Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.

Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson's disease (PD). Stabilization of PINK1 at the translocase of outer membrane (TOM) complex of damaged mitochondria is critical for its activation. The mechanism of how PINK1 is activated in the TOM complex is unclear. Here, we report that co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit toward PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These findings will aid in the development of small-molecule activators of PINK1 as a therapeutic strategy for PD.

Etiological characterization of acute undifferentiated febrile illness in Apartadó and Villeta municipalities, Colombia, during COVID-19 pandemic.

Background: Acute undifferentiated febrile illness (AUFI) is one of the leading causes of illness in tropical regions. Although malaria is the most important cause, other pathogens such as Dengue (DENV), Leptospira and recently, Coronavirus Disease 2019 (COVID-19) have gained importance. In Colombia, few studies aimed to identify the etiology of AUFI. Most of them performed in Apartadó and Villeta municipalities, identifying the active circulation of several pathogens. Thus, we conducted a cross-sectional study in these municipalities to characterize the etiologies of AUFI during COVID-19 pandemic. Methods: An active surveillance was conducted between September and December 2021 in local hospitals of Apartadó and Villeta municipalities. Febrile patients were enrolled after voluntarily agreeing to participate in the study. Ten different etiologies were evaluated through direct, serological, molecular and rapid diagnostic methods. Results: In Apartadó a confirmed etiology was found in 60% of subjects, DENV (25%) being the most frequent, followed by leptospirosis (16.7%), malaria (10%), COVID-19 (8.3%), spotted fever group (SFG) rickettsiosis (6.7%) and Chikungunya (1.7%). In Villeta, a specific etiology was confirmed in 55.4% of patients, of which SFG rickettsiosis (39.3%) was the most frequent, followed by leptospirosis (21.4%), DENV (3.6%) and malaria (1.8%). No cases due to Mayaro, Yellow Fever, Oropouche and Venezuelan Equine Encephalitis viruses were detected. Conclusion: We confirm the relevance of dengue fever, leptospirosis, SFG rickettsiosis, COVID-19 and malaria as causes of AUFI in the municipality of Apartadó, and highlight the great importance of SFG rickettsiosis as the main cause of AUFI in the municipality of Villeta.

Etiologies of Zoonotic Tropical Febrile Illnesses That Are Not Part of the Notifiable Diseases in Colombia.

In Colombia, tropical febrile illnesses represent one of the most important causes of clinical attention. Febrile illnesses in the tropics are mainly zoonotic and have a broad etiology. The Colombian surveillance system monitors some notifiable diseases. However, several etiologies are not monitored by this system. In the present review, we describe eleven different etiologies of zoonotic tropical febrile illnesses that are not monitored by the Colombian surveillance system but have scientific, historical, and contemporary data that confirm or suggest their presence in different regions of the country: Anaplasma, Arenavirus, Bartonella, relapsing fever group Borrelia, Coxiella burnetii, Ehrlichia, Hantavirus, Mayaro virus, Orientia, Oropouche virus, and Rickettsia. These could generate a risk for the local population, travelers, and immigrants, due to which they should be included in the mandatory notification system, considering their importance for Colombian public health.

Restoring polyamine levels by supplementation of spermidine modulates hepatic immune landscape in murine model of NASH.

AIMS: To determine if changes in polyamines metabolism occur during non-alcoholic steatohepatitis (NASH) in human patients and mice, as well as to assess systemic and liver-specific effects of spermidine administration into mice suffering from advanced NASH. MATERIALS AND METHODS: Human fecal samples were collected from 50 healthy and 50 NASH patients. For the preclinical studies C57Bl6/N male mice fed GAN or NIH-31 diet for 6 months were ordered from Taconic and liver biopsy was performed. Based on severity of liver fibrosis, body composition and body weight, the mice from both dietary groups were randomized into another two groups: half receiving 3 mM spermidine in drinking water, half normal water for subsequent 12 weeks. Body weight was measured weekly and glucose tolerance and body composition were assessed at the end. Blood and organs were collected during necropsy, and intrahepatic immune cells were isolated for flow cytometry analysis. RESULTS: Metabolomic analysis of human and murine feces confirmed that levels of polyamines decreased along NASH progression. Administration of exogenous spermidine to the mice from both dietary groups did not affect body weight, body composition or adiposity. Moreover, incidence of macroscopic hepatic lesions was higher in NASH mice receiving spermidine. On the other hand, spermidine normalized numbers of Kupffer cells in the livers of mice suffering from NASH, although these beneficial effects did not translate into improved liver steatosis or fibrosis severity. CONCLUSION: Levels of polyamines decrease during NASH in mice and human patients but spermidine administration does not improve advanced NASH.

