Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF

BACKGROUND Only 25% of IVF transfer cycles lead to a clinical pregnancy, calling for continued technical progress but also more in depth analysis of patients' individual characteristics. The interleukin-1 (IL-1) system and matrix metalloproteinases (MMPs) are strongly implicated in embryo implantation. The genes coding for IL-1Ra (gene symbol IL-1RN), IL-1β, MMP2 and MMP9 bear functional polymorphisms. We analysed the maternal genetic profile at these polymorphic sites in IVF patients, to determine possible correlations with IVF outcome. METHODS One hundred and sixty women undergoing an IVF cycle were enrolled and a buccal smear was obtained. The presence of IL-1RN variable number of tandem repeats and IL-1B + 3953, MMP2-1306 and MMP9-1562 single nucleotide substitutions were determined. Patients were divided into pregnancy failures (119), biochemical pregnancies (8) and clinical pregnancies (33). RESULTS There was a 40% decrease in IL-1RN*2 allele frequency (P = 0.024) and a 45% decrease in IL-1RN*2 carrier status in the clinical pregnancy group as compared to the pregnancy failure group (P = 0.017). This decrease was still statistically significant after a multivariate logistic regression analysis. The likelihood of a clinical pregnancy was decreased accordingly in IL-1RN*2 carriers: odds ratio = 0.349, 95% confidence interval = 0.2-0.8, P = 0.017. The IL-1B, MMP2 and MMP9 polymorphisms showed no correlation with IVF outcome. CONCLUSIONS IL-1RN*2 allele carriage is associated with a poor prognosis of achieving a pregnancy after IV

Conserved presence of G-quadruplex forming sequences in the Long Terminal Repeat Promoter of Lentiviruses

G-quadruplexes (G4s) are secondary structures of nucleic acids that epigenetically regulate cellular processes. In the human immunodeficiency lentivirus 1 (HIV-1), dynamic G4s are located in the unique viral LTR promoter. Folding of HIV-1 LTR G4s inhibits viral transcription; stabilization by G4 ligands intensifies this effect. Cellular proteins modulate viral transcription by inducing/unfolding LTR G4s. We here expanded our investigation on the presence of LTR G4s to all lentiviruses. G4s in the 5'-LTR U3 region were completely conserved in primate lentiviruses. A G4 was also present in a cattle-infecting lentivirus. All other non-primate lentiviruses displayed hints of less stable G4s. In primate lentiviruses, the possibility to fold into G4s was highly conserved among strains. LTR G4 sequences were very similar among phylogenetically related primate viruses, while they increasingly differed in viruses that diverged early from a common ancestor. A strong correlation between primate lentivirus LTR G4s and Sp1/NF\u3baB binding sites was found. All LTR G4s folded: their complexity was assessed by polymerase stop assay. Our data support a role of the lentiviruses 5'-LTR G4 region as control centre of viral transcription, where folding/unfolding of G4s and multiple recruitment of factors based on both sequence and structure may take place

The Mass-Lumped Midpoint Scheme for Computational Micromagnetics: Newton Linearization and Application to Magnetic Skyrmion Dynamics

We discuss a mass-lumped midpoint scheme for the numerical approximation of the Landau-Lifshitz-Gilbert equation, which models the dynamics of the magnetization in ferromagnetic materials. In addition to the classical micromagnetic field contributions, our setting covers the non-standard Dzyaloshinskii-Moriya interaction, which is the essential ingredient for the enucleation and stabilization of magnetic skyrmions. Our analysis also includes the inexact solution of the arising nonlinear systems, for which we discuss both a constraint-preserving fixed-point solver from the literature and a novel approach based on the Newton method. We numerically compare the two linearization techniques and show that the Newton solver leads to a considerably lower number of nonlinear iterations. Moreover, in a numerical study on magnetic skyrmions, we demonstrate that, for magnetization dynamics that are very sensitive to energy perturbations, the midpoint scheme, due to its conservation properties, is superior to the dissipative tangent plane schemes from the literature

EZETIMIBE PROTECTS THP-1 CELLS FROM ISCHEMIA-REPERFUSION INJURY REDUCING OXIDATIVE STRESS AND UP-REGULATING NRF2/ ARE GENE EXPRESSION

