The Analysis of Two Distinct Strategies toward the Enantioselective Formal Total Synthesis of (+)-Gelsenicine.

A full account of a formal enantioselective total synthesis of (+)-gelsenicine is described. Separate strategies based on catalytic cycloisomerization as the central step are considered. One plan involves chirality transfer from enantioenriched substrates, while the other employs asymmetric catalysis. The chirality transfer strategy is less effective, while in the latter, phosphoramidite- and bisphosphine-gold complexes are tested and ultimately provide a key intermediate in high enantiopurity in our Gelsemium alkaloid syntheses.

Multigram Synthesis of a Combustion-Relevant δ-Ketohydroperoxide through Sulfonylhydrazine Substitution.

A synthesis of a δ-ketohydroperoxide is described, addressing potential functional-group compatibilities in these elusive species relevant to combustion and atmospheric chemistries. The hydroperoxide is installed via sulfonylhydrazine substitution, which was found to be more effective than displacement of secondary halides. As part of this protocol, it was observed that 1,2-dimethoxyethane is an advantageous medium for the reaction, avoiding the formation of a tetrahydrofuran hydroperoxide side product. This discovery facilitated the multigram synthesis (6 steps, 41 % yield overall) and discrete characterization of the target δ-ketohydroperoxide.

Vomiting and Gastric Motility in Early Brain Damaged Children With Congenital Zika Syndrome.

OBJECTIVES: This study investigated the occurrence of vomiting and gastric dysmotility in dysphagic children with congenital Zika syndrome (CZS) and assessed possible associations of these findings with the severity of dysphagia and the presence of tube feeding. METHODS: Forty-six children with CZS were assessed for dysphagia, and the occurrence of vomiting, dietary volume tolerance <15 mL/kg, and feeding time per meal >30 minutes were evaluated. Gastric antrum ultrasonography was used to detect the frequency of contractions and measure antral areas (at fasting and 15 minutes postprandial), from which the gastric emptying rate (GER) was calculated. Antral ultrasonography findings were compared with those of ten healthy controls. Vomiting and gastric motility were compared between CZS patients according to the severity of dysphagia and the requirement for tube feeding. RESULTS: Overall, 76% (35/46) of children with CZS had moderate-to-severe dysphagia (MSD), among whom 60% (21/35) were tube fed [MSD tube fed (MSDTF)]. Vomiting occurred in 54% (25/46) of children, whereas dietary volume intolerance and prolonged feeding time were observed in 59% (27/46) and 37% (17/46), respectively, most frequently in MSDTF patients. On ultrasound, 61% (28/46) of children with CZS had no antral contractions, whereas 90% (9/10) of controls did. Compared to healthy controls, GER was eight-fold lower in children with CZS and 60-fold lower in MSDTF children. CONCLUSIONS: In dysphagic children with CZS, vomiting, volume intolerance, and prolonged feeding time were frequent and possibly associated with impaired antral contraction and delayed gastric emptying, especially in cases of severe dysphagia and tube feeding.

Combined effects of yacon flour and probiotic yogurt on the metabolic parameters and inflammatory and insulin signaling proteins in high-fat-diet-induced obese mice.

BACKGROUND: Prebiotics and probiotics may be effective dietary components that can alter the gut microbiota of the host and, consequently, overcome imbalances associated with obesity. This work aimed to evaluate the synergistic and isolated effects and mechanisms by which probiotic yogurt containing Bifidobacterium animalis and/or Lactobacillus acidophilus and yacon flour alter metabolic parameters and inflammatory and insulin signaling proteins in diet-induced obese mice. Swiss mice were fed a high-fat diet (n = 48) or a standard diet (control; n = 6) for 56 days. The 42 mice that gained the most weight were selected and divided into seven groups that received different combinations of probiotic yogurt and yacon flour. After 30 days, biochemical parameters (blood glucose, serum total cholesterol, and triacylglycerols), crude fat excretion in feces, and periepididymal fat were assessed and an immunoblotting analysis of insulin signaling proteins and interleukin-1ß was conducted. RESULTS: The combination of yacon flour and a yogurt with two strains of probiotics exerted positive effects on the parameters evaluated, such as decreased body weight (-6.5%; P < 0.05), fasting glucose (-23.1%; P < 0.05), and triacylglycerol levels (-21.4%; P < 0.05) and decreased periepididymal fat accumulation (-44.2%; P < 0.05). There was a decrease in inflammatory markers (P < 0.001) and an improvement in insulin signaling (P < 0.001). CONCLUSIONS: The combination of a prebiotic with two strains of probiotics in a food matrix may exert a protective effect against obesity-associated inflammation, improving insulin resistance, even in the short term. © 2022 Society of Chemical Industry.