Tautomerism unveils a self-inhibition mechanism of crystallization.

Modifiers are commonly used in natural, biological, and synthetic crystallization to tailor the growth of diverse materials. Here, we identify tautomers as a new class of modifiers where the dynamic interconversion between solute and its corresponding tautomer(s) produces native crystal growth inhibitors. The macroscopic and microscopic effects imposed by inhibitor-crystal interactions reveal dual mechanisms of inhibition where tautomer occlusion within crystals that leads to natural bending, tunes elastic modulus, and selectively alters the rate of crystal dissolution. Our study focuses on ammonium urate crystallization and shows that the keto-enol form of urate, which exists as a minor tautomer, is a potent inhibitor that nearly suppresses crystal growth at select solution alkalinity and supersaturation. The generalizability of this phenomenon is demonstrated for two additional tautomers with relevance to biological systems and pharmaceuticals. These findings offer potential routes in crystal engineering to strategically control the mechanical or physicochemical properties of tautomeric materials.

Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase.

The p97/Cdc48 ATPase and its ubiquitin receptors Ufd1-Npl4 are essential to unfold ubiquitylated proteins in many areas of eukaryotic cell biology. In yeast, Cdc48-Ufd1-Npl4 is controlled by a quality control mechanism, whereby substrates must be conjugated to at least five ubiquitins. Here, we show that mammalian p97-UFD1-NPL4 is governed by a complex interplay between additional p97 cofactors and the number of conjugated ubiquitins. Using reconstituted assays for the disassembly of ubiquitylated CMG (Cdc45-MCM-GINS) helicase by human p97-UFD1-NPL4, we show that the unfoldase has a high ubiquitin threshold for substrate unfolding, which can be reduced by the UBX proteins UBXN7, FAF1, or FAF2. Our data indicate that the UBX proteins function by binding to p97-UFD1-NPL4 and stabilising productive interactions between UFD1-NPL4 and K48-linked chains of at least five ubiquitins. Stimulation by UBXN7 is dependent upon known ubiquitin-binding motifs, whereas FAF1 and FAF2 use a previously uncharacterised coiled-coil domain to reduce the ubiquitin threshold of p97-UFD1-NPL4. We show that deleting the Ubnx7 and Faf1 genes impairs CMG disassembly during S-phase and mitosis and sensitises cells to reduced ubiquitin ligase activity. These findings indicate that multiple UBX proteins are important for the efficient unfolding of ubiquitylated proteins by p97-UFD1-NPL4 in mammalian cells.

Replicon-seq: seeing is believing.

Claussin et al. introduce Replicon-seq, a new genome-wide DNA sequencing technology that monitors the progression of individual replisomes at high resolution in vivo.

Affective modulation of cognitive control: A systematic review of EEG studies.

In recent years, a growing corpus of research has been conducted utilizing a variety of behavioral and neurophysiological methodologies to investigate the relationship of emotion and cognition, yielding unique insights into fundamental concerns about the human mind and mental disease. Electroencephalography (EEG) has been utilized to investigate how emotional states alter neural markers of cognitive control. The current study is a systematic analysis of EEG research that looks at affective modulation (mood, emotion) of cognitive control and its many sub-processes (e.g., cognitive flexibility, inhibitory control, and working memory). The PRISMA standards were followed in this review, which looked at experimental designs and tasks, as well as methodological elements of EEG recording and analysis across research. A total of 35 articles were chosen for qualitative synthesis as a consequence of the search. The examination of event-related potentials (ERPs), which showed affective modulation of 19 different components, was the most common electrophysiological approach used across research. The majority of the investigations focused on N2 and P3, indicating that affective induction has a strong influence on attentional processes and response inhibition. Future research should look into different methodologies such as source location and connection metrics to better understand the brain's areas and dynamic response during affective induction activities. It is also suggested that the technical components of the report be more explicit in order to promote study comparability and replication.

Effectiveness of a Gamification Strategy to Prevent Childhood Obesity in Schools: A Cluster Controlled Trial.