Background and Aims: We demonstrated that physical training, characterized by repeated ischemia-reperfusion (I-R) episodes (ischemic conditioning, IC), protects circulating cells from peripheral artery disease (PAD) patients against ischemic harms by reducing oxidative stress (OS) and by up-regulating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway expression. Ezetimibe (Eze) has been shown to alleviate OS enhancing Nrf2 nuclear translocation in an AMPK/p62-dependent manner. In a cellular I-R and IC model, we aimed to investigate: 1) the effect of Eze on OS and Nrf2/ARE gene expression 2) whether Eze could have a synergistic effect on IC. Methods: THP-1 cells were treated with or without Eze (50mM) overnight, then subjected to 1 or 6 repetitive I-R cycles using EVOS FL Auto Imaging System. Reactive oxygen species (ROS) formation was evaluated with DCF in cytofluorimetry. Nrf2/ARE and p62 gene expression were evaluated by RT-PCR and western blotting. Results: When THP-1 cells were exposed to 1 I-R cycle, the preincubation with Eze significantly reduced ROS formation (p<0.01) and up-regulated Nrf2/ARE pathway expression and p62 phosphorylation (p<0.001). Multiple I-R cycles, acting as IC, significantly reduced ROS formation and upregulated Nrf2/ARE gene expression (p<0.001); in these conditions, Eze preincubation was able not only to almost abolish ROS formation (p<0.01) but also further up-regulate Nrf2/ARE expression. Conclusions: In our I-R model, Eze not only restores I-R-induced oxidative damages through Nrf2/ARE signaling up-regulation but also has a synergistic effect on IC. This new \u201cpleiotropic\u201d effect, if confirmed in vivo, may strengthen the use of Eze in PAD patien

Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons.

Intronic hexanucleotide expansions in C9ORF72 are common in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non-ATG-initiated translation are responsible for the pathophysiology. We determined the interactome of C9ORF72 in motor neurons and found that C9ORF72 was present in a complex with cofilin and other actin binding proteins. Phosphorylation of cofilin was enhanced in C9ORF72-depleted motor neurons, in patient-derived lymphoblastoid cells, induced pluripotent stem cell-derived motor neurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIM-kinases 1 and 2 (LIMK1/2). This results in reduced axonal actin dynamics in C9ORF72-depleted motor neurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies

The science of Mars today for the scientists of Mars tomorrow

&amp;lt;p&amp;gt;RoadMap (ROle of and impAct of Dust and clouds in the Martian AtmosPhere: from lab to space)&amp;lt;br /&amp;gt;is a H2020 project led by a consortium of European scientific institutions which aims to improve&amp;lt;br /&amp;gt;our multidisciplinary understanding of the Martian atmosphere. The topics investigated by&amp;lt;br /&amp;gt;RoadMap will ensure that a large public will be reached and questions related to life emergence and&amp;lt;br /&amp;gt;space exploration will be addressed. The key audiences for our project are the scientific and&amp;lt;br /&amp;gt;education community, the specialized public, the general public (including students) and the media;&amp;lt;br /&amp;gt;local and national geographical groups.&amp;lt;br /&amp;gt;Raising awareness about Mars, Space Exploration, Solar System and ESA activities among&amp;lt;br /&amp;gt;teachers, students and general public is an important objective of the RoadMap Communication,&amp;lt;br /&amp;gt;Education and Public Outreach plan. We will present some of the EPO activities/tools developed in&amp;lt;br /&amp;gt;RoadMAp. Such is the case e.g. of Mars in a box an educational project aiming to introduce&amp;lt;br /&amp;gt;European secondary school students to fundamental science through cutting-edge research on Mars.&amp;lt;br /&amp;gt;Mars in a box combines the classic &amp;quot;experiment box&amp;quot; format with the power of online applications&amp;lt;br /&amp;gt;and the excitement of accessing, visualising and managing scientific data from cutting-edge space&amp;lt;br /&amp;gt;missions and ground-based laboratories, as well as the possibility of contacting professional&amp;lt;br /&amp;gt;researchers in the field of planetary science.&amp;lt;br /&amp;gt;The RoadMap consortium is composed of the Royal Belgian Institute for Space Aeronomy&amp;lt;br /&amp;gt;(BIRA-IASB, Belgium), Aarhus University (AU, Denmark), the Duisburg &amp;amp; Essen&amp;lt;br /&amp;gt;University (UDE, Germany), the Instituto de Cer&amp;amp;#225;mica y Vidrio (ICV-CSIC, Spain), and the&amp;lt;br /&amp;gt;Instituto de Astrof&amp;amp;#237;sica de Andaluc&amp;amp;#237;a (IAA-CSIC, Spain) belonging to the Spanish Research&amp;lt;br /&amp;gt;Council (CSIC).&amp;lt;/p&amp;gt;</jats:p

Experimental and Theoretical Analysis of the Thiol-Promoted Fragmentation of 2-Halo-3-tosyl-oxanorbornadienes

2-Halo-3-tosyl-oxanorbornadienes are able to accept two thiol molecules through an initial nucleophilic substitution, giving isolable oxabicyclic thiovinyl sulfones that, subsequently, can react with a second thiol molecule via thio-Michael addition. The resulting oxanorbornenic thioketals undergo retro-Diels-Alder (rDA) fragmentation to release a furan derivative and a ketene S,S-acetal. The substitution pattern of the oxanorbornadienic skeleton influences the rate of the rDA through electronic and steric factors examined by quantum mechanical calculations.Ministerio de Ciencia e Innovación PID2020-116460RB-100, PID2021- 125946OB-I00, CEX2021-001136-SJunta de Andalucía P20_00532European Union 67188