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BTK hang-up sensitizes Severe Lymphoblastic The leukemia disease to asparaginase by curbing the particular Amino Reply path.
Protein kinase inhibitors are potent anticancer therapeutics. For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for chronic myeloid leukemia by 80%, but 22 to 41% of patients acquire resistance to imatinib. About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain, where more than a hundred different mutations have been identified. Some mutations are located near the imatinib-binding site and cause resistance through altered interactions with the drug. However, many resistance mutations are located far from the drug-binding site, and it remains unclear how these mutations confer resistance. Additionally, earlier studies on small sets of patient-derived imatinib resistance mutations indicated that some of these mutant proteins were in fact sensitive to imatinib in cellular and biochemical studies. Here, we surveyed the resistance of 94 patient-derived Abl kinase domain mutations annotated as disease relevant or resistance causing using an engagement assay in live cells. We found that only two-thirds of mutations weaken imatinib affinity by more than twofold compared to Abl wild type. Surprisingly, one-third of mutations in the Abl kinase domain still remain sensitive to imatinib and bind with similar or higher affinity than wild type. Intriguingly, we identified three clinical Abl mutations that bind imatinib with wild type-like affinity but dissociate from imatinib considerably faster. Given the relevance of residence time for drug efficacy, mutations that alter binding kinetics could cause resistance in the nonequilibrium environment of the body where drug export and clearance play critical roles.COVID-19 has had worse health, education, and labor market effects on groups with low socioeconomic status (SES) than on those with high SES. Little is known, however, about whether COVID-19 has also had differential effects on noncognitive skills that are important for life outcomes. Using panel data from before and during the pandemic, we show that COVID-19 affects one key noncognitive skill, that is, prosociality. While prosociality is already lower for low-SES students prior to the pandemic, we show that COVID-19 infections within families amplify the prosociality gap between French high school students of high and low SES by almost tripling its size in comparison to pre-COVID-19 levels.In mammalian brain neurons, membrane depolarization leads to voltage-gated Ca2+ channel-mediated Ca2+ influx that triggers diverse cellular responses, including gene expression, in a process termed excitation-transcription coupling. Neuronal L-type Ca2+ channels, which have prominent populations on the soma and distal dendrites of hippocampal neurons, play a privileged role in excitation-transcription coupling. The voltage-gated K+ channel Kv2.1 organizes signaling complexes containing the L-type Ca2+ channel Cav1.2 at somatic endoplasmic reticulum-plasma membrane junctions. This leads to enhanced clustering of Cav1.2 channels, increasing their activity. However, the downstream consequences of the Kv2.1-mediated regulation of Cav1.2 localization and function on excitation-transcription coupling are not known. Here, we have identified a region between residues 478 to 486 of Kv2.1's C terminus that mediates the Kv2.1-dependent clustering of Cav1.2. By disrupting this Ca2+ channel association domain with either mutations or with a cell-penetrating interfering peptide, we blocked the Kv2.1-mediated clustering of Cav1.2 at endoplasmic reticulum-plasma membrane junctions and the subsequent enhancement of its channel activity and somatic Ca2+ signals without affecting the clustering of Kv2.1. These interventions abolished the depolarization-induced and L-type Ca2+ channel-dependent phosphorylation of the transcription factor CREB and the subsequent expression of c-Fos in hippocampal neurons. Our findings support a model whereby the Kv2.1-Ca2+ channel association domain-mediated clustering of Cav1.2 channels imparts a mechanism to control somatic Ca2+ signals that couple neuronal excitation to gene expression.DNA molecules are atomic-scale information storage molecules that promote reliable information transfer via fault-free repetitions of replications and transcriptions. Remarkable accuracy of compacting a few-meters-long DNA into a micrometer-scale object, and the reverse, makes the chromosome one of the most intriguing structures from both physical and biological viewpoints. However, its three-dimensional (3D) structure remains elusive with challenges in observing native structures of specimens at tens-of-nanometers resolution. Here, using cryogenic coherent X-ray diffraction imaging, we succeeded in obtaining nanoscale 3D structures of metaphase chromosomes that exhibited a random distribution of electron density without characteristics of high-order folding structures. Scaling analysis of the chromosomes, compared with a model structure having the same density profile as the experimental results, has discovered the fractal nature of density distributions. Quantitative 3D density maps, corroborated by molecular dynamics simulations, reveal that internal structures of chromosomes conform to diffusion-limited aggregation behavior, which indicates that 3D chromatin packing occurs via stochastic processes.The topology of structural brain networks shapes brain dynamics, including the correlation structure of brain activity (functional connectivity) as estimated from functional neuroimaging data. Empirical studies have shown that functional connectivity fluctuates over time, exhibiting patterns that vary in the spatial arrangement of correlations among segregated functional systems. Recently, an exact decomposition of functional connectivity into frame-wise contributions has revealed fine-scale dynamics that are punctuated by brief and intermittent episodes (events) of high-amplitude cofluctuations involving