OBJECTIVE: The aim of this study was to examine the effectiveness of a school-based gamification strategy to prevent childhood obesity. METHODS: Schools were randomized in Santiago, Chile, between March and May 2018 to control or to receive a nutrition and physical activity intervention using a gamification strategy (i.e., the use of points, levels, and rewards) to achieve healthy challenges. The intervention was delivered for 7 months and participants were assessed at 4 and 7 months. Primary outcomes were mean difference in BMI z score and waist circumference (WC) between trial arms at 7 months. Secondary outcomes were mean difference in BMI and systolic and diastolic blood pressure between trial arms at 7 months.  RESULTS: A total of 24 schools (5 controls) and 2,197 students (653 controls) were analyzed. Mean BMI z score was lower in the intervention arm compared with control (adjusted mean difference -0.133, 95% CI: -0.25 to -0.01), whereas no evidence of reduction in WC was found. Mean BMI and systolic blood pressure were lower in the intervention arm compared with control. No evidence of reduction in diastolic blood pressure was found. CONCLUSIONS: The multicomponent intervention was effective in preventing obesity but not in reducing WC. Gamification is a potentially powerful tool to increase the effectiveness of school-based interventions to prevent obesity.

Reconstitution of human CMG helicase ubiquitylation by CUL2LRR1 and multiple E2 enzymes.

Cullin ubiquitin ligases drive replisome disassembly during DNA replication termination. In worm, frog and mouse cells, CUL2LRR1 is required to ubiquitylate the MCM7 subunit of the CMG helicase. Here, we show that cullin ligases also drive CMG-MCM7 ubiquitylation in human cells, thereby making the helicase into a substrate for the p97 unfoldase. Using purified human proteins, including a panel of E2 ubiquitin-conjugating enzymes, we have reconstituted CMG helicase ubiquitylation, dependent upon neddylated CUL2LRR1. The reaction is highly specific to CMG-MCM7 and requires the LRR1 substrate targeting subunit, since replacement of LRR1 with the alternative CUL2 adaptor VHL switches ubiquitylation from CMG-MCM7 to HIF1. CUL2LRR1 firstly drives monoubiquitylation of CMG-MCM7 by the UBE2D class of E2 enzymes. Subsequently, CUL2LRR1 activates UBE2R1/R2 or UBE2G1/G2 to extend a single K48-linked ubiquitin chain on CMG-MCM7. Thereby, CUL2LRR1 converts CMG into a substrate for p97, which disassembles the ubiquitylated helicase during DNA replication termination.

Nuclear Dishevelled targets gene regulatory regions and promotes tumor growth.

Dishevelled (DVL) critically regulates Wnt signaling and contributes to a wide spectrum of diseases and is important in normal and pathophysiological settings. However, how it mediates diverse cellular functions remains poorly understood. Recent discoveries have revealed that constitutive Wnt pathway activation contributes to breast cancer malignancy, but the mechanisms by which this occurs are unknown and very few studies have examined the nuclear role of DVL. Here, we have performed DVL3 ChIP-seq analyses and identify novel target genes bound by DVL3. We show that DVL3 depletion alters KMT2D binding to novel targets and changes their epigenetic marks and mRNA levels. We further demonstrate that DVL3 inhibition leads to decreased tumor growth in two different breast cancer models in vivo. Our data uncover new DVL3 functions through its regulation of multiple genes involved in developmental biology, antigen presentation, metabolism, chromatin remodeling, and tumorigenesis. Overall, our study provides unique insight into the function of nuclear DVL, which helps to define its role in mediating aberrant Wnt signaling.

Different Responses to Stress, Health Practices, and Self-Care during COVID-19 Lockdown: A Stratified Analysis.

The aim of the present cross-sectional study was to analyze the differential impact of the first COVID-19 lockdown (3 April 2020) on stress, health practices, and self-care activities across different Hispanic countries, age range, and gender groups. One thousand and eighty-two participants from Spain, Chile, Colombia, and Ecuador took part in this study. Irrespective of the country, and controlling for income level, young people, especially females, suffered a greater level of stress, perceived the situation as more severe, showed less adherence to health guidelines, and reported lower levels of health consciousness, in comparison to their male peers and older groups. However, in the case of self-care, it seems that older and female groups are generally more involved in self-care activities and adopt more healthy daily routines. These results are mostly similar between Colombia, Ecuador, and Spain. However, Chile showed some different tendencies, as males reported higher levels of healthy daily routines and better adherence to health guidelines compared to females and people over the age of 60. Differences between countries, genders, and age ranges should be considered in order to improve health recommendations and adherence to guidelines. Moreover, developing community action and intersectoral strategies with a gender-based approach could help to reduce health inequalities and increase the success of people's adherence to health guidelines and self-care-promoting interventions. Future studies should be addressed to explore the possible causations of such differences in more cultural-distant samples and at later stages of the current outbreak.

Predicting ligand removal energetics in thiolate-protected nanoclusters from molecular complexes.

Thiolate-protected metal nanoclusters (TPNCs) have attracted great interest in the last few decades due to their high stability, atomically precise structure, and compelling physicochemical properties. Among their various applications, TPNCs exhibit excellent catalytic activity for numerous reactions; however, recent work revealed that these systems must undergo partial ligand removal in order to generate active sites. Despite the importance of ligand removal in both catalysis and stability of TPNCs, the role of ligands and metal type in the process is not well understood. Herein, we utilize Density Functional Theory to understand the energetic interplay between metal-sulfur and sulfur-ligand bond dissociation in metal-thiolate systems. We first probe 66 metal-thiolate molecular complexes across combinations of M = Ag, Au, and Cu with twenty-two different ligands (R). Our results reveal that the energetics to break the metal-sulfur and sulfur-ligand bonds are strongly correlated and can be connected across all complexes through metal atomic ionization potentials. We then extend our work to the experimentally relevant [M25(SR)18]- TPNC, revealing the same correlations at the nanocluster level. Importantly, we unify our work by introducing a simple methodology to predict TPNC ligand removal energetics solely from calculations performed on metal-ligand molecular complexes. Finally, a computational mechanistic study was performed to investigate the hydrogenation pathways for SCH3-based complexes. The energy barriers for these systems revealed, in addition to thermodynamics, that kinetics favor the break of S-R over the M-S bond in the case of the Au complex. Our computational results rationalize several experimental observations pertinent to ligand effects on TPNCs. Overall, our introduced model provides an accelerated path to predict TPNC ligand removal energies, thus aiding towards targeted design of TPNC catalysts.

CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.

The eukaryotic replisome assembles around the CMG helicase, which stably associates with DNA replication forks throughout elongation. When replication terminates, CMG is ubiquitylated on its Mcm7 subunit and disassembled by the Cdc48/p97 ATPase. Until now, the regulation that restricts CMG ubiquitylation to termination was unknown, as was the mechanism of disassembly. By reconstituting these processes with purified budding yeast proteins, we show that ubiquitylation is tightly repressed throughout elongation by the Y-shaped DNA structure of replication forks. Termination removes the repressive DNA structure, whereupon long K48-linked ubiquitin chains are conjugated to CMG-Mcm7, dependent on multiple replisome components that bind to the ubiquitin ligase SCFDia2. This mechanism pushes CMG beyond a '5-ubiquitin threshold' that is inherent to Cdc48, which specifically unfolds ubiquitylated Mcm7 and thereby disassembles CMG. These findings explain the exquisite regulation of CMG disassembly and provide a general model for the disassembly of ubiquitylated protein complexes by Cdc48.

Circulating Endothelial Cells From Septic Shock Patients Convert to Fibroblasts Are Associated With the Resuscitation Fluid Dose and Are Biomarkers for Survival Prediction.

OBJECTIVES: To determine whether circulating endothelial cells from septic shock patients and from nonseptic shock patients are transformed in activated fibroblast by changing the expression level of endothelial and fibrotic proteins, whether the level of the protein expression change is associated with the amount of administered resuscitation fluid, and whether this circulating endothelial cell protein expression change is a biomarker to predict sepsis survival. DESIGN: Prospective study. SETTING: Medical-surgical ICUs in a tertiary care hospital. PATIENTS: Forty-three patients admitted in ICU and 22 healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Circulating mature endothelial cells and circulating endothelial progenitor cells from septic shock and nonseptic shock patients showed evidence of endothelial fibrosis by changing the endothelial protein expression pattern. The endothelial proteins were downregulated, whereas fibroblast-specific markers were increased. The magnitude of the expression change in endothelial and fibrotic proteins was higher in the septic shock nonsurvivors patients but not in nonseptic shock. Interestingly, the decrease in the endothelial protein expression was correlated with the administered resuscitation fluid better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in the septic shock nonsurvivors patients but not in nonseptic shock. Notably, the significant difference between endothelial and fibrotic protein expression indicated a nonsurvival outcome in septic shock but not in nonseptic shock patients. Remarkably, area under the receiver operating characteristic curve analysis showed that endothelial protein expression levels predicted the survival outcome better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in septic shock but not in nonseptic shock patients. CONCLUSIONS: Circulating endothelial cells from septic shock patients are acutely converted into fibroblasts. Endothelial and fibrotic protein expression level are associated with resuscitation fluid administration magnitude and can be used as biomarkers for an early survival diagnosis of sepsis.

