Olssonwang9111

Fork reversal is a common response to replication stress, but it generates a DNA end that is susceptible to degradation. Many fork protection factors block degradation, but how they work remains unclear. Here, we find that 53BP1 protects forks from DNA2-mediated degradation in a cell type-specific manner. Fork protection by 53BP1 reduces S-phase DNA damage and hypersensitivity to replication stress. Unlike BRCA2, FANCD2, and ABRO1 that protect reversed forks generated by SMARCAL1, ZRANB3, and HLTF, 53BP1 protects forks remodeled by FBH1. This property is shared by the fork protection factors FANCA, FANCC, FANCG, BOD1L, and VHL. RAD51 is required to generate the resection substrate in all cases. Unexpectedly, BRCA2 is also required for fork degradation in the FBH1 pathway or when RAD51 activity is partially compromised. We conclude that there are multiple fork protection mechanisms that operate downstream of at least two RAD51-dependent fork remodeling pathways.Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28). Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Our data reinforce LMTK3 as a druggable target for cancer therapy.Diverse processes-e.g., environmental pollution, groundwater remediation, oil recovery, filtration, and drug delivery-involve the transport of colloidal particles in porous media. Using confocal microscopy, we directly visualize this process in situ and thereby identify the fundamental mechanisms by which particles are distributed throughout a medium. At high injection pressures, hydrodynamic stresses cause particles to be continually deposited on and eroded from the solid matrix-notably, forcing them to be distributed throughout the entire medium. By contrast, at low injection pressures, the relative influence of erosion is suppressed, causing particles to localize near the inlet of the medium. Olaparib Unexpectedly, these macroscopic distribution behaviors depend on imposed pressure in similar ways for particles of different charges, although the pore-scale distribution of deposition is sensitive to particle charge. These results reveal how the multiscale interactions between fluid, particles, and the solid matrix control how colloids are distributed in a porous medium.East Asian monsoon variability in the Pliocene warm world has not been sufficiently studied because of the lack of direct records. We present a high-resolution precipitation record from Pliocene fluvial-lacustrine sequences in the Weihe Basin, Central China, a region sensitive to the East Asian monsoon. The record shows an abrupt monsoon shift at ~4.2 million years ago, interpreted as the result of high-latitude cooling, with an extratropical temperature decrease across a critical threshold. The precipitation time series exhibits a pronounced ~100-thousand year periodicity and the presence of precession and half-precession cycles, which suggest low-latitude forcing. The synchronous phase but mismatched amplitudes of the East Asian monsoon precipitation proxy and eccentricity suggest a nonlinear but sensitive precipitation response to temperature forcing in the Pliocene warm world. These observations highlight the role of high- and low-latitude forcing of East Asian monsoon variations on tectonic and orbital time scales.Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell-derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.In the face of uncertainty, cell populations tend to diversify to enhance survival and growth. Previous studies established that cells can optimize such bet hedging upon environmental change by modulating gene expression to adapt both the average and diversity of phenotypes. Here, we demonstrate that cells can tune phenotypic diversity also using posttranslational modifications. In the chemotaxis network of Escherichia coli, we find, for both major chemoreceptors Tar and Tsr, that cell-to-cell variation in response sensitivity is dynamically modulated depending on the presence or absence of their cognate chemoeffector ligands in the environment. Combining experiments with mathematical modeling, we show that this diversity tuning requires only the environment-dependent covalent modification of chemoreceptors and a standing cell-to-cell variation in their allosteric coupling. Thus, when environmental cues are unavailable, phenotypic diversity enhances the population's readiness for many signals. However, once a signal is perceived, the population focuses on tracking that signal.