Trapping of a phenoxyl radical at a non-haem high-spin iron(II) centre.

The activation of dioxygen at haem and non-haem metal centres, and subsequent functionalization of unactivated C‒H bonds, has been a focal point of much research. In iron-mediated oxidation reactions, O2 binding at an iron(II) centre is often accompanied by an oxidation of the iron centre. Here we demonstrate dioxygen activation by sodium tetraphenylborate and protons in the presence of an iron(II) complex to form a reactive radical species, whereby the iron oxidation state remains unaltered in the presence of a highly oxidizing phenoxyl radical and O2. This complex, containing an unusual iron(II)-phenoxyl radical motif, represents an elusive example of a spectroscopically characterized oxygen-derived iron(II)-reactive intermediate during chemical and biological dioxygen activation at haem and non-haem iron active centres. The present report opens up strategies for the stabilization of a phenoxyl radical cofactor, with its full oxidizing capabilities, to act as an independent redox centre next to an iron(II) site during substrate oxidation reactions.

Violence and Clinical Learning Environments in Medical Residencies.

INTRODUCTION: The objective of this study was to describe and analyze residents' perceptions of characteristics on the expansive/restrictive continuum of their clinical learning environment. METHODS: We conducted a quantitative, descriptive and cross-sectional study. A self-administered questionnaire was designed, programmed and applied to residents at the Faculty of Medicine of the National Autonomous University of Mexico. The instrument was structured in eight sections, and for this article, Section 3, which referred to clinical environments and violence was considered. The questionnaire had an 85% response rate, with 12,612 residents from 113 medical units and 78 specialties participating. The reliability and internal consistency measured with alpha omega obtained a value of ω 0.835 (CI; 0.828-0.843). RESULTS: Unpleasant, competitive, tense and conflictive contexts were related to restrictive environments. Sexual orientation influenced the perception of intolerance in the clinical setting with respect to discriminatory comments, such that for gender minorities, the environment was experienced as exclusionary. First-year residents perceived environments as more aggressive, a perception that tended to decrease in later years of residency. DISCUSSION: Abuses in power relations, rigid hierarchical positions and offensive clinical interactions may foster restrictive environments. In such settings, the reproduction of socio-culturally learned violence is feasible; however, asymmetrical relationships may be deconstructed and transformed.

Quality of life and mental health in multiple sclerosis patients during the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic had a profound impact on mental health symptoms and quality of life (QoL) in the general population due to necessary public health restrictions such as social distancing. The psychosocial effect of the pandemic on vulnerable groups such as people living with Multiple Sclerosis (PwMS) has been scarcely explored in countries with additional socioeconomical burdens such as access to healthcare disparities METHODS: A questionnaire exploring sociodemographic variables, quality of life, mental health determinants and sleep quality was applied to 92 PwMS to explore changes prior and during the pandemic regarding these domains RESULTS: 58.8% of the subjects were female, median age was 37.1 (± 8.5) years and relapsing-remitting MS was the predominant clinical subtype (83.5%). Unemployment rate significantly increased during the pandemic (12.3% vs 27.8%; p= 0.001). Only 46.4% received medical follow-up care during the pandemic. QoL was affected predominantly due to limitations in instrumented activities of daily life (IADL). Neuropsychiatric symptoms, requiring healthcare during the pandemic, anxiety prior to the pandemic and restricted IADL were predictors of MS-related physical impact worsening, while decreased physical/emotional wellbeing selfcare, neuropsychiatric symptoms, bad sleep quality, anxiety prior to the pandemic and restricted non-instrumental ADL predicted aggravation of MS-related psychological impact measured by the MSIS-29. Curiously, specific items regarding anxiety were more prevalent prior to the pandemic (anxious mood; p=0.02, helplessness; p=0.01), sleep problems; p=0.001 and cardiovascular symptoms; p=0.001, nevertheless, stability was observed for most items. Importantly, 77.3% of PwMS reported at least one neuropsychiatric symptom CONCLUSION: The deleterious effects of the COVID-19 pandemic on psychosocial wellbeing in PwMS, QoL and mental health outcomes are frequently overseen in vulnerable populations such as PwMS. Albeit the limitations of this study, our results may help implement policies that prevent negative outcomes on psychosocial wellbeing due to public health measures (e.g., social distancing) in MS and other neurological diseases that inexorably need constant follow-up.

Spectroscopic Properties of a Biologically Relevant [Fe2 (µ-O)2 ] Diamond Core Motif with a Short Iron-Iron Distance.

Diiron cofactors in enzymes perform diverse challenging transformations. The structures of high valent intermediates (Q in methane monooxygenase and X in ribonucleotide reductase) are debated since Fe-Fe distances of 2.5-3.4 Šwere attributed to "open" or "closed" cores with bridging or terminal oxido groups. We report the crystallographic and spectroscopic characterization of a FeIII 2 (µ-O)2 complex (2) with tetrahedral (4C) centres and short Fe-Fe distance (2.52 Å), persisting in organic solutions. 2 shows a large Fe K-pre-edge intensity, which is caused by the pronounced asymmetry at the TD FeIII centres due to the short Fe-µ-O bonds. A ≈2.5 ŠFe-Fe distance is unlikely for six-coordinate sites in Q or X, but for a Fe2 (µ-O)2 core containing four-coordinate (or by possible extension five-coordinate) iron centres there may be enough flexibility to accommodate a particularly short Fe-Fe separation with intense pre-edge transition. This finding may broaden the scope of models considered for the structure of high-valent diiron intermediates formed upon O2 activation in biology.

Deep DNA sequencing of MGMT, TP53 and AGT in Mexican astrocytoma patients identifies an excess of genetic variants in women and a predictive biomarker.

PURPOSE: Astrocytomas are a type of malignant brain tumor with an unfavorable clinical course. The impact of AGT and MGMT somatic variants in the prognosis of astrocytoma is unknown, and it is controversial for TP53. Moreover, there is a lack of knowledge regarding the molecular characteristics of astrocytomas in Mexican patients. METHODS: We studied 48 Mexican patients, men and women, with astrocytoma (discovery cohort). We performed DNA deep sequencing in tumor samples, targeting AGT, MGMT and TP53, and we studied MGMT gene promoter methylation status. Then we compared our findings to a cohort which included data from patients with astrocytoma from The Cancer Genome Atlas (validation cohort). RESULTS: In the discovery cohort, we found a higher number of somatic variants in AGT and MGMT than in the validation cohort (10.4% vs < 1%, p < 0.001), and, in both cohorts, we observed only women carried variants AGT variants. We also found that the presence of either MGMT variant or promoter methylation was associated to better survival and response to chemotherapy, and, in conjunction with TP53 variants, to progression-free survival. CONCLUSIONS: The occurrence of AGT variants only in women expands our knowledge about the molecular differences in astrocytoma between men and women. The increased prevalence of AGT and MGMT variants in the discovery cohort also points towards possible distinctions in the molecular landscape of astrocytoma among populations. Our findings warrant further study.

Involuntary Emotional Expression Disorder in a Patient With Toluene Leukoencephalopathy.

OBJECTIVE: Inhalant users may develop toluene leukoencephalopathy, a devastating neuropsychiatric disorder. We present a case of toluene-induced damage to the corticospinal and the corticonuclear tracts, which presented with involuntary emotional expression disorder. METHODS: Case study of a 20-year-old man with a 3-year history of frequent solvent abuse was admitted to the Neuropsychiatry Unit of the National Institute of Neurology and Neurosurgery because "he could not speak or walk" but would keep "laughing and crying without reason". RESULTS: Neuropsychiatric examination revealed pathological laughter and crying, facial and speech apraxia, a bilateral pyramidal syndrome, and lack of control of urinary sphincter. Magnetic resonance imaging revealed a highly selective bilateral damage to the pyramidal system and the somatosensory pathway. SPECT imaging showed left fronto-parietal hypoperfusion. CONCLUSIONS: This document provides support for the understanding of involuntary emotional expression disorders as a differential diagnosis in the clinical practice of psychiatrists, as well as the functional anatomy of these conditions.

Involuntary Emotional Expression Disorder in a Patient With Toluene Leukoencephalopathy / Trastorno de expresión emocional involuntaria en un paciente con leucoencefalopatía por tolueno

ABSTRACT Objective: Inhalant users may develop toluene leukoencephalopathy, a devastating neuropsychiatric disorder. We present a case of toluene-induced damage to the corticospinal and the corticonuclear tracts, which presented with involuntary emotional expression dis-order. Methods: Case study of a 20-year-old man with a 3-year history of frequent solvent abuse was admitted to the Neuropsychiatry Unit of the National Institute of Neurology and Neurosurgery because "he could not speak or walk" but would keep "laughing and crying without reason". Results: Neuropsychiatric examination revealed pathological laughter and crying, facial and speech apraxia, a bilateral pyramidal syndrome, and lack of control of urinary sphincter. Magnetic resonance imaging revealed a highly selective bilateral damage to the pyramidal system and the somatosensory pathway. SPECT imaging showed left fronto-parietal hypoperfusion. Conclusions: This document provides support for the understanding of involuntary emotional expression disorders as a differential diagnosis in the clinical practice of psychiatrists, as well as the functional anatomy of these conditions.

