CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.

Broad-Scale Patterns of Late Jurassic Dinosaur Paleoecology

There have been numerous studies on dinosaur biogeographic distribution patterns. However, these distribution data have not yet been applied to ecological questions. Ecological studies of dinosaurs have tended to focus on reconstructing individual taxa, usually through comparisons to modern analogs. Fewer studies have sought to determine if the ecological structure of fossil assemblages is preserved and, if so, how dinosaur communities varied. Climate is a major component driving differences between communities. If the ecological structure of a fossil locality is preserved, we expect that dinosaur assemblages from similar environments will share a similar ecological structure.This study applies Ecological Structure Analysis (ESA) to a dataset of 100+ dinosaur taxa arranged into twelve composite fossil assemblages from around the world. Each assemblage was assigned a climate zone (biome) based on its location. Dinosaur taxa were placed into ecomorphological categories. The proportion of each category creates an ecological profile for the assemblage, which were compared using cluster and principal components analyses. Assemblages grouped according to biome, with most coming from arid or semi-arid/seasonal climates. Differences between assemblages are tied to the proportion of large high-browsing vs. small ground-foraging herbivores, which separates arid from semi-arid and moister environments, respectively. However, the effects of historical, taphonomic, and other environmental factors are still evident.This study is the first to show that the general ecological structure of Late Jurassic dinosaur assemblages is preserved at large scales and can be assessed quantitatively. Despite a broad similarity of climatic conditions, a degree of ecological variation is observed between assemblages, from arid to moist. Taxonomic differences between Asia and the other regions demonstrate at least one case of ecosystem convergence. The proportion of different ecomorphs, which reflects the prevailing climatic and environmental conditions present during fossil deposition, may therefore be used to differentiate Late Jurassic dinosaur fossil assemblages. This method is broadly applicable to different taxa and times, allowing one to address questions of evolutionary, biogeographic, and climatic importance

Jim Carrigan Observatory and directional drilling in Alaska

External field variations, such as those observed in one-minute observatory data are sources of error for magnetic down-hole survey tools used in directional drilling. These tools, which include magnetic probes, are used in measurement while drilling (MWD) methods to monitor the well-bore position and navigate to the planned oil or gas target. Significant deviations from the well plan can be avoided by using measurements from magnetic observatories to correct the surveys. In order to support directional drilling operations in Prudhoe Bay, Alaska, Jim Carrigan Observatory (JCO) was established in 1997 as a joint venture between science and industry and has operated to meet drilling needs ever since. The site was chosen to be as near to the well positions as possible providing the necessary data to combine the measured external field variations with global and crustal field models and thus provide accurate reference values for well-bore surveys in real time. We describe the JCO operations and developments made to help counteract the extreme weather conditions and other difficulties associated with its’ high latitude location. The data processing and quality control procedures required to enable the use of JCO data for real time MWD operations are discussed and examples of their use by industry are shown. We also present a summary of the JCO results since 2003, when the observatory was upgraded to the same standard as the other BGS operated observatories. We discuss the quality of these results and the potential for use of them in scientific studies

Major flood disturbance alters river ecosystem evolution

Floods, major formative drivers of channel and floodplain structure and associated riparian and in-stream communities, are increasing in intensity and magnitude with climate change in many regions of the world. However, predicting how floods will affect stream channels and their communities as climate changes is limited by a lack of long-term pre-flood baseline data sets across different organismal groups. Here we show salmon, macroinvertebrate and meiofauna communities, monitored for 30 years in a system evolving owing to glacier retreat, were modified significantly by a major rainfall event that caused substantial geomorphic change to the stream channel. Pink salmon, reduced to one-tenth of pre-flood spawner densities, recovered within two generations. Macroinvertebrate community structure was significantly different after the flood as some pioneer taxa, which had become locally extinct, recolonized whereas some later colonizers were eliminated. The trajectory of the macroinvertebrate succession was reset towards the community structure of 15 years earlier. Meiofaunal abundance recovered rapidly and richness increased post-flood with some previously unrecorded taxa colonizing. Biotic recovery was independent of geomorphological recovery. Markedly different responses according to the organismal group suggest caution is required when applying general aquatic ecosystem theories and concepts to predict flood events

NATO/CCMS Pilot study workshop on air pollution trarfsport and diffusion over coastal urban areas

The NATO/CCMS Pilot Study "Air pollution transport and diffusion over coastal urban areas" held an international workshop in Athens, 3-5 May 1993. The objective of this workshop was to develop guidelines for it reference experiment in a coastal urban area. It was intended that the guidelines would be sufficiently general that they could be applied to any coastal urban area, but Athens was bome in mind as a suitable candidate location. On the first day of the workshop, invited speakers delivered their lectures on different issues of dispersion in urban coastal areas. The second day was devoted to discussions in working groups focusing on key issues, such as, emissions' inventory, meteorological measurements, surface pollutant concentration measurements, aircraft measurements, remote sensing and model evaluation. On the final half-day the rapporteur from each working group reported on its work. Their reports are briefly summarized in the present paper. © 1995