Perception of health-related quality of life, sleep quality and sleepiness index in an educational environment at a dental school in Southeast Brazil.

INTRODUCTION: University entrance is often associated with changes in quality of life, individuals' cognitive and physical behavior. The present study aimed to evaluate health-related quality of life (HRQoL), sleep quality and sleepiness index in dentistry students at a university in Southeast Brazil, in different semesters of their course. MATERIALS AND METHODS: Samples were obtained from 55 students from the dentistry course at the Federal University of Alfenas (UNIFAL-MG). For collecting information, validated SF-36 questionnaires (Medical Outcomes Study 36-item Short-Form Health Survey), namely, Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), were used as instruments in an educational environment. The relationship between the association of demographic factors and academic performance with SF-36, PSQI and ESS was assessed with an alpha of 0.05. RESULTS: The worst HRQoL parameters reported by the participants were observed in the domains of body pain, vitality, general health perception, and limitations due to emotional and social aspects when associated with the investigated variables. Regarding the relative sleep quality index, differences in the PSQI domains were observed when related to demographic factors and academic performance. There was no significant difference in the sleepiness index of these students according to the mean values of the ESS domains. CONCLUSION: The SF-36, PSQI and ESS questionnaires indicated that it is a reliable instrument for measuring the impact of quality of life on dentistry students. In addition, dentistry students of UNIFAL-MG had poor indicators of quality of life associated with health and an inadequate index of quality of sleep.

Dearomative (3+2) Cycloadditions between Indoles and Vinyldiazo Species Enabled by a Red-Shifted Chromium Photocatalyst.

A direct dearomative photocatalyzed (3+2) cycloaddition between indoles and vinyldiazo reagents is described. The transformation is enabled by the development of a novel oxidizing CrIII photocatalyst, its specific reactivity attributed to increased absorptive properties over earlier Cr analogs and greater stability than Ru counterparts. A variety of fused indoline compounds are synthesized using this method, including densely functionalized ring systems that are feasible due to base-free conditions. Experimental insights corroborate a cycloaddition initiated by nucleophilic attack at C3 of the indole radical cation by the vinyldiazo species.

Maternal choline supplementation ameliorates Alzheimer's disease pathology by reducing brain homocysteine levels across multiple generations.

The lack of effective treatments for Alzheimer's disease (AD) is alarming, considering the number of people currently affected by this disorder and the projected increase over the next few decades. Elevated homocysteine (Hcy) levels double the risk of developing AD. Choline, a primary dietary source of methyl groups, converts Hcy to methionine and reduces age-dependent cognitive decline. Here, we tested the transgenerational benefits of maternal choline supplementation (ChS; 5.0 g/kg choline chloride) in two generations (Gen) of APP/PS1 mice. We first exposed 2.5-month-old mice to the ChS diet and allowed them to breed with each other to generate Gen-1 mice. Gen-1 mice were exposed to the ChS diet only during gestation and lactation; once weaned at postnatal day 21, Gen-1 mice were then kept on the control diet for the remainder of their life. We also bred a subset of Gen-1 mice to each other and obtained Gen-2 mice; these mice were never exposed to ChS. We found that ChS reduced Aß load and microglia activation, and improved cognitive deficits in old Gen-1 and Gen-2 APP/PS1 mice. Mechanistically, these changes were linked to a reduction in brain Hcy levels in both generations. Further, RNA-Seq data from APP/PS1 hippocampal tissue revealed that ChS significantly changed the expression of 27 genes. These genes were enriched for inflammation, histone modifications, and neuronal death functional classes. Our results are the first to demonstrate a transgenerational benefit of ChS and suggest that modifying the maternal diet with additional choline reduces AD pathology across multiple generations.

Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease.

Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in Aß and interferon-gamma (IFNγ) levels, and microgliosis. The changes in IFNγ levels are noteworthy as previously published evidence indicates that IFNγ can increase microglia activation and induce Aß production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.

Effects of sprouted and fermented quinoa (Chenopodium quinoa) on glycemic index of diet and biochemical parameters of blood of Wistar rats fed high carbohydrate diet.

