Asymmetric synthesis of N-aryl aziridines

The reactions of a variety of N-arylhydroxamates as nitrogen transfer reagents to acryloyl derivatives of (−)-8-phenylmenthol, (−)-quinine and (−)-Oppolzer’s sultam acting as Michael acceptors was studied. Poor to modest diastereoselection was observed in the formation of aziridines. The absolute structure of one of the pure diastereomers secured from Oppolzer’s auxiliary was established by X-ray crystallography and hence the absolute configuration of the derived methyl-N-phenylaziridine-2-carboxylate could be assigned. Whilst only poor facial selectivity was observed for chiral hydroxamic acid prepared from dehydroabietic acid, moderate to good enantioselection of aziridines could be achieved with the chiral quaternary salts based on cinchona alkaloids, especially with that of cinchonine. A model is presented to explain the origin of enantioselection and a mechanism is proposed for the aziridination reaction

A new approach for the surgical management of unilateral iliac artery occlusive disease: The iliofemoral crossover transposition

AbstractAortobifemoral bypass remains the standard therapy for aortoiliac occlusive disease. Extraanatomic revascularization has been considered as an acceptable alternative and provides reasonable long-term results. Because some of the causes for its failure are related to the prosthetic material used, a technique that uses autologous material and is applicable in patients with unilateral common iliac lesions was developed. Iliofemoral crossover transposition is a femorofemoral bypass procedure in which the external iliac artery is used as a graft. The procedure is easily performed and avoids the use of prosthetic materials, minimizing the risks of their related complications. Because its biologic behavior, including hemodynamic performance, has proven to be excellent, satisfactory long-term results can be anticipated. (J Vasc Surg 2002;36:404-7.

miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease

Copyright © 2021 Oliveira, Dionísio, Gaspar, Correia Guedes, Coelho, Rosa, Ferreira, Amaral and Rodrigues. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Parkinson's disease (PD) is mainly driven by dopaminergic neuronal degeneration in the substantia nigra pars compacta accompanied by chronic neuroinflammation. Despite being mainly sporadic, approximately 10% of all cases are defined as heritable forms of PD, with mutations in the leucine-rich repeat kinase (LRRK2) gene being the most frequent known cause of familial PD. MicroRNAs (miRNAs or miRs), including miR-335, are frequently deregulated in neurodegenerative diseases, such as PD. Here, we aimed to dissect the protective role of miR-335 during inflammation and/or neurodegenerative events in experimental models of PD. Our results showed that miR-335 is significantly downregulated in different PD-mimicking conditions, including BV2 microglia cells stimulated with lipopolysaccharide (LPS) and/or overexpressing wild-type LRRK2. Importantly, these results were confirmed in serum of mice injected with 1-methyl-1-4-phenyl-1,2,3,6-tetrahydripyridine hydrochloride (MPTP), and further validated in patients with idiopathic PD (iPD) and those harboring mutations in LRRK2 (LRRK2-PD), thus corroborating potential clinical relevance. Mechanistically, miR-335 directly targeted LRRK2 mRNA. In the BV2 and N9 microglia cell lines, miR-335 strongly counteracted LPS-induced proinflammatory gene expression, and downregulated receptor interacting protein 1 (RIP1) and RIP3, two important players of necroptotic and inflammatory signaling pathways. Further, miR-335 inhibited LPS-mediated ERK1/2 activation. LRRK2-Wt-induced proinflammatory gene expression was also significantly reduced by miR-335 overexpression. Finally, in SH-SY5Y neuroblastoma cells, miR-335 decreased the expression of pro-inflammatory genes triggered by α-synuclein. In conclusion, we revealed novel roles for miR-335 in both microglia and neuronal cells that strongly halt the effects of classical inflammatory stimuli or LRRK2-Wt overexpression, thus attenuating chronic neuroinflammation.This research was funded in part by UIDB/04138/2020 from Fundação para a Ciência e Tecnologia (FCT), Portugal. SO received a Ph.D. fellowship (PD/BD/128332/2017) from FCT.info:eu-repo/semantics/publishedVersio

