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"Gay, P"
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Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials
Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321,
n
= 17) and advanced solid tumors (NCT03291938,
n
= 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.
A mitochondrial complex I inhibitor exhibited dose-limiting toxicities, including neurotoxicity, in patients with acute myeloid leukemia and solid tumors, warranting further studies to evaluate the mechanism linking oxidative phosphorylation inhibition and neurotoxicity.
Journal Article
The geology and geophysics of Kuiper Belt object (486958) Arrokoth
The Cold Classical Kuiper Belt, a class of small bodies in undisturbed orbits beyond Neptune, is composed of primitive objects preserving information about Solar System formation. In January 2019, the New Horizons spacecraft flew past one of these objects, the 36-kilometer-long contact binary (486958) Arrokoth (provisional designation 2014 MU₆₉). Images from the flyby show that Arrokoth has no detectable rings, and no satellites (larger than 180 meters in diameter) within a radius of 8000 kilometers. Arrokoth has a lightly cratered, smooth surface with complex geological features, unlike those on previously visited Solar System bodies. The density of impact craters indicates the surface dates from the formation of the Solar System. The two lobes of the contact binary have closely aligned poles and equators, constraining their accretion mechanism.
Journal Article
Leaf Area Index evaluation in vineyards using 3D point clouds from UAV imagery
The Leaf Area Index (LAI) is an ecophysiology key parameter characterising the canopy-atmosphere interface where most of the energy fluxes are exchanged. However, producing maps for managing the spatial and temporal variability of LAI in large croplands with traditional techniques is typically laborious and expensive. The objective of this paper is to evaluate the reliability of LAI estimation by processing dense 3D point clouds as a cost-effective alternative to traditional LAI assessments. This would allow for high resolution, extensive and fast mapping of the index, even in hilly and not easily accessible regions. In this setting, the 3D point clouds were generated from UAV-based multispectral imagery and processed by using an innovative methodology presented here. The LAI was estimated by a multivariate linear regression model using crop canopy descriptors derived from the 3D point cloud, which account for canopy thickness, height and leaf density distribution along the wall. For the validation of the estimated LAI, an experiment was conducted in a vineyard in Piedmont: the leaf area of 704 vines was manually measured by the inclined point quadrant approach and six UAV flights were contextualLy performed to acquire the aerial images. The vineyard LAI estimated by the proposed methodology showed to be correlated with the ones obtained by the traditional manual method. Indeed, the obtained R2 value of 0.82 can be considered fully adequate, compatible to the accuracy of the reference LAI manual measurement.
Journal Article
Crater Population on Asteroid (101955) Bennu Indicates Impact Armouring and a Young Surface
The impactor-to-crater size scaling relationships that enable estimates of planetary surface ages rely on an accurate formulation of impactor–target physics. An armouring regime, specific to rubble-pile surfaces, has been proposed to occur when an impactor is comparable in diameter to a target surface particle (for example, a boulder). Armouring is proposed to reduce crater diameter, or prevent crater formation in the asteroid surface, at small crater diameters. Here, using measurements of 1,560 craters on the rubble-pile asteroid (101955) Bennu, we show that the boulder population controls a transition from crater formation to armouring at crater diameters ~2–3 m, below which crater formation in the bulk surface is increasingly rare. By combining estimates of impactor flux with the armouring scaling relationship, we find that Bennu’s crater retention age (surface age derived from crater abundance) spans from 1.6–2.2 Myr for craters less than a few meters to ~10–65 Myr for craters >100 m in diameter, reducing the maximum surface age by a factor of >15 relative to previous estimates. The range of crater retention ages, together with latitudinal variations in large-crater spatial density, indicate that ongoing resurfacing processes render the surface many times younger than the bulk asteroid.
Journal Article
PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.
Statement of significance
PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.
Arginine methylation by PRMTs is dysregulated in cancer. Here, the authors use functional genomics screens and identify PRMT1 as a vulnerability in pancreatic ductal adenocarcinoma, and further show that PRMT1 regulates RNA metabolism and coordinates expression of genes in cell cycle progression, maintaining genomic stability and tumour growth.
Journal Article
Combining high-throughput micro-CT-RGB phenotyping and genome-wide association study to dissect the genetic architecture of tiller growth in rice
Manual phenotyping of rice tillers is time consuming and labor intensive, and lags behind the rapid development of rice functional genomics. Thus, automated, non-destructive methods of phenotyping rice tiller traits at a high spatial resolution and high throughput for large-scale assessment of rice accessions are urgently needed. In this study, we developed a high-throughput micro-CT-RGB imaging system to non-destructively extract 739 traits from 234 rice accessions at nine time points. We could explain 30% of the grain yield variance from two tiller traits assessed in the early growth stages. A total of 402 significantly associated loci were identified by genome-wide association study, and dynamic and static genetic components were found across the nine time points. A major locus associated with tiller angle was detected at time point 9, which contained a major gene, TAC1. Significant variants associated with tiller angle were enriched in the 3ʹ-untranslated region of TAC1. Three haplotypes for the gene were found, and rice accessions containing haplotype H3 displayed much smaller tiller angles. Further, we found two loci containing associations with both vigor-related traits identified by high-throughput micro-CT-RGB imaging and yield. The superior alleles would be beneficial for breeding for high yield and dense planting.
Journal Article
Depth Dependent Deformation and Anisotropy of Pyrolite in the Earth's Lower Mantle
Seismic anisotropy is a powerful tool to map deformation processes in the deep Earth. Below 660 km, however, observations are scarce and conflicting. In addition, the underlying crystal scale mechanisms, leading to microstructures and crystal orientations, remain poorly constrained. Here, we use multigrain X‐ray diffraction in the laser‐heated diamond anvil cell to investigate the orientations of hundreds of grains in pyrolite, a model composition of the Earth's mantle, at in situ pressure and temperature. Bridgmanite in pyrolite exhibits three regimes of microstructures, due to transformation and deformation at low and high pressure. These microstructures result in predictions of 1.5%–2% shear wave splitting between 660 and 2,000 km with reversals in fast S‐wave polarization direction at about 1,300 km depth. Anisotropy can develop in pyrolite at lower mantle conditions, but pressure has a significant impact on the plastic behavior of bridgmanite, and hence seismic observations, which may explain conflicting anisotropy observations. Plain Language Summary Seismologists rely on observable data to construct models that describe the dynamic state of the Earth's lower mantle. These models, however, require constraints such as mantle composition and material behavior at high pressures and temperatures, which can be provided through experimental mineral physics. In this study, we use a high pressure devices and X‐rays to impose deformation and image the state of our sample with increasing pressure and temperature. We are able to extract information of individual mineral grains within our assemblage, such as the number of grains per phase and their orientations. Using this experimental data, we identify three regimes of grain orientations in bridgmanite in the lower mantle, corresponding to transformation from lower pressure phases, and deformation at low and high pressure. With this information, we are able to make predictions about how seismic waves travel and behave based on the deformation state of the lower mantle. Key Points Three microstructure/anisotopy regimes in bridgmanite in the Earth's lower mantle: transformation, low‐P deformation, high‐P deformation Effect of pressure on the active slip systems of bridgmanite with a shift at approximately 50 GPa or 1,300 km depth in the Earth's mantle Up to 2% shear wave splitting predicted at all depth with changes in fast polarization direction for each microstructural regime
Journal Article