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"Messengers."
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A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus
Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 (
NCT03829384
). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18–50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg
−1
, or two weekly doses at 0.3 mg kg
−1
. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml
−1
) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg
−1
(mean t
1/2
approximately 69 d). A second 0.3 mg kg
−1
dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.
An mRNA-based therapeutic can drive expression of a functional antibody in humans at levels capable of neutralizing Chikungunya virus ex vivo.
Journal Article
The diamond of Darkhold
When a roamer trades them an ancient book with only a few pages remaining, Lina and Doon return to Ember to seek the machine the book seems to describe in hopes that it will get their new community, Sparks, through the winter.
Book
Human 5′ UTR design and variant effect prediction from a massively parallel translation assay
The ability to predict the impact of cis-regulatory sequences on gene expression would facilitate discovery in fundamental and applied biology. Here we combine polysome profiling of a library of 280,000 randomized 5′ untranslated regions (UTRs) with deep learning to build a predictive model that relates human 5′ UTR sequence to translation. Together with a genetic algorithm, we use the model to engineer new 5′ UTRs that accurately direct specified levels of ribosome loading, providing the ability to tune sequences for optimal protein expression. We show that the same approach can be extended to chemically modified RNA, an important feature for applications in mRNA therapeutics and synthetic biology. We test 35,212 truncated human 5′ UTRs and 3,577 naturally occurring variants and show that the model predicts ribosome loading of these sequences. Finally, we provide evidence of 45 single-nucleotide variants (SNVs) associated with human diseases that substantially change ribosome loading and thus may represent a molecular basis for disease.
Journal Article
Blackveil
Legendary Green Rider Karigan G'ladheon--one of the magical messengers of the king--defends her king and fellow riders from an insurrection led by dark magicians that threatens to break the boundaries of ancient, evil Blackveil Forest--releasing powerful dark magics that have been shut away for a millennium.
Book
Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis
The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study (
NCT04405076
) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (
n
= 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (
P
< 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (
P
< 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing.
Preliminary and exploratory analyses show that a third dose of the COVID-19 vaccine mRNA-1273 or variant-modified boosters can boost levels of neutralizing antibodies against SARS-CoV-2 variants.
Journal Article
Firebrand
\"Zachary Davriel Hillander, High King of Sacoridia, rues how much he has had to give up to lead his realm, including the freedom to live and love as he chooses. When an embassy from Eletia arrives to propose a joint venture between their realms to seek out an old ally in the north, he is dismayed to learn that the one Sacoridian they have in mind to accompany their guide is the woman he truly loves but cannot have: Green Rider Karigan G'ladheon. Karigan has only just returned from a dark future where Sacoridia has been conquered and is ruled by a despotic emperor, and she has not recovered in heart or mind. As if that is not enough, the castle ghosts won't leave her alone. Though Zachary is loath to part from her so soon after her return, he knows she is the best choice to undertake the mission to the north. Each step on their journey places Karigan and her companions closer to enemy territory and danger, for northward lie the forces of Second Empire, Sacoridia's longtime foe, and Grandmother, the necromantic leader of Second Empire, has not been idle. She uses her magic to summon a wild elemental spirit to wreak havoc upon Zachary and his wife, Queen Estora. At first the Sacoridians succeed in fending off the creature, but it so covets Estora that it can't stay away. It abducts Zachary, assuming his form and his place at Estora's side--but when it is finally ousted, Zachary is still missing. Estora, alone and heavy with twins, must prepare her realm for the coming conflict from the confines of her bedchamber. Meanwhile, the danger only deepens for Karigan and her companions as they journey north. When she finds herself caught in the midst of a clash between forces, Karigan must rescue and protect her king before she falls into a trap set by Grandmother--a trap that could give Second Empire the power to control the dead and all the demons of the hells\" -- provided by publisher.
Book
Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy
In this phase 3 trial, among infants with spinal muscular atrophy, those who received nusinersen were more likely to achieve major motor milestones and less likely to need permanent assisted ventilation than those who underwent a sham procedure.
Journal Article
The dream gatherer : a green rider novella and other stories
\"In The Dream Gatherer, Kristen Britain presents a novella and two short stories set in the universe of her best selling Green Rider series in celebration of the twentieth anniversary of the publication of her first novel, Green Rider.\"--Amazon.
Book
Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses
Recently, the World Health Organization confirmed 120 new human cases of avian H7N9 influenza in China resulting in 37 deaths, highlighting the concern for a potential pandemic and the need for an effective, safe, and high-speed vaccine production platform. Production speed and scale of mRNA-based vaccines make them ideally suited to impede potential pandemic threats. Here we show that lipid nanoparticle (LNP)-formulated, modified mRNA vaccines, encoding hemagglutinin (HA) proteins of H10N8 (A/Jiangxi-Donghu/346/2013) or H7N9 (A/Anhui/1/2013), generated rapid and robust immune responses in mice, ferrets, and nonhuman primates, as measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays. A single dose of H7N9 mRNA protected mice from a lethal challenge and reduced lung viral titers in ferrets. Interim results from a first-in-human, escalating-dose, phase 1 H10N8 study show very high seroconversion rates, demonstrating robust prophylactic immunity in humans. Adverse events (AEs) were mild or moderate with only a few severe and no serious events. These data show that LNP-formulated, modified mRNA vaccines can induce protective immunogenicity with acceptable tolerability profiles.
Potential pandemic influenzas and the need for an effective, safe, and high-speed vaccine production platform have been widely discussed in the scientific community. Bahl et al. report the rapid and robust immune responses achieved against H10N8 and H7N9 viruses from modified mRNA vaccines with an acceptable safety profile.
Journal Article