Sprouted and fermented foods have shown hypoglycemic effects on humans and animals, by reducing concentrations of soluble carbohydrates, and increasing dietary fiber and resistant starch content. In this study, diets with high levels of simple carbohydrates supplemented with toasted quinoa flour, sprouted and toasted quinoa flour, fermented and toasted quinoa flour or sprouted/fermented and toasted quinoa flour were given to Wistar rats. During the experiment, the glycemic index (GI) of the diets were measure and, at the end of 47 days of feeding, the effects of the diets on physical and biochemical parameters of the animals were evaluated. Results indicated that the processes of sprouting and/or fermentation potentiate the ability of quinoa to reduce GI of diets with high levels of simple carbohydrates. Moreover, food intake, blood glucose and lipid levels, and accumulation of epididymal adipose tissue were reduced in rats fed diets supplemented with quinoa. These effects may be due to the nutritional composition of the supplemented diets, besides the chemical changes promoted by processing quinoa. These results are particularly relevant once sprouted and fermented quinoa could be an alimentary source of interest, especially for disease risk prevention such as diabetes, obesity and dyslipidemias.

Cyclopentene Annulations of Alkene Radical Cations with Vinyl Diazo Species Using Photocatalysis.

A direct (3+2) cycloaddition between alkenes and vinyl diazo reagents using either Cr or Ru photocatalysis is described. The intermediacy of a radical cation species enables a nucleophilic interception by vinyl diazo compounds, a departure from their traditional electrophilic behavior. A variety of cyclopentenes are synthesized using this method, and experimental insights implicate a direct cycloaddition instead of a cyclopropanation/rearrangement process.

Engineering a bacterial platform for total biosynthesis of caffeic acid derived phenethyl esters and amides.

Caffeic acid has been widely recognized as a versatile pharmacophore for synthesis of new chemical entities, among which caffeic acid derived phenethyl esters and amides are the most extensively-investigated bioactive compounds with potential therapeutical applications. However, the natural biosynthetic routes for caffeic acid derived phenethyl esters or amides remain enigmatic, limiting their bio-based production. Herein, product-directed design of biosynthetic schemes allowed the development of thermodynamically favorable pathways for these compounds via acyltransferase (ATF) mediated trans-esterification. Production based screening identified a microbial O-ATF from Saccharomyces cerevisiae and a plant N-ATF from Capsicum annuum capable of forming caffeic acid derived esters and amides, respectively. Subsequent combinatorial incorporation of caffeic acid with various aromatic alcohol or amine biosynthetic pathways permitted the de novo bacterial production of a panel of caffeic acid derived phenethyl esters or amides in Escherichia coli for the first time. Particularly, host strain engineering via systematic knocking out endogenous caffeoyl-CoA degrading thioesterase and pathway optimization via titrating co-substrates enabled production enhancement of five caffeic acid derived phenethyl esters and amides, with titers ranging from 9.2 to 369.1mg/L. This platform expanded the capabilities of bacterial production of high-value natural aromatic esters and amides from renewable carbon source via tailoring non-natural biosynthetic pathways.

Meta-Selective C-H Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold.

The first example of meta-selective C-H arylations of arene alcohol-based substrates is described. The strategy involves the combination of the transient norbornene strategy with the quinoline-based acetal scaffold to achieve the formation of biaryl compounds. Both a two-step meta-arylation/scaffold cleavage process and a total telescoping procedure are described, highlighting the convenient attributes of attachment, removal, and recovery of the acetal scaffold. Moreover, the meta-arylated compounds can be further derivatized via ortho-selective functionalizations. These processes establish a foundation for catalytic polyfunctionalization of alcohol-based compounds.

Total Synthesis of Gelsenicine via a Catalyzed Cycloisomerization Strategy.

The first total synthesis of (±)-gelsenicine is reported. The synthetic route is highly efficient (13 steps), featuring (1) a pivotal metal-catalyzed isomerization/rearrangement process that forges the central core of the molecule and (2) two facile C-N bond-forming steps that establish the flanking heterocycles.

Uncovering the Roles of Oxygen in Cr(III) Photoredox Catalysis.