Impact of implementing a vancomycin protocol to reduce kidney toxicity: A comparative study

Introduction: Vancomycin is a frequently used antibiotic for treating severe infections caused by multidrug-resistant, Gram-positive pathogens. To ensure its effectiveness and minimize the risk of nephrotoxicity, safe administration and dose monitoring are crucial. Understanding the impact of vancomycin serum levels on clinical outcomes is of paramount importance, necessitating improved knowledge on its use, dose monitoring, nephrotoxicity, and safe administration.Objective: This study aimed to evaluate the incidence of acute kidney injury (AKI) in patients receiving vancomycin before and after the implementation of an institutional protocol for vancomycin administration in a public tertiary hospital in southern Brazil.Materials and methods: A cross-sectional study design was employed, analyzing data from the electronic medical records of 422 patients who received vancomycin. The patient population was divided into two independent cohorts: those treated in 2016 (pre-protocol) and those treated in 2018 (post-protocol), following the implementation of the institutional vancomycin administration protocol.Results: The study included 211 patients in each year of assessment. Patients from both cohorts had a Charlson Comorbidity Index (CCI) score of 4. The post-protocol cohort consisted of older individuals, with a mean age of 62.8 years. In addition, patients in the post-protocol year had higher baseline creatinine levels, higher rates of intensive care unit (ICU) hospitalization, and increased use of vasopressors. In the pre-protocol year, patients received vancomycin therapy for a longer duration. When comparing the incidence of AKI between the two groups, an intervention study revealed rates of 38.4% in group 1 and 20.9% in group 2, indicating a significant reduction (p < 0.001) in the post-protocol group. A logistic regression model was developed to predict AKI, incorporating variables that demonstrated significance (p ≤ 0.250) in bivariate analysis and those recognized in the literature as important factors for AKI, such as the duration of therapy, vancomycin serum level, and ICU hospitalization. The logistic regression classification performance was assessed using a receiver operating characteristic (ROC) curve, yielding an area under the curve of 0.764, signifying acceptable discrimination of the regression model.Conclusion: Implementation of the institutional protocol for vancomycin administration resulted in a significant and cost-effective impact, ensuring appropriate therapeutic dosing, reducing adverse events (e.g., nephrotoxicity), and improving clinical outcomes for patients in the study population

Convergence of miRNA Expression Profiling, α-Synuclein Interacton and GWAS in Parkinson's Disease

miRNAs were recently implicated in the pathogenesis of numerous diseases, including neurological disorders such as Parkinson's disease (PD). miRNAs are abundant in the nervous system, essential for efficient brain function and play important roles in neuronal patterning and cell specification. To further investigate their involvement in the etiology of PD, we conducted miRNA expression profiling in peripheral blood mononuclear cells (PBMCs) of 19 patients and 13 controls using microarrays. We found 18 miRNAs differentially expressed, and pathway analysis of 662 predicted target genes of 11 of these miRNAs revealed an over-representation in pathways previously linked to PD as well as novel pathways. To narrow down the genes for further investigations, we undertook a parallel approach using chromatin immunoprecipitation-sequencing (ChIP-seq) analysis to uncover genome-wide interactions of α-synuclein, a molecule with a central role in both monogenic and idiopathic PD. Convergence of ChIP-seq and miRNomics data highlighted the glycosphingolipid biosynthesis and the ubiquitin proteasome system as key players in PD. We then tested the association of target genes belonging to these pathways with PD risk, and identified nine SNPs in USP37 consistently associated with PD susceptibility in three genome-wide association studies (GWAS) datasets (0.46≤OR≤0.63) and highly significant in the meta-dataset (3.36×10−4<p<1.94×10−3). A SNP in ST8SIA4 was also highly associated with PD (p = 6.15×10−3) in the meta-dataset. These findings suggest that several miRNAs may act as regulators of both known and novel biological processes leading to idiopathic PD

Water vapor retrievals from spectral direct irradiance measured with an EKO MS-711 spectroradiometer—intercomparison with other techniques

