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Although tumor genomic profiling has identified small subsets of gastric cancer (GC) patients with clinical benefit from anti-PD-1 treatment, not all responses can be explained by tumor sequencing alone. We investigate epigenetic elements responsible for the differential response to anti-PD-1 therapy by quantitatively assessing the genome-wide chromatin accessibility of circulating CD8+ T cells in patients' peripheral blood. Using an assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify unique open regions of chromatin that significantly distinguish anti-PD-1 therapy responders from non-responders. GC patients with high chromatin openness of circulating CD8+ T cells are significantly enriched in the responder group. Concordantly, patients with high chromatin openness at specific genomic positions of their circulating CD8+ T cells demonstrate significantly better survival than those with closed chromatin. Here we reveal that epigenetic characteristics of baseline CD8+ T cells can be used to identify metastatic GC patients who may benefit from anti-PD-1 therapy.Epigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, μM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 μM). Large scale atomistic simulations (>100 μs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG's anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.Systemic AA amyloidosis is a world-wide occurring protein misfolding disease of humans and animals. selleck products It arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein. Using cryo electron microscopy we here show that amyloid fibrils which were purified from AA amyloidotic mice are structurally different from fibrils formed from recombinant SAA protein in vitro. Ex vivo amyloid fibrils consist of fibril proteins that contain more residues within their ordered parts and possess a higher β-sheet content than in vitro fibril proteins. They are also more resistant to proteolysis than their in vitro formed counterparts. These data suggest that pathogenic amyloid fibrils may originate from proteolytic selection, allowing specific fibril morphologies to proliferate and to cause damage to the surrounding tissue.The use of alkyl chlorides in Pd-catalyzed Mizoroki-Heck coupling reactions remains an unsolved problem despite their significant potential for synthetic utility and applicability. The combination of the high thermodynamic barrier of alkyl chloride activation and kinetic propensity of alkylpalladium complexes to undergo undesired β-hydride elimination provides significant challenges. Herein, a variety of alkyl chlorides, even tertiary chlorides, are shown to efficiently participate in Mizoroki-Heck cross-coupling reactions with excellent functional group compatibility under mild reaction conditions via photoinduced Pd catalysis. The reaction is applied to late-stage functionalizations of diverse biologically significant scaffolds and iterative double Mizoroki-Heck annulations, affording high molecular complexity in a single step. Notably, studies on the kinetic isotope effects in combination with density functional theory (DFT)-computations completely exclude the involvement of a previously proposed β-hydride elimination in the catalytic cycle, revealing that the chlorine atom transfer process is the key catalytic turnover step. This distinctive single-electron transfer mediated reaction pathway resolves a longstanding challenge in traditional two-electron based Pd-catalyzed Mizoroki-Heck cross-coupling with alkyl electrophiles, wherein the β-hydride elimination is involved in the formation of both the desired product and undesired by-products.Band bending at semiconductor surfaces induced by chemical doping or electric fields can create metallic surfaces with properties not found in the bulk, such as high electron mobility, magnetism or superconductivity. Optical generation of such metallic surfaces on ultrafast timescales would be appealing for high-speed electronics. Here, we demonstrate the ultrafast generation of a metal at the (10-10) surface of ZnO upon photoexcitation. Compared to hitherto known ultrafast photoinduced semiconductor-to-metal transitions that occur in the bulk of inorganic semiconductors, the metallization of the ZnO surface is launched by 3-4 orders of magnitude lower photon fluxes. Using time- and angle-resolved photoelectron spectroscopy, we show that the phase transition is caused by photoinduced downward surface band bending due to photodepletion of donor-type deep surface defects. The discovered mechanism is in analogy to chemical doping of semiconductor surfaces and presents a general route for controlling surface-confined metallicity on ultrafast timescales.Clarifying the relation between the whole and its parts is crucial for many problems in science. In quantum mechanics, this question manifests itself in the quantum marginal problem, which asks whether there is a global pure quantum state for some given marginals. This problem arises in many contexts, ranging from quantum chemistry to entanglement theory and quantum error