Biological Role of Aldo–Keto Reductases in Retinoic Acid Biosynthesis and Signaling

Several aldo–keto reductase (AKR) enzymes from subfamilies 1B and 1C show retinaldehyde reductase activity, having low Km and kcat values. Only AKR1B10 and 1B12, with all-trans-retinaldehyde, and AKR1C3, with 9-cis-retinaldehyde, display high catalytic efficiency. Major structural determinants for retinaldehyde isomer specificity are located in the external loops (A and C for AKR1B10, and B for AKR1C3), as assessed by site-directed mutagenesis and molecular dynamics. Cellular models have shown that AKR1B and 1C enzymes are well suited to work in vivo as retinaldehyde reductases and to regulate retinoic acid (RA) biosynthesis at hormone pre-receptor level. An additional physiological role for the retinaldehyde reductase activity of these enzymes, consistent with their tissue localization, is their participation in β-carotene absorption. Retinaldehyde metabolism may be subjected to subcellular compartmentalization, based on enzyme localization. While retinaldehyde oxidation to RA takes place in the cytosol, reduction to retinol could take place in the cytosol by AKRs or in the membranes of endoplasmic reticulum by microsomal retinaldehyde reductases. Upregulation of some AKR1 enzymes in different cancer types may be linked to their induction by oxidative stress and to their participation in different signaling pathways related to cell proliferation. AKR1B10 and AKR1C3, through their retinaldehyde reductase activity, trigger a decrease in the RA biosynthesis flow, resulting in RA deprivation and consequently lower differentiation, with an increased cancer risk in target tissues. Rational design of selective AKR inhibitors could lead to development of novel drugs for cancer treatment as well as reduction of chemotherapeutic drug resistance

New families of symplectic splitting methods for numerical integration in dynamical astronomy

We present new splitting methods designed for the numerical integration of near-integrable Hamiltonian systems, and in particular for planetary N-body problems, when one is interested in very accurate results over a large time span. We derive in a systematic way an independent set of necessary and sufficient conditions to be satisfied by the coefficients of splitting methods to achieve a prescribed order of accuracy. Splitting methods satisfying such (generalized) order conditions are appropriate in particular for the numerical simulation of the Solar System described in Jacobi coordinates. We show that, when using Poincar\'e Heliocentric coordinates, the same order of accuracy may be obtained by imposing an additional polynomial equation on the coefficients of the splitting method. We construct several splitting methods appropriate for each of the two sets of coordinates by solving the corresponding systems of polynomial equations and finding the optimal solutions. The experiments reported here indicate that the efficiency of our new schemes is clearly superior to previous integrators when high accuracy is required.Comment: 24 pages, 2 figures. Revised version, accepted for publication in Applied Numerical Mathematic

The turtles from the upper Eocene, Osona County (Ebro Basin, Catalonia, Spain): new material and its faunistic and environmental context

Eochelone voltregana n. sp. is a new marine cryptodiran cheloniid found at the Priabonian levels (latest Eocene) of the Vespella marls member of the Vic–Manlleu marls formation. It is the second cheloniid from Santa Cecília de Voltregà (Osona County, Spain), the first one being Osonachelus decorata from the same formation. Shell parameters indicate that the new species belongs to a branch of sea turtles including the Eocene Anglo–Franco–Belgian forms Argillochelys, Puppigerus and Eochelone (the shell of the latter was studied here for the first time) as well as Glarichelys from the Oligocene of Switzerland, all of them predating the worldwide living Miocene genera. The description of two other more littoral–continental Eocene species is given: Trionyx sp., from an older layer of the same formation; and the podocnemidid erymnochelyine, Cordichelys from a more basal layer of a middle Eocene (Lutetian) formation. The last one is identified as the only evidence of the Shweboemys subgroup in the European record, being distinct from the other known Osona County pleurodire Eocenochelus farresi, which is a member of the Erymnochelys group (same subfamily), from the younger Priabonian Sant Martí Xic layer. Thus, an update on the marine turtle fauna of the eastern Ebro Basin that variably opened in the east during Eocene times is provided. The turtles of Osona County belong to two suborders and five genera with three new species and extend the known distribution of their families (LSID urn:lsid:zoobank.org:act:48CE8676-7B82-4EF2-8165-27BEE90129F2).</p

Crystallization and preliminary X-ray analysis of NADP(H)-dependent alcohol dehydrogenases from Saccharomyces cerevisiae and Rana perezi