Catalytic radical difluoromethoxylation of arenes and heteroarenes.

Intermolecular C-H difluoromethoxylation of (hetero)arenes remains a long-standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a redox-active difluoromethoxylating reagent 1a and photoredox catalysts for the direct C-H difluoromethoxylation of (hetero)arenes. Our approach is operationally simple, proceeds at room temperature, and uses bench-stable reagents. Its synthetic utility is highlighted by mild reaction conditions that tolerate a wide variety of functional groups and biorelevant molecules. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1a forming a neutral radical intermediate that liberates the OCF2H radical exclusively. Addition of this radical to (hetero)arenes gives difluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of difluoromethoxylation.

Plasma lactate and leukocyte mitochondrial DNA copy number as biomarkers of insulin sensitivity in non-diabetic women.

High plasma lactate levels have been associated with reduced mitochondrial respiratory capacity and increased type 2 diabetes risk, while mitochondrial DNA (mtDNA) copy number has been proposed as a biomarker of mitochondrial function linked to glucose homeostasis. The aim of this study was to evaluate the association between circulating lactate levels and leukocyte mtDNA copy numbers with insulin secretion/sensitivity indexes in 65 Chilean non-diabetic women. mtDNA copy numbers were measured in leukocytes using qPCR and digital-droplet PCR. A 75-g Oral Glucose Tolerance Test (OGTT) was performed to calculate systemic and tissue-specific insulin sensitivity indexes, as well as insulin secretion surrogates based on plasma c-peptide. An intravenous glucose tolerance test (IVGTT; 0.3 g/kg) was also carried out. Disposition indexes were calculated as the product of insulin secretion × sensitivity. Plasma levels of leptin, adiponectin, TNF-α, MCP-1, and non-esterified fatty acids were also determined. Fasting plasma lactate shows a significant association with a wide range of insulin sensitivity/resistance indexes based on fasting plasma samples (HOMA-S, adipose IR index, Revised-QUICKI, leptin-adiponectin ratio, TyG index, McAuley index and TG-to-HDL-C ratio), as well as OGTT-based measures such as the Matsuda index, the hepatic insulin resistance index, and the disposition index. Fasting plasma lactate was also positively associated with the circulating adipokines TNF-α and MCP-1. We also detected a direct association between fasting plasma lactate with leukocyte mtDNA copy numbers. The above results support the use of fasting plasma lactate, and possibly leukocyte mtDNA copy numbers, as biomarkers of reduced oxidative mitochondrial capacity, decreased hepatic insulin sensitivity, and future diabetes risk.

Validación de una cartilla pedagógica para enseñar ética de manera crítica y reflexiva en psicología / Validation of a pedagogical booklet to teach ethics in a critical and reflective way in psychology / Validação de uma cartilha educativa para ensinar ética de maneira crítica e reflexiva em psicologia

La educación ética en las universidades ha estado caracterizada por la transmisión de corrientes filosóficas, normas o códigos, dirigidos a ser una guía para el actuar en forma de máximas que han de ser rectores de la conducta y excelencia profesional. No obstante, esta educación ha demostrado ser inefectiva. Como resultado, es frecuente encontrar errores de tipo ético en la praxis de las disciplinas. Atendiendo a la necesidad de trascender la formación ética teórica, y buscar una educación práctica y aplicada, con la finalidad de fomentar el desarrollo de profesionales autónomos, responsables, críticos y con sentido de excelencia en el actuar profesional, se han recopilado experiencias formativas basadas en la promoción del pensamiento crítico y reflexivo. En primer lugar, se realizó una revisión teórica enfocada en las principales deficiencias de la educación en ética. En segundo lugar, se recopilaron estrategias didácticas que han demostrado ser valiosas para el cultivo de la deliberación y el pensamiento crítico y reflexivo en los estudiantes. Por último, como resultado de la investigación y entendiendo la necesidad de llevar la información recogida a los docentes comprometidos en la transformación educativa, se realizó una cartilla dinámica, amigable al lector y con la finalidad de ser un apoyo a los docentes encargados de enseñar ética en las universidades. La cartilla fue validada a nivel de contenido a través del juicio de expertos y el análisis de V de Aiken, mostrando ser coherente conceptualmente y de utilidad de acuerdo al objetivo de la misma.

