Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.

The inhibition of mutant KRAS proteins has emerged as a promising approach for treating KRAS-driven cancers, as evidenced by the clinical success of KRAS G12C inhibitors. KRAS G12D, the most common mutant, promises significant expansion of the addressable patient population; however, the reduced nucleophilicity of aspartate compared to cysteine poses significant challenges in balancing sufficient potency with ADME properties to support oral exposure. Herein, we describe the discovery of KRAS G12D inhibitor (), which achieves oral exposure in nonhuman primate (NHP).

Diverse microbiome functions, limited temporal variation and substantial genomic conservation within sedimentary and granite rock deep underground research laboratories.

Background: Underground research laboratories (URLs) provide a window on the deep biosphere and enable investigation of potential microbial impacts on nuclear waste, CO and H stored in the subsurface. We carried out the first multi-year study of groundwater microbiomes sampled from defined intervals between 140 and 400 m below the surface of the Horonobe and Mizunami URLs, Japan.

Results: We reconstructed draft genomes for > 90% of all organisms detected over a four year period.

A multicontinental dataset of butterfly thermal physiological traits.

Butterflies serve as key indicators of climate change impacts such as shifts in emergence timing and shifts in geographic range and distribution. However, the development of commonly used ecological forecasts based on butterfly physiological tolerance of temperature change has lagged behind that of other taxonomic groups. Here, we provide a series of related datasets comprising butterfly thermal physiological traits to enable such forecasts.

Effects of Salt Concentration on a Magnetic Nanoparticle-Based Aggregation Assay with a Tunable Dynamic Range.

Magnetic nanoparticles (MNPs) can be functionalized with antibodies to give them an affinity for a biomarker of interest. Functionalized MNPs (fMNPs) cluster in the presence of a multivalent target, causing a change in their magnetization. Target concentration can be proportional to the 3rd harmonic phase of the fMNP magnetization signal.

Hypophosphatemia Correction Reduces ICANS Incidence and Duration in CAR T-cell Therapy: A Pooled Clinical Trial Analysis.

Unlabelled: A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020.

Desiccated Cyanobacteria Serve As Efficient Plasmid DNA Carriers in Space Flight.

Effective transport of biological systems as cargo during space travel is a critical requirement to use synthetic biology and biomanufacturing in outer space. Bioproduction using microbes will drive the extent to which many human needs can be met in environments with limited resources. Vast repositories of biological parts and strains are available to meet this need, but their on-site availability requires effective transport.

Perception of wide-expanse symmetric patterns.

Humans are remarkably proficient at the task of distinguishing between symmetric and non-symmetric visual patterns. The neural mechanisms underlying this ability are still unclear. Here we examine symmetry perception along a dimension that can help place some constraints on the nature of these mechanisms.

Single-fly genome assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life.

Long-read sequencing is driving rapid progress in genome assembly across all major groups of life, including species of the family Drosophilidae, a longtime model system for genetics, genomics, and evolution. We previously developed a cost-effective hybrid Oxford Nanopore (ONT) long-read and Illumina short-read sequencing approach and used it to assemble 101 drosophilid genomes from laboratory cultures, greatly increasing the number of genome assemblies for this taxonomic group. The next major challenge is to address the laboratory culture bias in taxon sampling by sequencing genomes of species that cannot easily be reared in the lab.

Local climate change velocities and evolutionary history explain multidirectional range shifts in a North American butterfly assemblage.

Species are often expected to shift their distributions either poleward or upslope to evade warming climates and colonise new suitable climatic niches. However, from 18-years of fixed transect monitoring data on 88 species of butterfly in the midwestern United States, we show that butterflies are shifting their centroids in all directions, except towards regions that are warming the fastest (southeast). Butterflies shifted their centroids at a mean rate of 4.

Coexistence of Nonequilibrium Density and Equilibrium Energy Distribution of Quasiparticles in a Superconducting Qubit.

The density of quasiparticles typically observed in superconducting qubits exceeds the value expected in equilibrium by many orders of magnitude. Can this out-of-equilibrium quasiparticle density still possess an energy distribution in equilibrium with the phonon bath? Here, we answer this question affirmatively by measuring the thermal activation of charge-parity switching in a transmon qubit with a difference in superconducting gap on the two sides of the Josephson junction. We then demonstrate how the gap asymmetry of the device can be exploited to manipulate its parity.

Impact of early visual experience on later usage of color cues.

Human visual recognition is remarkably robust to chromatic changes. In this work, we provide a potential account of the roots of this resilience based on observations with 10 congenitally blind children who gained sight late in life. Several months or years following their sight-restoring surgeries, the removal of color cues markedly reduced their recognition performance, whereas age-matched normally sighted children showed no such decrement.

Evidence of plasticity, but not evolutionary divergence, in the thermal limits of a highly successful urban butterfly.

Despite the generally negative impact of urbanization on insect biodiversity, some insect species persist in urban habitats. Understanding the mechanisms underpinning the ability of insects to tolerate urban habitats is critical given the contribution of land-use change to the global insect decline. Compensatory mechanisms such as phenotypic plasticity and evolutionary change in thermal physiological traits could allow urban populations to persist under the altered thermal regimes of urban habitats.

Development of a Self-Report Measure of Prediction in Daily Life: The Prediction-Related Experiences Questionnaire.