RESUMEN Objetivo: Los usuarios de inhalantes pueden contraer leucoencefalopatía por tolueno, un trastorno neuropsiquiátrico devastador. Se presenta un caso de daño inducido por tolueno en el tracto corticoespinal y corticonuclear, que se manifestó con un trastorno involuntario de la expresión emocional. Métodos: Un varón de 20 años con antecedente de 3 años de abuso de solventes ingresó en la Unidad de Neuropsiquiatría del Instituto Nacional de Neurología y Neurocirugía porque «no podía hablar ni caminar¼ y presentaba episodios súbitos de risa y llanto sin razón aparente. Resultados: La valoración neuropsiquiátrica reveló risa y llanto patológicos, apraxia facial y fonatoria, síndrome piramidal bilateral y ausencia de control del esfínter urinario. La resonancia magnética cerebral mostró un daño bilateral muy selectivo del sistema piramidal y la vía somatosensorial. La imagen de tomografía computarizada por emisión monofotónica mostró hipoperfusión frontoparietal izquierda. Conclusiones: Este documento proporciona apoyo para la comprensión de los trastornos de la expresión emocional involuntaria como diagnóstico diferencial en la práctica clínica de los psiquiatras, así como de la anatomía funcional de estas condiciones.

Onychomycosis Caused by Kloeckera apiculata: A Case Report in a Patient with Multiple Sclerosis.

We report the first case of onychomycosis caused by Kloeckera apiculata in a woman with multiple sclerosis. Video-dermoscopic examination showed a spiked pattern and distal irregular aspect. Colonies on Sabouraud agar were white, creamy, and smooth. A microscopic examination showed blastoconidia. MALDI-TOF confirmed Kloeckera apiculata as the causal agent.

Analysis of Se and Hg biomolecules distribution and Se speciation in poorly studied protein fractions of muscle tissues of highly consumed fishes by SEC-UV-ICP-MS and HPLC-ESI-MS/MS.

Distribution of Se and Hg in sarcoplasmic, myofibrillar and alkali-soluble protein fractions extracted from muscle tissue of tuna, swordfish and salmon (wild vs. farmed) is investigated for the first time. SEC-UV-ICP-MS analyses revealed that Se and Hg are mostly bound to proteins of 2-12 kDa and up to 574 kDa, respectively. Moreover, Se and Hg appeared associated to proteins of same molecular weight, evidencing that Se-Hg interaction may occur at the level of the fish tissue evaluated. Important differences were found between farmed and wild salmon, suggesting the effect of the type of feed and growing conditions on Se and Hg content and their distribution through protein fractions. Finally, Se speciation studies performed by HPLC-ICP-MS and confirmed by HPLC-ESI-MS/MS showed SeMeSeCys as the only Se specie found in soluble, sarcoplasmic, myofibrillar and alkali-soluble proteins of all fishes analysed, except in soluble proteins extracted from tuna, where SeMet was also identified.

Interaction of HLA Class II rs9272219 and TMPO rs17028450 (Arg690Cys) Variants Affects Neuromyelitis Optica Spectrum Disorder Susceptibility in an Admixed Mexican Population.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a demyelinating autoimmune disease of the central nervous system, more prevalent in individuals of non-European ancestry. Few studies have analyzed genetic risk factors in NMOSD, and HLA class II gene variation has been associated NMOSD risk in various populations including Mexicans. Thymopoietin (TMPO) has not been tested as a candidate gene for NMOSD or other autoimmune disease, however, experimental evidence suggests this gene may be involved in negative selection of autoreactive T cells and autoimmunity. We thus investigated whether the missense TMPO variant rs17028450 (Arg630Cys, frequent in Latin America) is associated with NMOSD, and whether this variant shows an interaction with HLA-class II rs9272219, previously associated with NMOSD risk. A total of 119 Mexican NMOSD patients, 1208 controls and 357 Native Mexican individuals were included. The HLA rs9272219 "T" risk allele frequency ranged from 21 to 68%, while the rs17028450 "T" minor allele frequency was as high as 18% in Native Mexican groups. Both rs9272219 and rs17028450 were significantly associated with NMOSD risk under additive models (OR = 2.48; p = 8 × 10-10 and OR = 1.59; p = 0.0075, respectively), and a significant interaction between both variants was identified with logistic regression models (p = 0.048). Individuals bearing both risk alleles had an estimated 3.9-fold increased risk of NMOSD. To our knowledge, this is the first study reporting an association of TMPO gene variation with an autoimmune disorder and the interaction of specific susceptibility gene variants, that may contribute to the genetic architecture of NMOSD in admixed Latin American populations.