Ethics in education topics has been in universities has been characterized by Models of philosophical, rules or codes, intended to be a guide for acting as maxims. That must be a guide of principles be guiding principles of behavior and professional excellence. However, this education has proven to be ineffective. As a result, it is common to find errors of an ethical nature in the practice of disciplines. With the need to transcend the theoretical ethics training, and in the seek of practical and applied education, in order to promote the development of autonomous professionals, responsible, and in a sense of excellence in professional act, have compiled training experiences based on promoting critical and reflective thinking. First, a theoretical review focused on the main shortcomings of education in ethics. In the second place, on teaching strategies that have proven valuable for cultivation of deliberation and critical and reflective thinking in students collected performed. Finally, because of the research and understanding the need to bring the information collected to teachers engaged in educational transformation, a dynamic booklet was carried out, friendly to the reader and in order to be a support to teachers in charge of teaching ethics in the universities. The booklet content was validated level through an expert judgment and analysis to V of Aiken, showing conceptually be consistent and useful according to the objective there of.

A educação ética nas universidades tem se caracterizado pela transmissão de correntes filosóficas, normas ou códigos, direcionados a servir de guia para atuar na forma de máximas que devem ser reitores da conduta e da excelência profissional. No entanto, essa educação se mostrou ineficaz. Como resultado, é comum encontrar erros de natureza ética na prática das disciplinas. Experiências de formação com a necessidade de transcender a formação teórica ética e buscar prático e educação aplicada, a fim de promover o desenvolvimento de profissionais autônomos, responsáveis, críticos e senso de excelência em ato profissional, têm compilados com base em a promoção do pensamento crítico e reflexivo. Primeiramente, realizou-se uma revisão teórica focada nas principais deficiências da educação ética. Em segundo lugar, de estratégias didáticas que se mostraram valiosas para o cultivo da deliberação e pensamento crítico e reflexivo nos alunos. Enfim, como resultado de uma pesquisa e compreender a necessidade dos professores informação recolhida envolvidos na transformação educacional, um leitor amigável e, a fim de ser um apoio para os professores que ensinam ética em universidades cartilha dinâmica foi realizada. O primer foi validado em nível de conteúdo através de julgamento de especialistas e análise de Aiken, mostrando-se coerente conceitualmente e útil de acordo com o objetivo do mesmo.

Redox-Active Reagents for Photocatalytic Generation of the OCF3 Radical and (Hetero)Aryl C-H Trifluoromethoxylation.

The trifluoromethoxy (OCF3 ) radical is of great importance in organic chemistry. Yet, the catalytic and selective generation of this radical at room temperature and pressure remains a longstanding challenge. Herein, the design and development of a redox-active cationic reagent (1) that enables the formation of the OCF3 radical in a controllable, selective, and catalytic fashion under visible-light photocatalytic conditions is reported. More importantly, the reagent allows catalytic, intermolecular C-H trifluoromethoxylation of a broad array of (hetero)arenes and biorelevant compounds. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1 resulting in exclusive liberation of the OCF3 radical. Addition of this radical to (hetero)arenes gives trifluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of trifluoromethoxylation.

Epimerization of Tertiary Carbon Centers via Reversible Radical Cleavage of Unactivated C(sp3)-H Bonds.

Reversible cleavage of C(sp3)-H bonds can enable racemization or epimerization, offering a valuable tool to edit the stereochemistry of organic compounds. While epimerization reactions operating via cleavage of acidic C(sp3)-H bonds, such as the Cα-H of carbonyl compounds, have been widely used in organic synthesis and enzyme-catalyzed biosynthesis, epimerization of tertiary carbons bearing a nonacidic C(sp3)-H bond is much more challenging with few practical methods available. Herein, we report the first synthetically useful protocol for the epimerization of tertiary carbons via reversible radical cleavage of unactivated C(sp3)-H bonds with hypervalent iodine reagent benziodoxole azide and H2O under mild conditions. These reactions exhibit excellent reactivity and selectivity for unactivated 3° C-H bonds of various cycloalkanes and offer a powerful strategy for editing the stereochemical configurations of carbon scaffolds intractable to conventional methods. Mechanistic study suggests that the unique ability of N3• to serve as a catalytic H atom shuttle is critical to reversibly break and reform 3° C-H bonds with high efficiency and selectivity.