A combined experimental and theoretical investigation aims to elucidate the necessary roles of oxygen in photoredox catalysis of radical cation based Diels-Alder cycloadditions mediated by the first-row transition metal complex [Cr(Ph2phen)3](3+), where Ph2phen = bathophenanthroline. We employ a diverse array of techniques, including catalysis screening, electrochemistry, time-resolved spectroscopy, and computational analyses of reaction thermodynamics. Our key finding is that oxygen acts as a renewable energy and electron shuttle following photoexcitation of the Cr(III) catalyst. First, oxygen quenches the excited Cr(3+)* complex; this energy transfer process protects the catalyst from decomposition while preserving a synthetically useful 13 µs excited state and produces singlet oxygen. Second, singlet oxygen returns the reduced catalyst to the Cr(III) ground state, forming superoxide. Third, the superoxide species reduces the Diels-Alder cycloadduct radical cation to the final product and reforms oxygen. We compare the results of these studies with those from cycloadditions mediated by related Ru(II)-containing complexes and find that the distinct reaction pathways are likely part of a unified mechanistic framework where the photophysical and photochemical properties of the catalyst species lead to oxygen-mediated photocatalysis for the Cr-containing complex but radical chain initiation for the Ru congener. These results provide insight into how oxygen can participate as a sustainable reagent in photocatalysis.

Palladium(II)-Catalyzed ortho-Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold.

A palladium(II)-catalyzed C-H arylation process of alcohols has been developed. The strategy utilizes a novel quinoline-based hemiacetal scaffold that can direct the selective C-H bond functionalization. This reaction provides a useful method to construct biaryl compounds of benzyl alcohols in good to excellent yields. The new molecular scaffold can be readily attached, removed, and recovered.

Spiritual Religious Coping is Associated with Quality of Life in Institutionalized Older Adults.

The purpose of this study was to investigate the relationship between spiritual/religious coping (SRCOPE) strategies and quality of life (QoL) in institutionalized older adults. This is a cross-sectional, correlational study, with a sample of 77 older adults in Brazil. The present study found long-term care patients use religious and spiritual coping strategies to deal with their chronic health conditions. Positive SRCOPE and Total SRCOPE have positive correlations with most QoL domains from the WHOQOL-OLD and WHOQOL-BREF. On the other hand, Negative SRCOPE strategies correlated negatively with the facets of "death and dying" from the WHOQOL-OLD. These results suggest the need for an integrative approach for long-term care patients, considering the positive and negative aspects of coping.

An analysis of the complementary stereoselective alkylations of imidazolidinone derivatives toward α-quaternary proline-based amino amides.

Alkylations of proline-based imidazolidinones are described based on the principle of self-regeneration of stereocenters (SRS), affording high levels of either the cis or trans configured products. Stereoselectivity is dictated solely on the nature of the "temporary" group, where isobutyraldehyde-derived imidazolidinones provide the cis configured products and 1-naphthaldehyde-derived imidazolidinones afford the complementary trans configured products. These stereodivergent products can be readily cleaved to afford both α-alkylated proline enantiomers from readily available L-proline. A series of imidazolidinones were alkylated to investigate the origin of the anti-selectivity. Potential contributions toward the observed anti-selectivity are discussed on the basis of these experiments, suggesting a refined hypothesis for selectivity may be in order.

Photooxidizing chromium catalysts for promoting radical cation cycloadditions.

The photooxidizing capabilities of selected Cr(III) complexes for promoting radical cation cycloadditions are described. These complexes have sufficiently long-lived excited states to oxidize electron-rich alkenes, thereby initiating [4+2] processes. These metal species augment the spectrum of catalysts explored in photoredox systems, as they feature unique properties that can result in differential reactivity from the more commonly employed ruthenium or iridium catalysts.

An examination of the scope and stereochemistry of the Ireland-Claisen rearrangement of boron ketene acetals.

The Ireland-Claisen rearrangement of boron ketene acetals is described. The boron ketene acetal intermediates are formed through a soft enolization that obviates the use of strong bases and the intermediacy of alkali metal enolates. Yields and diastereoselectivities of these rearrangements are very sensitive to the choice of boron reagent, even among those that have been shown to effect quantitative formation of boron ketene acetals from esters. The rearrangement occurs at room temperature for all substrates with generally high levels of stereoselectivity. In contrast to previous reports using boron triflates, the use of a commercially available boron iodide reagent allows for a wider substrate scope that extends to propionates and arylacetates, as well as the previously described α-oxygenated esters. This work also provides insight into the dynamic nature of boron ketene acetals and the ramifications of this behavior for reactions in which they are intermediates.