Heparins Sourced From Bovine and Porcine Mucosa Gain Exclusive Monographs in the Brazilian Pharmacopeia

Most of the unfractionated heparin (UFH) consumed worldwide is manufactured using porcine mucosa as raw material (HPI); however, some countries also employ products sourced from bovine mucosa (HBI) as interchangeable versions of the gold standard HPI. Although accounted as a single UFH, HBI, and HPI have differing anticoagulant activities (~100 and 200 IU mg−1, respectively) because of their compositional dissimilarities. The concomitant use of HBI and HPI in Brazil had already provoked serious bleeding incidents, which led to the withdrawal of HBI products in 2009. In 2010, the Brazilian Pharmacopeia (BP) formed a special committee to develop two complementary monographs approaching HBI and HPI separately, as distinct active pharmaceutical ingredients (APIs). The committee has rapidly agreed on requirements concerning the composition and presence of contaminants based on nuclear magnetic resonance and anion-exchange chromatography. On the other hand, consensus on the anticoagulant activity of HBI was the subject of long and intense discussions. Nevertheless, the committee has ultimately agreed to recommend minimum anti-FIIa activities of 100 IU mg−1 for HBI and 180 IU mg−1 for HPI. Upon the approval by the Brazilian Health Authority (ANVISA), the BP published the new monographs for HPI and HBI APIs in 2016 and 2017, respectively. These pioneer monographs represent a pivotal step toward the safest use of HBI and HPI as interchangeable anticoagulants and serve as a valuable template for the reformulation of pharmacopeias of other countries willing to introduce HBI

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Debate propositivo sobre os biossimilares de enoxaparina no Brasil

Algumas patentes das heparinas de baixo peso molecular expiraram e outras estão vencendo. Versões biossimilares desses fármacos estão disponíveis para o uso clínico em vários países. Entretanto, ainda persiste ceticismo sobre a possibilidade de se obter preparações semelhantes ao medicamento original em razão do complexo processo para gerar heparina de baixo peso molecular. Nosso laboratório analisou, nos últimos anos, amostras de enoxaparina disponíveis para uso clínico no Brasil. Já analisamos 30 lotes distintos e 70 produtos acabados. Essas preparações foram avaliadas quanto à estrutura química, distribuição de peso molecular, atividade anticoagulante in vitro e efeitos farmacológicos em modelos animais de trombose e sangramento. Claramente, nossos resultados indicam que as preparações biossimilares de enoxaparina são semelhantes ao medicamento original. Nossos resultados indicam que essas versões biossimilares de enoxaparina são uma alternativa terapêutica válida, mas que requerem regulamentação adequada para assegurar o atendimento de requisitos regulatórios apropriados

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

PM20D1 is a quantitative trait locus associated with Alzheimer’s disease

The chances to develop Alzheimer’s disease (AD) result from a combination of genetic and non-genetic risk factors1, the latter likely being mediated by epigenetic mechanisms2. In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology3, but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS4. Here, combining both approaches, we report a previously unidentified association of the peptidase M20-domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation and expression quantitative trait locus coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increased following AD-related neurotoxic insults at symptomatic stages in the APP/PS1 mouse model of AD and in human patients with AD who are carriers of the non-risk haplotype. In line, genetically increasing or decreasing the expression of PM20D1 reduces and aggravates AD-related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD

MOONS: a multi-object optical and near-infrared spectrograph for the VLT

International audienceMOONS is a new conceptual design for a Multi-Object Optical and Near-infrared Spectrograph for the Very Large Telescope (VLT), selected by ESO for a Phase A study. The baseline design consists of ~1000 fibers deployable over a field of view of ~500 square arcmin, the largest patrol field offered by the Nasmyth focus at the VLT. The total wavelength coverage is 0.8mum-1.8mum and two resolution modes: medium resolution and high resolution. In the medium resolution mode (R~4,000-6,000) the entire wavelength range 0.8mum-1.8mum is observed simultaneously, while the high resolution mode covers simultaneously three selected spectral regions: one around the CaII triplet (at R~8,000) to measure radial velocities, and two regions at R~20,000 one in the J-band and one in the H-band, for detailed measurements of chemical abundances. The grasp of the 8.2m Very Large Telescope (VLT) combined with the large multiplex and wavelength coverage of MOONS - extending into the near-IR - will provide the observational power necessary to study galaxy formation and evolution over the entire history of the Universe, from our Milky Way, through the redshift desert and up to the epoch of re-ionization at