The hallmarks of cancer, first proposed in 2000, have since provided a unified framework for understanding the complexity of carcinogenesis. This conceptual model has profoundly influenced the treatment landscape of primary liver cancer, which includes hepatocellular carcinoma (HCC, ∼85%) and intrahepatic cholangiocarcinoma (iCCA, 10%)-malignancies with high mortality. Key hallmarks exhibited by HCC include sustaining proliferative signaling, inducing or accessing vasculature, and avoiding immune detection. Over the past two decades, outcomes for patients with advanced HCC have significantly improved with immunotherapies. iCCA is characterized by hallmarks such as sustaining proliferative signaling, deregulating cellular metabolism, and avoiding immune detection. Unlike HCC, roughly 45% of iCCA harbor alterations amenable to precision oncology approaches, including fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, ERBB2 alterations, and BRAF mutations. In this review, we explore how this framework has reshaped liver cancer care and discuss the resulting breakthroughs in management and emerging directions that may further improve therapeutic strategies.
High field (W-band, 95 GHz) pulsed electron-nuclear double resonance (ENDOR) measurements were carried out on a number of proteins that contain the mixed-valence, binuclear electron-mediating Cu(A) center. These include nitrous oxide reductase (N(2)OR), the recombinant water-soluble fragment of subunit II of Thermus thermophilus cytochrome c oxidase (COX) ba(3) (M160T9), its M160QT0 mutant, where the weak axial methionine ligand has been replaced by a glutamine, and the engineered "purple" azurin (purpAz). The three-dimensional (3-D) structures of these proteins, apart from the mutant, are known. The EPR spectra of all samples showed the presence of a mononuclear Cu(II) impurity with EPR characteristics of a type II copper. At W-band, the g( perpendicular) features of this center and of Cu(A) are well resolved, thus allowing us to obtain a clean Cu(A) ENDOR spectrum. The latter consists of two types of ENDOR signals. The first includes the signals of the four strongly coupled cysteine beta-protons, with isotropic hyperfine couplings, A(iso), in the 7-15 MHz range. The second group consists of weakly coupled protons with a primarily anisotropic character with A(zz) < 3 MHz. Orientation selective ENDOR spectra were collected for N(2)OR, M160QT0, and purpAz, and simulations of the cysteine beta-protons signals provided their isotropic and anisotropic hyperfine interactions. A linear correlation with a negative slope was found between the maximum A(iso) value of the beta-protons and the copper hyperfine interaction. Comparison of the best-fit anisotropic hyperfine parameters with those calculated from dipolar interactions extracted from the available 3-D structures sets limit to the sulfur spin densities. Similarly, the small coupling spectral region was simulated on the basis of the 3-D structures and compared with the experimental spectra. It was found that the width of the powder patterns of the weakly coupled protons recorded at g(perpendicular) is mainly determined by the histidine H(epsilon)(1) protons. Furthermore, the splitting in the outer wings of these powder patterns indicates differences in the positions of the imidazole rings relative to the Cu(2)S(2) core. Comparison of the spectral features of the weakly coupled protons of M160QT0 with those of the other investigated proteins shows that they are very similar to those of purpAz, where the Cu(A) center is the most symmetric, but the copper spin density and the H(epsilon)(1)-Cu distances are somewhat smaller. All proteins show the presence of a proton with a significantly negative A(iso) value which is assigned to an amide proton of one of the cysteines. The simulations of both strongly and weakly coupled protons, along with the known copper hyperfine couplings, were used to estimate and compare the spin density distribution in the various Cu(A) centers. The largest sulfur spin density was found in M160T9, and the lowest was found in purpAz. In addition, using the relation between the A(iso) values of the four cysteine beta-protons and the H-C-S-S dihedral angles, the relative contribution of the hyperconjugation mechanism to A(iso) was determined. The largest contribution was found for M160T9, and the lowest was found for purpAz. Possible correlations between the spin density distribution, structural features, and electron-transfer functionality are finally suggested.
Abstract Refractory high-entropy alloys (RHEAs) hold promise for applications in extreme environments. However, conventional as-cast RHEAs are constrained by the trade-off between strength and ductility, necessitating time- and energy-intensive post-processing. Here, we propose a streamlined strategy to fabricate RHEAs via laser directed energy deposition (LDED) using elemental powder blends, eliminating the need for post heat treatments. The additively manufactured (AMed) Nb 40 Ta 25 Ti 15 Hf 15 Zr 5 alloy, characterized by a high density of intrinsic edge dislocations introduced during the thermal cycling of the process, demonstrates a remarkable tensile strength of ~497.3 MPa and a uniform elongation of ~6.8 % at 1000 °C, representing a ~ 37.8% and ~61.9% increase, respectively, over its as-cast counterparts. It is found that the intrinsic edge dislocations generated during AM process significantly enhances the alloy’s strain hardening capability at elevated temperatures. Simultaneously, the high density of edge dislocations effectively enhance material deformability through kink band formation and the stochastic nature of dislocation motion. This work presents a cost-effective pathway for the rapid fabrication of AMed RHEAs with an exceptional combination of high-temperature strength and ductility, paving the way for next-generation structural alloys in extreme environments.
This folder contains the raw data that was used for quantifications (and the quantifications in an Excel sheet). The raw data (.txt files called EasyQuant files) was extracted from autoradiographs of SDS-PAGE gels using the ImageGauge software from Fuji (associated with the Fuji gel scanner). This machine has since been discontinued (these data were collected 2014-2016). The .txt files were imported into EasyQuant and fitted to a Gaussian distribution automatically by the software (software developed in the Gunnar von Heijne lab by Dr. Rickard Hedman), and the Ffl (fraction full length) was calculated.
The bending fatigue resistance of superelastic shape memory alloys (SMAs) is a key determinant for their reliable function in cyclic applications such as biomedical implants, adaptive actuators, and elastocaloric devices. However, conventional NiTi alloys exhibit limited fatigue life due to premature crack initiation and propagation under cyclic tensile loading. Here, we report a surface engineering strategy that overcomes this limitation by inducing a hierarchical surface architecture via pre-strain warm laser shock peening (pw-LSP). This architecture integrates a high-strength titanium nitride-enriched top layer, an ultrafine-grained layer with an inverse grain size gradient and a B19′–R–B2 phase gradient, and a substantial compressive residual stress exceeding 1 GPa. These features act synergistically to suppress crack nucleation and arrest propagation through a crack-tip shielding mechanism. As a result, the treated NiTi demonstrates a bending fatigue life exceeding 5 million cycles at a maximum surface tensile strain of 1.94%—representing a more than 3000-fold enhancement over untreated nanocrystalline NiTi. This work presents a robust and scalable approach for designing fatigue-resistant SMAs with broad implications for high-cycle, high-reliability applications. Laser-based surface treatment creates a hierarchical architecture in superelastic NiTi, integrating hard nitrides, graded grains and phases, and high compressive stress. This synergy suppresses cracking and extends bending fatigue life beyond 5 million cycles.
Read moreThis folder contains the raw data that was used for quantifications (and the quantifications in an Excel sheet). The raw data (.txt files called EasyQuant files) was extracted from autoradiographs of SDS-PAGE gels using the ImageGauge software from Fuji (associated with the Fuji gel scanner). This machine has since been discontinued (these data were collected 2014-2016). The .txt files were imported into EasyQuant and fitted to a Gaussian distribution automatically by the software (software developed in the Gunnar von Heijne lab by Dr. Rickard Hedman), and the Ffl (fraction full length) was calculated.
Read moreIn this work, we assess the accuracy of the approximate fourth-order N-electron valence perturbation theory (NEVPT4(SD)) methodology for computing excited states of organic molecules. The well-established Thiel benchmark set was employed, comprising 225 vertical excitations spanning π → π*, <i>n</i> → π*, and σ → π* transition types. A state-specific canonicalization procedure was applied, enabling a direct comparison with CC3 reference data reported by Schreiber et al. <i>J. Chem. Phys.</i>, <b>2008</b>, <i>128</i>, 134110. For both singlet and triplet excitations, NEVPT4(SD) systematically outperforms lower-order NEVPT variants, as well as previously reported complete active space second-order perturbation theory (CASPT2) results. A detailed analysis of the singlet excitations reveals that <i>n</i> → π* transitions have a slight tendency to be overestimated (by about 0.1 eV), while π → π* excitations tend to be slightly underestimated (by -0.04 eV). While this shift persists across all NEVPT perturbation orders, its magnitude decreases with higher-order treatments. Across the entire test set, NEVPT4(SD) has a very narrow error distribution with a peak very close to 0. Thus, this study demonstrates the robustness and high accuracy of NEVPT4(SD) for vertical excitation energies, highlighting its clear advantages over lower-order perturbative approaches while remaining computationally much more affordable than other multireference correlation approaches that proceed beyond second-order perturbation theory.
