HYPERFINE-STRUCTURE IN THE 6SNH (1 = 5) RYDBERG SERIES OF BARIUM

The hyperfine structure in the odd-parity 6snh (9 ≤ n ≤ 40) Rydberg series of barium has been investigated, using a single cw ring dye laser and a beam of neutral atoms in the metastable 5

Bacteriophages a bio sustainable solution to tackle Alzheimer´s disease

Introduction: Amyloid-beta (AB) is a prime suspect to cause Alzheimers disease (AD), an irreversible, progressive and age-dependent neurodegenerative disorder affecting millions of people worldwide. An accumulation of AB in the brain leads to its aggregation into soluble oligomeric and fibrillar clusters, which are the culprits to impair synaptic function and memory formation in mice models. Currently, we lack diagnostic tools to detect AB oligomers (ABOs) in the brain, all the methods used provide a late diagnosis when there are already symptoms. Moreover, the existence of the blood-brain-barrier (BBB) is the major bottleneck for reaching the brain. To overcome this, bacteriophages (phages: bacterial viruses) are a solution, once they posses the capacity to cross the BBB. Aims: Hence, our main goals were the development of a solution to 1) detect ABOs in the brain and monitor AD progression and 2) delay or prevent the onset of the symptoms. Methods: We resorted to phage engineering with AB-targeting peptides described to recognize ABOs and fibrils with high affinity. These were tested for their capacity to detect ABOs in tissues samples and their effect on AB aggregation. Results: The engineered phages are able to detect the early and toxic forms of AB in brain tissue of APP/PS1 transgenic mice and human donors. Moreover, these phages also possess a high therapeutic potential by inhibiting the aggregation process of AB. Conclusion: We provide a highly versatile bio-inspired solution based on phages displaying AB peptides to detect early soluble AB oligomers in the brain, and possibly prevent, or delay, the onset of the symptoms, consequently inhibiting AD progression.The authors thank the Project EARLY - Phage towards initial amyloid-beta funded by TecMinho through the iProof initiative, in the scope of the project UI-Transfer, co-financed by COMPETE 2020, through Fundo Europeu de Desenvolvimento Regional (FEDER). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit, and by LABBELS – Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems, LA/P/0029/2020, center grant UID/MULTI/04046/2020 (to BioISI), PhD fellowship SFRH/BD/101171/2014 (to J.S.C.), and by Alzheimer Nederland (H.W.K.).info:eu-repo/semantics/publishedVersio

M13 phage grafted with peptide motifs as a tool to detect amyloid- oligomers in brain tissue

Oligomeric clusters of amyloid- (A) are one of the major biomarkers for Alzheimers disease (AD). However, proficient methods to detect A-oligomers in brain tissue are lacking. Here we show that synthetic M13 bacteriophages displaying A-derived peptides on their surface preferentially interact with A-oligomers. When exposed to brain tissue isolated from APP/PS1-transgenic mice, these bacteriophages detect small-sized A-aggregates in hippocampus at an early age, prior to the occurrence of A-plaques. Similarly, the bacteriophages reveal the presence of such small A-aggregates in post-mortem hippocampus tissue of ADpatients. These results advocate bacteriophages displaying A-peptides as a convenient and low-cost tool to identify A-oligomers in post-mortem brain tissue of AD-model mice and AD patients.FCT -Fundação para a Ciência e a Tecnologia(SFRH/BD/101171/2014)info:eu-repo/semantics/publishedVersio

Cdx1 and Cdx2 have Overlapping Functions in Anteroposterior Patterning and Posterior Axis Elongation

Mouse Cdx and Hox genes presumably evolved from genes on a common ancestor cluster involved in anteroposterior patterning. Drosophila caudal (cad) is involved in specifying the posterior end of the early embryo, and is essential for patterning tissues derived from the most caudal segment, the analia. Two of the three mouse Cdx paralogues, Cdx 1 and Cdx2, are expressed early in a Hox-like manner in the three germ layers. In the nascent paraxial mesoderm, both genes are expressed in cells contributing first to the most rostral, and then to progressively more caudal parts of the vertebral column. Later, expression regresses from the anterior sclerotomes, and is only maintained for Cdx1 in the dorsal part of the somites, and for both genes in the tail bud. Cdx1 null mutants show anterior homeosis of upper cervical and thoracic vertebrae. Cdx2-null embryos die before gastrulation, and Cdx2 heterozygotes display anterior transformations of lower cervical and thoracic vertebrae. We have analysed the genetic interactions between Cdx1 and Cdx2 in compound mutants. Combining mutant alleles for both genes gives rise to anterior homeotic transformations along a more extensive length of the vertebral column than do single mutations. The most severely affected Cdx1 null/Cdx2 heterozygous mice display a posterior shift of their cranio-cervical, cervico-thoracic, thoraco-lumbar, lumbo-sacral and sacro-caudal transitions. The effects of the mutations in Cdx1 and Cdx2 were co-operative in severity, and a more extensive posterior shift of the expression of three Hox genes was observed in double mutants. The alteration in Hox expression boundaries occurred early. We conclude that both Cdx genes cooperate at early stages in instructing the vertebral progenitors all along the axis, at least in part by setting the rostral expression boundaries of Hox genes. In addition, Cdx mutants transiently exhibit alterations in the extent of Hox expression domains in the spinal cord, reminding of the strong effects of overexpressing Cdx genes on Hox gene expression in the neurectoderm. Phenotypical alterations in the peripheral nervous system were observed at mid-gestation stages. Strikingly, the altered phenotype at caudal levels included a posterior truncation of the tail, mildly affecting Cdx2 heterozygotes, but more severely affecting Cdx1/Cdx2 double heterozygotes and Cdx1 null/Cdx2 heterozygotes. Mutations in Cdx1 and Cdx2 therefore also interfere with axis elongation in a cooperative way. The function of Cdx genes in morphogenetic processes during gastrulation and tail bud extension, and their relationship with the Hox genes are discussed in the light of available data in Amphioxus, C. elegans, Drosophila and mice

Second intravenous immunoglobulin dose in patients with Guillain-Barre syndrome with poor prognosis (SID-GBS):a double-blind, randomised, placebo-controlled trial

Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (>= 12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of >= 6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1.4 (95% CI 0.6-3.3; p=0.45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products. Copyright (C) 2021 Elsevier Ltd. All rights reserved