RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral RNA. We identified potent lipophilic small interfering RNA (siRNA) conjugates targeting highly conserved regions of SARS-CoV-2 outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single siRNA approach.
View Article and Find Full Text PDFObjectives: We tested abortion messaging to develop evidence-based communication recommendations for doctors who provide abortion care.
Study Design: We conducted an online survey in a nationally representative sample of 1215 people, using National Opinion Research Center's Amerispeak Panel. We surveyed participants before and after viewing two brief videos featuring doctors who provide abortion care speaking about their work.
The global energy budget is pivotal to understanding planetary evolution and climate behaviors. Assessing the energy budget of giant planets, particularly those with large seasonal cycles, however, remains a challenge without long-term observations. Evolution models of Saturn cannot explain its estimated Bond albedo and internal heat flux, mainly because previous estimates were based on limited observations.
View Article and Find Full Text PDFAsteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky-O'Keefe-Radzievskii-Paddack effect) to be a notable factor in their evolution. (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 AU; its S-type spectrum is typical of bodies in this part of the main belt.
View Article and Find Full Text PDFGivosiran (trade name GIVLAARI) is a small interfering ribonucleic acid that targets hepatic delta-aminolevulinic acid synthase 1 (ALAS1) messenger RNA for degradation through RNA interference (RNAi) that has been approved for the treatment of acute hepatic porphyria (AHP). RNAi therapeutics, such as givosiran, have a low liability for drug-drug interactions (DDIs) because they are not metabolized by cytochrome 450 (CYP) enzymes, and do not directly inhibit or induce CYP enzymes in the liver. The pharmacodynamic effect of givosiran (lowering of hepatic ALAS1, the first and rate limiting enzyme in the heme biosynthesis pathway) presents a unique scenario where givosiran could potentially impact heme-dependent activities in the liver, such as CYP enzyme activity.
View Article and Find Full Text PDFAcute hepatic porphyria (AHP) is a family of rare, serious, and potentially life-threatening metabolic disorders caused by mutations in genes encoding enzymes involved in hepatic heme biosynthesis. AHP is characterized by accumulation of neurotoxic heme intermediates, δ-aminolevulinic acid (ALA), and porphobilinogen (PBG), which are thought to be causal for the disease manifestations. Novel therapeutic treatments such as givosiran, an RNA interference therapeutic that was recently approved for treatment of adults with AHP, are focused on reducing the levels of ALA and PBG in patients toward levels observed in a healthy population.
View Article and Find Full Text PDFAsteroid (101955) Bennu is a dark asteroid on an Earth-crossing orbit that is thought to have assembled from the fragments of an ancient collision. We use spatially resolved visible and near-infrared spectra of Bennu to investigate its surface properties and composition. In addition to a hydrated phyllosilicate band, we detect a ubiquitous 3.
View Article and Find Full Text PDFIn the first 20 orbits of the Juno spacecraft around Jupiter, we have identified a variety of wave-like features in images made by its public-outreach camera, JunoCam. Because of Juno's unprecedented and repeated proximity to Jupiter's cloud tops during its close approaches, JunoCam has detected more wave structures than any previous surveys. Most of the waves appear in long wave packets, oriented east-west and populated by narrow wave crests.
View Article and Find Full Text PDFBackground: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.
Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.
Givosiran is a small interfering ribonucleic acid agent that was recently approved in the United States for the treatment of acute hepatic porphyria (AHP). This phase I study evaluated the safety, pharmacokinetic, and pharmacodynamic profile of subcutaneously (SC) administered givosiran in patients with acute intermittent porphyria, the most common AHP type. Givosiran was rapidly absorbed from the SC injection site with peak plasma concentrations achieved within 0.
View Article and Find Full Text PDFThe United States Public Health Service National Clinical Pharmacy Specialist Committee issues a report on the impact of pharmacy-managed clinics across the Bureau of Prisons, Immigration and Customs Enforcement, Indian Health Service, and US Coast Guard.
View Article and Find Full Text PDFBackground And Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.
View Article and Find Full Text PDFBackground: Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis.
Methods: We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria.
Small-scale waves were observed along the boundary between Jupiter's North Equatorial Belt and North Tropical Zone, ~16.5° N planetographic latitude in Hubble Space Telescope data in 2012 and throughout 2015 to 2018, observable at all wavelengths from the UV to the near IR. At peak visibility, the waves have sufficient contrast (~10%) to be observed from ground-based telescopes.
View Article and Find Full Text PDFObjective: Acute intermittent porphyria is a rare metabolic disorder that affects heme synthesis. Patients with acute intermittent porphyria may experience acute debilitating neurovisceral attacks that require frequent hospitalizations and negatively impact quality of life. Although clinical aspects of acute intermittent porphyria attacks have been documented, the experience of patients is not well known, particularly for those more severely affected patients who experience frequent attacks.
View Article and Find Full Text PDFIn October and November 2014, spectra covering the 1.436 - 1.863-μm wavelength range from the SINFONI Integral Field Unit Spectrometer on the Very Large Telescope showed the presence of a vast bright North polar cap on Uranus, extending northward from about 40°N and at all longitudes observed.
View Article and Find Full Text PDFObservations of Neptune with the Space Telescope yield a 49 day light curve with 98% coverage at a 1 minute cadence. A significant signature in the light curve comes from discrete cloud features. We compare results extracted from the light curve data with contemporaneous disk-resolved imaging of Neptune from the Keck 10-m telescope at 1.
View Article and Find Full Text PDFBackground: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.
Methods: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated.
J Geophys Res Planets
September 2016
We use observations from the Imaging Science Subsystem on Cassini to create maps of Saturn's Northern Hemisphere (NH) from 2008 to 2015, a time period including a seasonal transition (i.e., Spring Equinox in 2009) and the 2010 giant storm.
View Article and Find Full Text PDFThe acute hepatic porphyrias are caused by inherited enzymatic deficiencies in the heme biosynthesis pathway. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) by triggers such as fasting or drug exposure can lead to accumulation of neurotoxic heme intermediates that cause disease symptoms. We have demonstrated that hepatic ALAS1 silencing using siRNA in a lipid nanoparticle effectively prevents and treats induced attacks in a mouse model of acute intermittent porphyria.
View Article and Find Full Text PDFBackground: Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo.
Methods: We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS.
Hemophilia A and B are inherited bleeding disorders characterized by deficiencies in procoagulant factor VIII (FVIII) or factor IX (FIX), respectively. There remains a substantial unmet medical need in hemophilia, especially in patients with inhibitory antibodies against replacement factor therapy, for novel and improved therapeutic agents that can be used prophylactically to provide effective hemostasis. Guided by reports suggesting that co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, we developed an RNA interference (RNAi) therapeutic (ALN-AT3) targeting antithrombin (AT) as a means to promote hemostasis in hemophilia.
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