Precipitable water vapor retrievals are of major importance for assessing and understanding atmospheric radiative balance and solar radiation resources. On that basis, this study presents the first PWV values measured with a novel EKO MS-711 grating spectroradiometer from direct normal irradiance in the spectral range between 930 and 960 nm at the Izaña Observatory (IZO, Spain) between April and December 2019. The expanded uncertainty of PWV (U$_{PWV}$) was theoretically evaluated using the Monte-Carlo method, obtaining an averaged value of 0.37 ± 0.11 mm. The estimated uncertainty presents a clear dependence on PWV. For PWV ≤ 5 mm (62% of the data), the mean U$_{PWV}$ is 0.31 ± 0.07 mm, while for PWV > 5 mm (38% of the data) is 0.47 ± 0.08 mm. In addition, the EKO PWV retrievals were comprehensively compared against the PWV measurements from several reference techniques available at IZO, including meteorological radiosondes, Global Navigation Satellite System (GNSS), CIMEL-AERONET sun photometer and Fourier Transform Infrared spectrometry (FTIR). The EKO PWV values closely align with the above mentioned different techniques, providing a mean bias and standard deviation of −0.30 ± 0.89 mm, 0.02 ± 0.68 mm, −0.57 ± 0.68 mm, and 0.33 ± 0.59 mm, with respect to the RS92, GNSS, FTIR and CIMEL-AERONET, respectively. According to the theoretical analysis, MB decreases when comparing values for PWV > 5 mm, leading to a PWV MB between −0.45 mm (EKO vs. FTIR), and 0.11 mm (EKO vs. CIMEL-AERONET). These results confirm that the EKO MS-711 spectroradiometer is precise enough to provide reliable PWV data on a routine basis and, as a result, can complement existing ground-based PWV observations. The implementation of PWV measurements in a spectroradiometer increases the capabilities of these types of instruments to simultaneously obtain key parameters used in certain applications such as monitoring solar power plants performance

High Piezoelectric Output Voltage from Blue Fluorescent N,N-Dimethyl-4-nitroaniline Nano Crystals in Poly-L-Lactic Acid Electrospun Fibers

N,N-dimethyl-4-nitroaniline is a piezoelectric organic superplastic and superelastic charge transfer molecular crystal that crystallizes in an acentric structure. Organic mechanical flexible crystals are of great importance as they stand between soft matter and inorganic crystals. Highly aligned poly-l-lactic acid polymer microfibers with embedded N,N-dimethyl-4-nitroaniline nanocrystals are fabricated using the electrospinning technique, and their piezoelectric and optical properties are explored as hybrid systems. The composite fibers display an extraordinarily high piezoelectric output response, where for a small stress of 5.0 × 103 Nm−2, an effective piezoelectric voltage coefficient of geff = 4.1 VmN−1 is obtained, which is one of the highest among piezoelectric polymers and organic lead perovskites. Mechanically, they exhibit an average increase of 67% in the Young modulus compared to polymer microfibers alone, reaching 55 MPa, while the tensile strength reaches 2.8 MPa. Furthermore, the fibers show solid-state blue fluorescence, important for emission applications, with a long lifetime decay (147 ns) lifetime decay. The present results show that nanocrystals from small organic molecules with luminescent, elastic and piezoelectric properties form a mechanically strong hybrid functional 2-dimensional array, promising for applications in energy harvesting through the piezoelectric effect and as solid-state blue emitters.This research was funded by Fundação para a Ciência e Tecnologia through FEDER (European Fund for Regional Development)-COMPETE-QREN-EU (ref. UID/FIS/04650/2013 and UID/FIS/04650/2019) and E-Field - "Electric-Field Engineered Lattice Distortions (E-FiELD) for optoelectronic devices", ref. PTDC/NAN-MAT/0098/2020

Gene expression differences in peripheral blood of Parkinson's disease patients with distinct progression profiles

The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention

Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients

<p>Abstract</p> <p>Background</p> <p>The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk.</p> <p>Methods</p> <p>We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk.</p> <p>Results</p> <p>Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45–0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41–7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13–7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect.</p> <p>Conclusion</p> <p>Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.</p