Read moreUnderstanding how grain boundaries mediate fracture remains a critical challenge in designing ductile, high-performance refractory alloys. Here, we extend the Rice-Thomson criterion to account for the angle between cracks and the impinging grain boundaries (GBs), capturing the competition between intergranular fracture and dislocation-mediated plasticity. Using machine learning interatomic potentials, we performed molecular statics simulations to probe fracture mechanisms in nanocrystalline NbMoTaW and Nb<sub>45</sub>Ta<sub>25</sub>Ti<sub>15</sub>Hf<sub>15</sub>, each with two different grain sizes, revealing trends consistent with experimental observations and the extended Rice model. Comparison with averaged R-curves for bulk samples demonstrates that GBs enhance ductility in Nb<sub>45</sub>Ta<sub>25</sub>Ti<sub>15</sub>Hf<sub>15</sub> in both grain sizes investigated. In contrast, GBs only locally improve fracture resistance in NbMoTaW when cracks are temporarily pinned at GBs inclined at high angles from the crack, but generally promote brittle intergranular fracture. These contrasting behaviors are attributed to differences in GB cohesion, reflecting clear alloying trends that align with ab-initio calculations and trends observed experimentally. Our results bridge classical fracture theory, atomistic simulations, and experimental observations, providing a comprehensive understanding of the fracture mechanisms in nanocrystalline refractory complex concentrated alloys.
Read moreMetal–organic frameworks (MOFs), composed of metal nodes coordinated with organic ligands, have emerged as a versatile class of functional materials for next‐generation smart textile systems. Their high surface area, tunable pore chemistry, and modular structural diversity enable multifunctional textile platforms. When integrated into textile substrates, MOFs can retain the properties, breathability, and comfort of fabrics while imparting advanced functionalities significant for sensing, environmental protection, biomedical interfaces, and energy‐related applications. This review provides a comprehensive overview of recent advances in MOF‐integrated smart textiles, focusing on material design principles, integration strategies, and application‐driven performance. Key fabrication approaches including surface coating, in situ growth, post‐synthetic modification, hydrothermal assembly, and emerging printing techniques such as inkjet and electrohydrodynamic jet are critically examined with respect to scalability, durability, and textile compatibility. Representative applications spanning gas and chemical sensing, detoxification, antimicrobial and biomedical functions, energy harvesting, and flexible energy storage are systematically discussed. Finally, current challenges and future opportunities are outlined, highlighting pathways toward scalable, durable, and application‐oriented MOF‐based smart textiles for real‐world applications.
Read moreBenthic prokaryotic communities in deep-sea sediments remain poorly studied. They are constrained by organic matter availability and oxygenation in warm deep-sea ecosystems. Here, we investigated benthic prokaryotic communities and carbon uptake in deep Red Sea sediments (218–2415 m seafloor depth), where persistently warm (~21.5 °C) waters and a strong south–north productivity gradient co-occur. Sediment particulate organic carbon (POC), prokaryotic abundance (PA), and [13C]-D-glucose-based carbon uptake and uptake kinetics were examined in two sediment layers (0–1 and 4–5 cm), while bacterial communities were characterized using 16S rRNA gene sequencing of the 0–1 cm layer. Sediment POC, PA, and carbon uptake declined northward, consistent with reduced organic-carbon supply to the seafloor. Bacterial community composition differed significantly across the ~500 m depth associated with the Red Sea oxygen minimum zone (OMZ). Sediments from the relatively low-oxygen upper OMZ-range (200–500 m) had higher sediment POC and PA, and were enriched in putatively anaerobe-associated taxa, whereas deeper sediments (>500 m) below the OMZ exhibited more fragmented co-occurrence networks. These results suggest that organic-carbon availability defines the basin-scale metabolic backdrop, whereas bacterial community differentiation was more clearly resolved between upper OMZ-range and below-OMZ sediments than along latitude alone.
Read moreThe vertebrate brain must balance internally generated predictions with constraints of environmental affordances. This balance constitutes a fundamental principle of neural organization that underwrites cortical computation. Using the prosomeric model of the neuraxis, we show how dorsalizing and ventralizing morphogenetic gradients specify excitatory and inhibitory lineages during development, establishing the functional architecture of active affordance. These developmental asymmetries are elaborated through telencephalic expansion, pallial-subpallial integration, and laminar differentiation of the neocortex, as described by the structural model. We demonstrate that motor control emerges within a sensory-predictive architecture due to the alar origin of the telencephalon and that increasing excitatory-inhibitory complementarity within the mammalian neocortex enables selective, context-sensitive action. Subpallial and diencephalic systems provide inhibitory governance over cortical action tendencies, supporting policy evaluation and selection in the framework of active inference. At the base of this hierarchy, the hypothalamus integrates homeostatic and allostatic signals to bias the landscape of affordances, shaping the likelihood of action policies. Together, these findings establish active affordance as a developmental and evolutionary framework linking prosomeric neurodevelopment, cortical architecture, subcortical control, and adaptive behavior. Active inference is thereby situated as the mature cortical expression of a conserved biological solution to acting in an uncertain world.
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