Zoology. Oxford, UK Instituto Evandro Chagas. Centro de Tecnologia e Inovação. Ananindeua, PA, Brasil Instituto Evandro Chagas. Centro de Tecnologia e Inovação. Ananindeua, PA, Brasil Instituto Evandro Chagas. Centro de Tecnologia e Inovação. Ananindeua, PA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder characterized by irregular multidirectional eye movements, myoclonus, cerebellar ataxia, sleep disturbances, and cognitive dysfunction. Although most commonly related to paraneoplastic syndrome, this condition has occasionally been described following infectious illnesses. This article reports the first case of OMAS in association with chikungunya and dengue virus co-infection. The genetic analysis identified chikungunya virus of East/Central/South African genotype and dengue serotype 4 virus of genotype II. This report represents an unusual clinical syndrome associated with viral co-infection and reinforces the need for clinical vigilance with regard to neurological syndromes in the context of emergent arboviruses

Quasi-elastic processes of the 48Ca + 120Sn system and the 48Ca nuclear matter density

We present the results of a high-precision quasi-elastic excitation function measurement for the 48Ca + 120Sn system at θLAB = 160 at near-barrier energies in steps of 1.0 MeV. The corresponding quasi-elastic barrier distribution is derived. A large-scale coupled-channel calculation was performed to investigate the role of several reaction channels in the reaction mechanism. An excellent agreement between theory and data was obtained for the barrier distribution. The first quadrupole vibrations of the 48Ca and 120Sn, the 2n, and the 4He transfers have a strong influence on the reaction mechanism and are responsible for the good agreement achieved. The 1n transfer has a minor importance in the result when compared with the 2n transfer, which suggests that the pairing correlation might play an important role in the 2n-neutron transfer process. However, if the octupole vibration of the projectile is included in the coupling scheme, the agreement with the data gets worse. The comparison of the coupled-channel calculations with experimental data leads to the conclusion that the nuclear matter diffuseness of the 48Ca nucleus is 0.56 fm in agreement with most of the double-magic nuclei.European Community 26201

3’Nucleotidase/nuclease is required for Leishmania infantum clinical isolate susceptibility to miltefosine

Summary Background Miltefosine treatment failure in visceral leishmaniasis in Brazil has been associated with deletion of the miltefosine susceptibility locus (MSL) in Leishmania infantum. The MSL comprises four genes, 3′ -nucleotidase/nucleases (NUC1 and NUC2); helicase-like protein (HLP); and 3,2-trans-enoyl-CoA isomerase (TEI). Methods In this study CRISPR-Cas9 was used to either epitope tag or delete NUC1, NUC2, HLP and TEI, to investigate their role in miltefosine resistance mechanisms. Additionally, miltefosine transporter genes and miltefosine-mediated reactive oxygen species homeostasis were assessed in 26 L. infantum clinical isolates. A comparative lipidomic analysis was also performed to investigate the molecular basis of miltefosine resistance. Findings Deletion of both NUC1, NUC2 from the MSL was associated with a significant decrease in miltefosine susceptibility, which was restored after re-expression. Metabolomic analysis of parasites lacking the MSL or NUC1 and NUC2 identified an increase in the parasite lipid content, including ergosterol; these lipids may contribute to miltefosine resistance by binding the drug in the membrane. Parasites lacking the MSL are more resistant to lipid metabolism perturbation caused by miltefosine and NUC1 and NUC2 are involved in this pathway. Additionally, L. infantum parasites lacking the MSL isolated from patients who relapsed after miltefosine treatment were found to modulate nitric oxide accumulation in host macrophages. Interpretation Altogether, these data indicate that multifactorial mechanisms are involved in natural resistance to miltefosine in L. infantum and that the absence of the 3’nucleotidase/nuclease genes NUC1 and NUC2 contributes to the phenotype.publishersversionpublishe

HIV-1-Transmitted Drug Resistance and Transmission Clusters in Newly Diagnosed Patients in Portugal Between 2014 and 2019

Objective: To describe and analyze transmitted drug resistance (TDR) between 2014 and 2019 in newly infected patients with HIV-1 in Portugal and to characterize its transmission networks. Methods: Clinical, socioepidemiological, and risk behavior data were collected from 820 newly diagnosed patients in Portugal between September 2014 and December 2019. The sequences obtained from drug resistance testing were used for subtyping, TDR determination, and transmission cluster (TC) analyses. Results: In Portugal, the overall prevalence of TDR between 2014 and 2019 was 11.0%. TDR presented a decreasing trend from 16.7% in 2014 to 9.2% in 2016 (p for-trend = 0.114). Multivariate analysis indicated that TDR was significantly associated with transmission route (MSM presented a lower probability of presenting TDR when compared to heterosexual contact) and with subtype (subtype C presented significantly more TDR when compared to subtype B). TC analysis corroborated that the heterosexual risk group presented a higher proportion of TDR in TCs when compared to MSMs. Among subtype A1, TDR reached 16.6% in heterosexuals, followed by 14.2% in patients infected with subtype B and 9.4% in patients infected with subtype G. Conclusion: Our molecular epidemiology approach indicates that the HIV-1 epidemic in Portugal is changing among risk group populations, with heterosexuals showing increasing levels of HIV-1 transmission and TDR. Prevention measures for this subpopulation should be reinforced.info:eu-repo/semantics/publishedVersio

Depression in medical students: insights from a longitudinal study

Background: Factors associated with depression of medical students are poorly understood. The purpose of this study is to determine the prevalence of depression in medical students, its change during the course, if depression persists for affected students, what are the factors associated with depression and how these factors change over time. Methods: A prospective, longitudinal observational study was conducted at the Medical School of the University of Minho, Portugal, between academic years 2009-2010 to 2012-2013. We included students who maintained their participation by annually completing a questionnaire including Beck Depression Inventory (BDI). Anxiety and burnout were assessed using the State Trait Anxiety Inventory and Maslach Burnout Inventory. Surveys on socio-demographic variables were applied to evaluate potential predictors, personal and academic characteristics and perceived difficulties. ANOVA with multiple comparisons were used to compare means of BDI score. The medical students were organized into subgroups by K-means cluster analyses. ANOVA mixed-design repeated measurement was performed to assess a possible interaction between variables associated with depression. Results: The response rate was 84, 92, 88 and 81% for academic years 2009-2010, 2010-2011,2011-2012 and 2012/2013, respectively. Two hundred thirty-eight medical students were evaluated longitudinally. For depression the prevalence ranged from 21.5 to 12.7% (academic years 2009/2010 and 2012/2013). BDI scores decreased during medical school. 19.7% of students recorded sustained high BDI over time. These students had high levels of trait-anxiety and choose medicine for anticipated income and prestige, reported more relationship issues, cynicism, and decreased satisfaction with social activities. Students with high BDI scores at initial evaluation with low levels of trait-anxiety and a primary interest in medicine as a career tended to improve their mood and reported reduced burnout, low perceived learning problems and increased satisfaction with social activities at last evaluation. No difference was detected between men and women in the median BDI score over time. Conclusions: Our findings suggest that personal factors (anxiety traits, medicine choice factors, relationship patterns and academic burnout) are relevant for persistence of high levels of BDI during medical training. Medical schools need to identity students who experience depression and support then, as early as possible, particularly when depression has been present over time.info:eu-repo/semantics/publishedVersio

Erratum to: The study of cardiovascular risk in adolescents – ERICA: rationale, design and sample characteristics of a national survey examining cardiovascular risk factor profile in Brazilian adolescents

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