large sets of brain regions. Their origin is currently unclear. Here, we demonstrate that similar episodes readily appear in silico using computational simulations of whole-brain dynamics. As in empirical data, simulated events contribute disproportionately to long-time functional connectivity, involve recurrence of patterned cofluctuations, and can be clustered into distinct families. Importantly, comparison of event-related patterns of cofluctuations to underlying patterns of structural connectivity reveals that modular organization present in the coupling matrix shapes patterns of event-related cofluctuations. Our work suggests that brief, intermittent events in functional dynamics are partly shaped by modular organization of structural connectivity.Air pollution is a reversible cause of significant global mortality and morbidity. Epidemiological evidence suggests associations between air pollution exposure and impaired cognition and increased risk for major depressive disorders. However, the neural bases of these associations have been unclear. Here, in healthy human subjects exposed to relatively high air pollution and controlling for socioeconomic, genomic, and other confounders, we examine across multiple levels of brain network function the extent to which particulate matter (PM2.5) exposure influences putative genetic risk mechanisms associated with depression. Increased ambient PM2.5 exposure was associated with poorer reasoning and problem solving and higher-trait anxiety/depression. Working memory and stress-related information transfer (effective connectivity) across cortical and subcortical brain networks were influenced by PM2.5 exposure to differing extents depending on the polygenic risk for depression in gene-by-environment interactions. Effective connectivity patterns from individuals with higher polygenic risk for depression and higher exposures with PM2.5, but not from those with lower genetic risk or lower exposures, correlated spatially with the coexpression of depression-associated genes across corresponding brain regions in the Allen Brain Atlas. These converging data suggest that PM2.5 exposure affects brain network functions implicated in the genetic mechanisms of depression.We here demonstrate common neurocognitive long-term memory effects of active learning that generalize over course subjects (mathematics and vocabulary) by the use of fMRI. One week after active learning, relative to more passive learning, performance and fronto-parietal brain activity was significantly higher during retesting, possibly related to the formation and reactivation of semantic representations. These observations indicate that active learning conditions stimulate common processes that become part of the representations and can be reactivated during retrieval to support performance. Our findings are of broad interest and educational significance related to the emerging consensus of active learning as critical in promoting good long-term retention.Darwin's finches are a classic example of adaptive radiation, exemplified by their adaptive and functional beak morphologies. To quantify their form, we carry out a morphometric analysis of the three-dimensional beak shapes of all of Darwin's finches and find that they can be fit by a transverse parabolic shape with a curvature that increases linearly from the base toward the tip of the beak. The morphological variation of beak orientation, aspect ratios, and curvatures allows us to quantify beak function in terms of the elementary theory of machines, consistent with the dietary variations across finches. Finally, to explain the origin of the evolutionary morphometry and the developmental morphogenesis of the finch beak, we propose an experimentally motivated growth law at the cellular level that simplifies to a variant of curvature-driven flow at the tissue level and captures the range of observed beak shapes in terms of a simple morphospace. Altogether, our study illuminates how a minimal combination of geometry and dynamics allows for functional form to develop and evolve.When and how Earth's earliest continents-the cratons-first emerged above the oceans (i.e., emersion) remain uncertain. Here, we analyze a craton-wide record of Paleo-to-Mesoarchean granitoid magmatism and terrestrial to shallow-marine sedimentation preserved in the Singhbhum Craton (India) and combine the results with isostatic modeling to examine the timing and mechanism of one of the earliest episodes of large-scale continental emersion on Earth. BMS493 chemical structure Detrital zircon U-Pb(-Hf) data constrain the timing of terrestrial to shallow-marine sedimentation on the Singhbhum Craton, which resolves the timing of craton-wide emersion. Time-integrated petrogenetic modeling of the granitoids quantifies the progressive changes in the cratonic crustal thickness and composition and the pressure-temperature conditions of granitoid magmatism, which elucidates the underlying mechanism and tectonic setting of emersion. The results show that the entire Singhbhum Craton became subaerial ∼3.3 to 3.2 billion years ago (Ga) due to progressive crustal maturation and thickening driven by voluminous granitoid magmatism within a plateau-like setting. A similar sedimentary-magmatic evolution also accompanied the early (>3 Ga) emersion of other cratons (e.g., Kaapvaal Craton). Therefore, we propose that the emersion of Earth's earliest continents began during the late Paleoarchean to early Mesoarchean and was driven by the isostatic rise of their magmatically thickened (∼50 km thick), buoyant, silica-rich crust. The inferred plateau-like tectonic settings suggest that subduction collision-driven compressional orogenesis was not essential in driving continental emersion, at least before the Neoarchean. We further surmise that this early emersion of cratons could be responsible for the transient and localized episodes of atmospheric-oceanic oxygenation (O2-whiffs) and glaciation on Archean Earth.
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