Onychomycosis in patients with multiple sclerosis: prevalence, clinical description, mycological, and dermoscopic study in a Mexican population.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease related to HLA-DR8. Susceptibility to onychomycosis has been found in Mexican mestizos with HLA-DR8. The frequency of onychomycosis in this neurological disease is unknown. OBJECTIVES: To determine the frequency of onychomycosis and its clinical, mycological, and dermoscopic characteristics in patients with MS in comparison with the general population. METHODS: Observational, cross-sectional, case-control study in patients with MS from October 2017 to February 2018. Age, gender, MS type, and time of progression from diagnosis to date and baseline treatment were collected after signed informed consent. A neurological exploration and clinical examination of fingernails and toenails for onychomycosis was conducted. Mycological and dermoscopic studies of the infected nails were performed on patients with clinical diagnosis of onychomycosis. A healthy control group was taken for each case (1:1), paired by age and gender. RESULTS: The frequency of onychomycosis in patients with MS was higher than the healthy population (32% vs. 26%, P = 0.509). A higher frequency of non-dermatophyte fungi was found, although it was not statistically significant. The clinical manifestations and dermoscopic findings in patients with MS and onychomycosis were similar to those of the general population. CONCLUSION: The frequency of onychomycosis in patients with MS is slightly higher than that of the general population. A possible association of HLA-DR8 as a susceptibility factor for onychomycosis is proposed. The etiology of opportunistic fungi in MS patients with onychomycosis may be related to immunosuppressive treatment.

Landscape of Germline Genetic Variants in AGT, MGMT, and TP53 in Mexican Adult Patients with Astrocytoma.

Astrocytoma is the most common type of primary brain tumor. The risk factors for astrocytoma are poorly understood; however, germline genetic variants account for 25% of the risk of developing gliomas. In this study, we assessed the risk of astrocytoma associated with variants in AGT, known by its role in angiogenesis, TP53, a well-known tumor suppressor and the DNA repair gene MGMT in a Mexican population. A case-control study was performed in 49 adult Mexican patients with grade II-IV astrocytoma. Sequencing of exons and untranslated regions of AGT, MGMT, and TP53 from was carried in an Ion Torrent platform. Individuals with Mexican Ancestry from the 1000 Genomes Project were used as controls. Variants found in our cohort were then assessed in a The Cancer Genome Atlas astrocytoma pan-ethnic validation cohort. Variants rs1926723 located in AGT (OR 2.74, 1.40-5.36 95% CI), rs7896488 in MGMT (OR 3.43, 1.17-10.10 95% CI), and rs4968187 in TP53 (OR 2.48, 1.26-4.88 95% CI) were significantly associated with the risk of astrocytoma after multiple-testing correction. This is the first study where the AGT rs1926723 variant, TP53 rs4968187, and MGMT rs7896488 were found to be associated with the risk of developing an astrocytoma.

Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma.

BACKGROUND: Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. METHODS: We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. RESULTS: GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model. CONCLUSIONS: SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.

Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population.

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10-6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10-10). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.

Sex effects across the lifespan in women with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation.

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.

Stoichiometric Formation of an Oxoiron(IV) Complex by a Soluble Methane Monooxygenase Type Activation of O2 at an Iron(II)-Cyclam Center.

In soluble methane monooxygenase enzymes (sMMO), dioxygen (O2) is activated at a diiron(II) center to form an oxodiiron(IV) intermediate Q that performs the challenging oxidation of methane to methanol. An analogous mechanism of O2 activation at mono- or dinuclear iron centers is rare in the synthetic chemistry. Herein, we report a mononuclear non-heme iron(II)-cyclam complex, 1-trans, that activates O2 to form the corresponding iron(IV)-oxo complex, 2-trans, via a mechanism reminiscent of the O2 activation process in sMMO. The conversion of 1-trans to 2-trans proceeds via the intermediate formation of an iron(III)-superoxide species 3, which could be trapped and spectroscopically characterized at -50 °C. Surprisingly, 3 is a stronger oxygen atom transfer (OAT) agent than 2-trans; 3 performs OAT to 1-trans or PPh3 to yield 2-trans quantitatively. Furthermore, 2-trans oxidizes the aromatic C-H bonds of 2,6-di-tert-butylphenol, which, together with the strong OAT ability of 3, represents new domains of oxoiron(IV) and superoxoiron(III) reactivities.