Purpose: Predictions are complex, multisensory, and dynamic processes involving real-time adjustments based on environmental inputs. Disruptions to prediction abilities have been proposed to underlie characteristics associated with autism. While there is substantial empirical literature related to prediction, the field lacks a self-assessment measure of prediction skills related to daily tasks.

Physiology Evolves Convergently but Lags Behind Warming in Cities.

Cities, through the generation of urban heat islands, provide a venue for exploring contemporary convergent evolution to climatic warming. We quantified how repeatable the evolution of heat tolerance, cold tolerance, and body size was among diverse lineages in response to urban heat islands. Our study revealed significant shifts toward higher heat tolerance and diminished cold tolerance among urban populations.

Bringing traits back into the equation: A roadmap to understand species redistribution.

Ecological and evolutionary theories have proposed that species traits should be important in mediating species responses to contemporary climate change; yet, empirical evidence has so far provided mixed evidence for the role of behavioral, life history, or ecological characteristics in facilitating or hindering species range shifts. As such, the utility of trait-based approaches to predict species redistribution under climate change has been called into question. We develop the perspective, supported by evidence, that trait variation, if used carefully can have high potential utility, but that past analyses have in many cases failed to identify an explanatory value for traits by not fully embracing the complexity of species range shifts.

Next generation microfluidics: fulfilling the promise of lab-on-a-chip technologies.

Microfluidic lab-on-a-chip technologies enable the analysis and manipulation of small fluid volumes and particles at small scales and the control of fluid flow and transport processes at the microscale, leading to the development of new methods to address a broad range of scientific and medical challenges. Microfluidic and lab-on-a-chip technologies have made a noteworthy impact in basic, preclinical, and clinical research, especially in hematology and vascular biology due to the inherent ability of microfluidics to mimic physiologic flow conditions in blood vessels and capillaries. With the potential to significantly impact translational research and clinical diagnostics, technical issues and incentive mismatches have stymied microfluidics from fulfilling this promise.

Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity.

Fluorescent peptide for detecting factor XIIIa activity and fibrin in whole blood clots forming under flow.

Background: During clotting, thrombin generates fibrin monomers and activates plasma-derived transglutaminase factor (F) XIIIa; collagen and thrombin-activated platelets offer thrombin-independent cellular FXIIIa (cFXIIIa) for clotting. Detecting fibrin on collagen and tissue factor surfaces in whole blood clotting typically uses complex reagents like fluorescent fibrinogen or antifibrin antibody.

Objectives: We want to test whether the peptide using the α2- antiplasmin crosslinking mechanism by FXIIIa is a useful tool in both monitoring FXIIIa activity, and visualize and monitor fibrin formation, deposition, and extent of crosslinking within fibrin structures in whole blood clots formed under flow.

Single-fly assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life.

Long-read sequencing is driving rapid progress in genome assembly across all major groups of life, including species of the family Drosophilidae, a longtime model system for genetics, genomics, and evolution. We previously developed a cost-effective hybrid Oxford Nanopore (ONT) long-read and Illumina short-read sequencing approach and used it to assemble 101 drosophilid genomes from laboratory cultures, greatly increasing the number of genome assemblies for this taxonomic group. The next major challenge is to address the laboratory culture bias in taxon sampling by sequencing genomes of species that cannot easily be reared in the lab.

Vitamin interdependencies predicted by metagenomics-informed network analyses and validated in microbial community microcosms.

Metagenomic or metabarcoding data are often used to predict microbial interactions in complex communities, but these predictions are rarely explored experimentally. Here, we use an organism abundance correlation network to investigate factors that control community organization in mine tailings-derived laboratory microbial consortia grown under dozens of conditions. The network is overlaid with metagenomic information about functional capacities to generate testable hypotheses.

Life cycle complexity and body mass drive erratic changes in climate vulnerability across ontogeny in a seasonally migrating butterfly.

Physiological traits are often used for vulnerability assessments of organismal responses to climate change. Trait values can change dramatically over the life cycle of organisms but are typically assessed at a single developmental stage. Reconciling ontogenetic changes in physiological traits with vulnerability assessments often reveals early life-stage vulnerabilities.

Tourniquet Use in Extremity-Based Microsurgery.

Background:  The use of tourniquets and their role in extremity-based microsurgery has not been thoroughly investigated. The purpose of this study was to investigate tourniquet use and its associated outcomes and complications. The authors hypothesize that tourniquets enhance visualization, bloodless approaches to vessel harvest, flap elevation, and anastomosis without added complications.

The use of abdominal wall tissue expansion prior to herniorrhaphy in massive ventral hernia defects.

Background: Massive ventral hernias pose a challenging reconstructive problem. In comparison to bridging mesh repair, the primary fascial repair is associated with significantly reduced rates of hernia recurrence. This study will review our experience with massive ventral hernia repairs using tissue expansion and anterior component separation as well as present the largest case series to date.

Fine scale sampling reveals early differentiation of rhizosphere microbiome from bulk soil in young Brachypodium plant roots.

For a deeper and comprehensive understanding of the composition and function of rhizosphere microbiomes, we need to focus at the scale of individual roots in standardized growth containers. Root exudation patterns are known to vary along distinct parts of the root even in juvenile plants giving rise to spatially distinct microbial niches. To address this, we analyzed the microbial community from two spatially distinct zones of the developing primary root (tip and base) in young Brachypodium distachyon grown in natural soil using standardized fabricated ecosystems known as EcoFABs as well as in more conventional pot and tubes.