correcting codes. In this paper, we prove a correspondence of the marginal problem to the separability problem. Based on this, we describe a sequence of semidefinite programs which can decide whether some given marginals are compatible with some pure global quantum state. As an application, we prove that the existence of multiparticle absolutely maximally entangled states for a given dimension is equivalent to the separability of an explicitly given two-party quantum state. Finally, we show that the existence of quantum codes with given parameters can also be interpreted as a marginal problem, hence, our complete hierarchy can also be used.Plasmonic nanostructures hold promise for the realization of ultra-thin sub-wavelength devices, reducing power operating thresholds and enabling nonlinear optical functionality in metasurfaces. However, this promise is substantially undercut by absorption introduced by resistive losses, causing the metasurface community to turn away from plasmonics in favour of alternative material platforms (e.g., dielectrics) that provide weaker field enhancement, but more tolerable losses. Here, we report a plasmonic metasurface with a quality-factor (Q-factor) of 2340 in the telecommunication C band by exploiting surface lattice resonances (SLRs), exceeding the record by an order of magnitude. Additionally, we show that SLRs retain many of the same benefits as localized plasmonic resonances, such as field enhancement and strong confinement of light along the metal surface. Our results demonstrate that SLRs provide an exciting and unexplored method to tailor incident light fields, and could pave the way to flexible wavelength-scale devices for any optical resonating application.The life cycle of Baculoviridae family insect viruses depends on the viral protein kinase, PK-1, to phosphorylate the regulatory protein, p6.9, to induce baculoviral genome release. Here, we report the crystal structure of Cydia pomenella granulovirus PK-1, which, owing to its likely ancestral origin among host cell AGC kinases, exhibits a eukaryotic protein kinase fold. PK-1 occurs as a rigid dimer, where an antiparallel arrangement of the αC helices at the dimer core stabilizes PK-1 in a closed, active conformation. Dimerization is facilitated by C-lobeC-lobe and N-lobeN-lobe interactions between protomers, including the domain-swapping of an N-terminal helix that crowns a contiguous β-sheet formed by the two N-lobes. PK-1 retains a dimeric conformation in solution, which is crucial for catalytic activity. Our studies raise the prospect that parallel, side-to-side dimeric arrangements that lock kinase domains in a catalytically-active conformation could function more broadly as a regulatory mechanism among eukaryotic protein kinases.Genotoxic colibactin-producing pks+ Escherichia coli induce DNA double-strand breaks, mutations, and promote tumor development in mouse models of colorectal cancer (CRC). Colibactin's distinct mutational signature is reflected in human CRC, suggesting a causal link. Here, we investigate its transformation potential using organoids from primary murine colon epithelial cells. Organoids recovered from short-term infection with pks+ E. coli show characteristics of CRC cells, e.g., enhanced proliferation, Wnt-independence, and impaired differentiation. Sequence analysis of Wnt-independent organoids reveals an enhanced mutational burden, including chromosomal aberrations typical of genomic instability. Although we do not find classic Wnt-signaling mutations, we identify several mutations in genes related to p53-signaling, including miR-34a. Knockout of Trp53 or miR-34 in organoids results in Wnt-independence, corroborating a functional interplay between the p53 and Wnt pathways. We propose larger chromosomal alterations and aneuploidy as the basis of transformation in these organoids, consistent with the early appearance of chromosomal instability in CRC.Oxynitride photocatalysts hold promise for renewable solar hydrogen production via water splitting owing to their intense visible light absorption. Cocatalyst loading is essential for activation of such oxynitride photocatalysts. However, cocatalyst nanoparticles form aggregates and exhibit weak interaction with photocatalysts, which prevents eliciting their intrinsic photocatalytic performance. Here, we demonstrate efficient utilization of photoexcited electrons in a single-crystalline particulate BaTaO2N photocatalyst prepared with the assistance of RbCl flux for H2 evolution reactions via sequential decoration of Pt cocatalyst by impregnation-reduction followed by site-selective photodeposition. The Pt-loaded BaTaO2N photocatalyst evolves H2 over 100 times more efficiently than before, with an apparent quantum yield of 6.8% at the wavelength of 420 nm, from a methanol aqueous solution, and a solar-to-hydrogen energy conversion efficiency of 0.24% in Z-scheme water splitting. Enabling uniform dispersion and intimate contact of cocatalyst nanoparticles on single-crystalline narrow-bandgap particulate photocatalysts is a key to efficient solar-to-chemical energy conversion.