Different crystal forms diffracting to high resolution have been obtained for two NADP(H)-dependent alcohol dehydrogenases, members of the medium-chain dehydrogenase/reductase superfamily: ScADHVI from Saccharomyces cerevisiae and ADH8 from Rana perezi. ScADHVI is a broad-specificity enzyme, with a sequence identity lower than 25% with respect to all other ADHs of known structure. The best crystals of ScADHVI diffracted beyond 2.8 Å resolution and belonged to the trigonal space group P3121 (or to its enantiomorph P3221), with unit-cell parameters a = b = 102.2, c = 149.7 Å, γ = 120°. These crystals were produced by the hanging-drop vapour-diffusion method using ammonium sulfate as precipitant. Packing considerations together with the self-rotation function and the native Patterson map seem to indicate the presence of only one subunit per asymmetric unit, with a volume solvent content of about 80%. ADH8 from R. perezi is the only NADP(H)-dependent ADH from vertebrates characterized to date. Crystals of ADH8 obtained both in the absence and in the presence of NADP+ using polyethylene glycol and lithium sulfate as precipitants diffracted to 2.2 and 1.8 Å, respectively, using synchrotron radiation. These crystals were isomorphous, space group C2, with approximate unit-cell parameters a = 122, b = 79, c = 91 Å, β = 113° and contain one dimer per asymmetric unit, with a volume solvent content of about 50%

Tsunami detection using the PARIS concept

Abstract On 26 December 2004 a tsunami generated by an earthquake with its epicentre in the Indian Ocean West of Indonesia caused a real human and material catastrophe in the region. After the event some proposals to establish a network of sensors for tsunami detection were put forward. This paper presents an alternative concept that can be applied from satellite, aircraft or from the coast, and which can complement such a network of sensors for fast tsunami detection. The concept makes use of GNSS signals reflected from the ocean&apos;s surface to perform mesoscale ocean altimetry. The technique, designated PARIS (Passive Reflectometry and Interferometry System), aims at capturing fast topographic events happening on the ocean surface such as eddies and fronts. The paper includes details of some aircraft experiments whereby a PARIS altimeter was used to map a topographic signature with amplitude and wavelength similar to a tsunami in open ocean

The mechanism of macroautophagy: The movie

This animated movie presents the mechanism of macroautophagy, hereafter autophagy, by showing the molecular features of the formation of autophagosomes, the hallmark organelle of this intracellular catabolic pathway. It is based on our current knowledge and it also illustrates how autophagosomes can recognize and eliminate selected cargoes.</p

Adherence to Interferon β-1b Treatment in Patients with Multiple Sclerosis in Spain

Adherence to interferon β-1b (INFβ-1b) therapy is essential to maximize the beneficial effects of treatment in multiple sclerosis (MS). For that reason, the main objectives of this study are to assess adherence to INFβ-1b in patients suffering from MS in Spain, and to identify the factors responsible for adherence in routine clinical practice.This was an observational, retrospective, cross-sectional study including 120 Spanish patients with MS under INFβ-1b treatment. Therapeutic adherence was assessed with Morisky-Green test and with the percentage of doses received. The proportion of adherent patients assessed by Morisky-Green test was 68.3%, being indicative of poor adherence. Nevertheless, the percentage of doses received, which was based on the number of injected medication, was 94.3%. The main reason for missing INFβ-1b injections was forgetting some of the administrations (64%). Therefore, interventions that diminish forgetfulness might have a positive effect in the proportion of adherent patients and in the percentage of doses received. In addition, age and comorbidities had a significant effect in the number of doses injected per month, and should be considered in the management of adherence in MS patients.Among all the available methods for assessing adherence, the overall consumption of the intended dose has to be considered when addressing adherence

Modeling-Dependent Protein Characterization of the Rice Aldehyde Dehydrogenase (ALDH) Superfamily Reveals Distinct Functional and Structural Features

The completion of the rice genome sequence has made it possible to identify and characterize new genes and to perform comparative genomics studies across taxa. The aldehyde dehydrogenase (ALDH) gene superfamily encoding for NAD(P)+-dependent enzymes is found in all major plant and animal taxa. However, the characterization of plant ALDHs has lagged behind their animal- and prokaryotic-ALDH homologs. In plants, ALDHs are involved in abiotic stress tolerance, male sterility restoration, embryo development and seed viability and maturation. However, there is still no structural property-dependent functional characterization of ALDH protein superfamily in plants. In this paper, we identify members of the rice ALDH gene superfamily and use the evolutionary nesting events of retrotransposons and protein-modeling–based structural reconstitution to report the genetic and molecular and structural features of each member of the rice ALDH superfamily in abiotic/biotic stress responses and developmental processes. Our results indicate that rice-ALDHs are the most expanded plant ALDHs ever characterized. This work represents the first report of specific structural features mediating functionality of the whole families of ALDHs in an organism ever characterized

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified