Hetero-cycloreversions Mediated by Photoinduced Electron Transfer

[EN] Discovered more than eight decades ago, the Diels-Alder (DA) cycloaddition (CA) remains one of the most versatile tools in synthetic organic chemistry. Hetero-DA processes are powerful methods for the synthesis of densely functionalized six-membered heterocycles, ubiquitous substructures found in natural products and bioactive compounds. These reactions frequently employ azadienes and oxadienes, but only a few groups have reported DA processes with thiadienes. The electron transfer (ET) version of the DA reaction, though less investigated, has emerged as a subject of increasing interest. In the last two decades, researchers have paid closer attention to radical ionic hetero-cycloreversions, mainly in connection with their possible involvement in the repair of pyrimidine(6-4)pyrimidone photolesions in DNA by photolyases. In biological systems, these reactions likely occur through a reductive photosensitization mechanism. In addition, photooxidation can lead to cycloreversion (CR) reactions, and researchers can exploit this strategy for DNA repair therapies. In this Account, we discuss electron-transfer (ET) mediated hetero-CR reactions. We focus on the oxidative and reductive ET splitting of oxetanes, azetidines, and thietanes. Photoinduced electron transfer facilitates the splitting of a variety of four-membered heterocycles. In this context, researchers have commonly examined oxetanes, both experimentally and theoretically. Although a few studies have reported the cycloreversion of azetidines and thietanes carried out under electron transfer conditions, the number of examples remains limited. In general, the cleavage of the ionized four-membered rings appears to occur via a nonconcerted two-step mechanism. The trapping of the intermediate 1,4-radical ions and transient absorption spectroscopy data support this hypothesis, and it explains the observed loss of stereochemistry in the products. In the initial step, either C-C or C-X bond breaking may occur, and the preferred route depends on the substitution pattern of the ring, the type of heteroatom, and various experimental conditions. To better accommodate spin and charge, C-X cleavage happens more frequently, especially in the radical anionic version of the reaction. The addition or withdrawal of a single electron provides a new complementary synthetic strategy to activate hetero-cycloreversions. Despite its potential, this strategy remains largely unexplored. However, it offers a useful method to achieve C=X/olefin metathesis or, upon ring expansion, to construct six-membered heterocyclic rings.Financial support from the Spanish Government (Grants CTQ2010-14882, SEV2012-0267, and JCI-2010-06204) and the Generalitat Valenciana (Prometeo II/2013/005) is gratefully acknowledged.Pérez Ruiz, R.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2014). Hetero-cycloreversions Mediated by Photoinduced Electron Transfer. Accounts of Chemical Research. 47(4):1359-1368. https://doi.org/10.1021/ar4003224S1359136847

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Reactive DESI-MS imaging of biological tissues with dicationic ion-pairing compounds

This work illustrates reactive desorption electrospray ionization mass spectrometry (DESI-MS) with a stable dication on biological tissues. Rat brain and zebra fish tissues were investigated with reactive DESI-MS in which the dictation forms a stable bond with biological tissue fatty acids and lipids. Tandem mass spectrometry (MS/MS) was used to characterize the dication (DC9) and to identify linked lipid-dication compounds formed. The fragment m/z 85 common to both DC9 fragmentation and DC9-lipid fragmentation was used to confirm that DC9 is indeed bonded with the lipids. Lipid signals in the range of m/z 250–350 and phosphoethanolamines (PE) m/z 700–800 observed in negative ion mode were also detected in positive ion mode with reactive DESI-MS with enhanced signal intensity. Reactive DESI-MS imaging in positive ion mode of rat brain and zebra fish tissues allowed enhanced detection of compounds commonly observed in the negative ion mode

Repositioning Salirasib as New Antimalarial Agent

The antiplasmodial activity assay was performed using a simple, high-sensitivity methodology based on nanoluciferase (nLuc)-transfected P. falciparum parasites. The results showed that some of the analogs were active at low micromolar concentration. The most potent member of the series has S-farnesyl and the triazole moiety substituted with methyl-naphtyl. The low cytotoxicity in eukaryotic cells of the most active analogs provided good therapeutic indexes, being promising candidates for future antimalarial drugs development. Our results provide structure-activity relationship data for the design of new antimalarial drugs. </p

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans

Accurate chromosome segregation requires a cohesin-mediated physical attachment between chromosomes that are to be segregated apart, and a bipolar spindle with microtubule plus ends emanating from exactly two poles toward the paired chromosomes. We asked whether the striking bipolar structure of C. elegans meiotic chromosomes is required for bipolarity of acentriolar female meiotic spindles by time-lapse imaging of mutants that lack cohesion between chromosomes. Both a spo-11 rec-8 coh-4 coh-3 quadruple mutant and a spo-11 rec-8 double mutant entered M phase with separated sister chromatids lacking any cohesion. However, the quadruple mutant formed an apolar spindle whereas the double mutant formed a bipolar spindle that segregated chromatids into two roughly equal masses. Residual non-cohesive COH-3/4-dependent cohesin on separated sister chromatids of the double mutant was sufficient to recruit haspin-dependent Aurora B kinase, which mediated bipolar spindle assembly in the apparent absence of chromosomal bipolarity. We hypothesized that cohesin-dependent Aurora B might activate or inhibit spindle assembly factors in a manner that would affect their localization on chromosomes and found that the chromosomal localization patterns of KLP-7 and CLS-2 correlated with Aurora B loading on chromosomes. These results demonstrate that cohesin is essential for spindle assembly and chromosome segregation independent of its role in sister chromatid cohesion

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans.

Accurate chromosome segregation requires a cohesin-mediated physical attachment between chromosomes that are to be segregated apart, and a bipolar spindle with microtubule plus ends emanating from exactly two poles toward the paired chromosomes. We asked whether the striking bipolar structure of C. elegans meiotic chromosomes is required for bipolarity of acentriolar female meiotic spindles by time-lapse imaging of mutants that lack cohesion between chromosomes. Both a spo-11 rec-8 coh-4 coh-3 quadruple mutant and a spo-11 rec-8 double mutant entered M phase with separated sister chromatids lacking any cohesion. However, the quadruple mutant formed an apolar spindle whereas the double mutant formed a bipolar spindle that segregated chromatids into two roughly equal masses. Residual non-cohesive COH-3/4-dependent cohesin on separated sister chromatids of the double mutant was sufficient to recruit haspin-dependent Aurora B kinase, which mediated bipolar spindle assembly in the apparent absence of chromosomal bipolarity. We hypothesized that cohesin-dependent Aurora B might activate or inhibit spindle assembly factors in a manner that would affect their localization on chromosomes and found that the chromosomal localization patterns of KLP-7 and CLS-2 correlated with Aurora B loading on chromosomes. These results demonstrate that cohesin is essential for spindle assembly and chromosome segregation independent of its role in sister chromatid cohesion