Searching for tritium permeation barriers with high radiation resistance and a high permeation reduction factor (PRF) is an urgent task for commercial nuclear fusion. In this work, (TiVAlCrZr)O multi-component metal oxide coatings prepared as tritium permeation barrier (TPB) were irradiated with He+ ions and Ar2+ ions at different fluences to investigate the effect of irradiation on its deuterium permeation resistance. All the irradiated samples had the permeation reduction factors (PRFs) higher than 1000 at 500 degrees C. In contrast to the fast decrease of permeation resistance for traditional TPB, the PRFs at 500 degrees C of Ar2+ ion irradiated coatings to 2 x 1015 and 1 x 1016 ions/cm2 with peak damages of 5.2 and 26 dpa were found to be enhanced by 5.3 and 4.6 times, respectively, compared to the pristine coatings. The PRFs at 500 degrees C of He+ ion irradiated coatings to 5 x 1016 and 3 x 1017 ions/cm2 with peak damages of 4.6 and 27.6 dpa were found to be improved by 1.3 and 3.1 times, respectively. It is found that the main reasons for the enhanced deuterium permeation resistance are irradiation induced ion recombination and thermal spike effect.

Abstract The small membrane-bound GTPase KRAS functions as an on/off switch for multiple important cellular signaling pathways, including RAF/MEK/ERK and PI3K/AKT. As one of the most prevalent cancer drivers, KRAS alterations occur in approximately 17% of all solid tumors, including pancreatic, colorectal, lung adenocarcinoma, and esophagogastric cancers. Despite recent advances, KRAS G12C-selective inhibitors face clinical challenges in achieving durable therapeutic efficacy due to acquired drug resistance, while the mutational diversity of KRAS-driven cancers restricts their utility across patient populations, representing a significant unmet medical need. On the other hand, targeting all RAS proteins, including HRAS and NRAS, might raise potential toxicity risk, as the RAS family is essential in normal cells. Here, we report an oral pan-KRAS (ON/OFF) inhibitor ISM7713 that selectively targets all major oncogenic KRAS variants in both inactive and active conformations across multiple solid tumors while sparing HRAS and NRAS. Surface plasmon resonance revealed that ISM7713 binds to GDP-bound KRAS (inactive, or “off”) with picomolar affinity and to GTP-bound KRAS (active, or “on”) with sub-nanomolar affinity. Nucleotide exchange assays and RAS-cRAF binding assays further supported dual inhibitory function, together identifying sub-nanomolar IC50 values against KRAS variants (G12D, G12V, G12C, and WT). In cellular assays, ISM7713 suppressed cell growth with single-digit nanomolar IC50 values across cancer cell lines harboring major KRAS mutations or KRAS amplification, including GP2D (KRAS G12D), SW620 (KRAS G12V), NCI-H358 (KRAS G12C), and MKN1 (KRAS WT amplification). Treatment in vivo at 10-30 mg/kg (BID) induced tumor regression in multiple CDX models driven by different KRAS alterations (KRAS G12D/V/C mutations or KRAS amplification), along with dose-dependent pharmacodynamic responses, including changes in ERK phosphorylation and DUSP6 transcription. ISM7713 demonstrated reasonable solubility and permeability. In vivo, it exhibited good plasma clearance and bioavailability across mouse, rat, dog, and monkey. Additionally, mini-Ames and off-target safety panel profiling indicated no potential risk. Collectively, these findings highlight the potential of this novel molecule as a potent pan-KRAS (ON/OFF) inhibitor for the treatment of solid tumors with KRAS alterations. Citation Format: Sujing Shi, Defeng Shen, Jianping Wu, Tingting Liu, Jinxin Liu, Qingshuo Meng, Zuoxiao Shi, Suguna Rachakonda, David Gennert, Luoheng Qin, Xin Cai, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM7713, a novel oral pan-KRAS (ON/OFF) inhibitor, shows robust anti-tumor activity in solid tumors with KRAS alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 425.

Searching for tritium permeation barrier (TPB) with high tritium permeation resistance is one of the key tasks in the development of nuclear fusion reactor systems. In this study, we propose a novel N doped multi-component metal oxide coating (MCMO), where nitrogen doping can significantly improve the deuterium permeation resistance of the coating. Such a system can also be used to simulate the influence of produced N by the transmutation reaction of neutrons with oxygen in oxide TPB coating. Grazing incidence X-ray diffraction (GIXRD) analysis revealed that the phase structure of the coating remained amorphous after N doping. Through deuterium permeation testing, it was found that the coating has a very high PRF value of 12000 at 500 degrees C, which has 2.2 times enhancement in PRF compared to that of the pristine (TiVAlCrZr)O coating. Notably, the permeation process does not change the coating microstructure. Ab initio calculations reveal that the N species acts as cages to mitigate the hydrogen isotope permeation. Therefore, nitrogen doping is expected to be a new strategy to further enhance the performance of metal oxide tritium permeation barrier.

Developing advanced structural materials for next-generation nuclear reactors that simultaneously achieve superior radiation tolerance, excellent mechanical properties, and manufacturable components remains a significant challenge. Additive manufacturing via laser powder bed fusion (LPBF) offers a promising pathway to engineer high-performance reactor materials with tailored microstructures. Herein, oxide dispersion-strengthened (ODS) Fe-Cr steels with near-full density (>99 %) and uniformly dispersed Y-Ti-O nanoprecipitates (number density approximately 4 x 10(20)/m(3)) were fabricated by LPBF using gas-atomized reaction-synthesized powders. In-situ formed Y-Ti-O nanoprecipitates during the intrinsic heat treatment of the LPBF process enhanced the energy barrier to plastic deformation in ODS Fe-Cr steel by impeding dislocation motion and climb, thereby conferring superior high-temperature strength and creep resistance compared to the Fe-Cr steel counterpart. Furthermore, energetic Au+ and He+ ion irradiations, coupled with transmission electron microscopy and nanoindentation analyses, demonstrate that the LPBF-engineered high-density interfaces between Y-Ti-O nanoparticles and the Fe-Cr matrix serve as efficient sinks for irradiation-induced defects. This interface-mediated defect annihilation mechanism mitigated radiation damage, ensured microstructural stability, and reduced irradiation hardening. This work provides valuable insights into the design and manufacturing of irradiation-resistant ODS steel components via LPBF for advanced nuclear reactors.

Abstract CDK4/6 kinases drive the G1-S cell cycle transition, and overactive cyclin-CDK4/6 complexes are common across cancer types. While clinically approved CDK4/6 inhibitors have benefited patients with HR+/HER2- breast cancer, their efficacy is constrained by dose-limiting hematological toxicities, particularly CDK6-driven myelosuppression. Hematopoietic stem cell activation relies primarily on CDK6, but breast cancer cells are more dependent on CDK4, suggesting a potential therapeutic window for a CDK4-selective inhibitor. Here, we report the development and preclinical characterization of ISM6210, an orally bioavailable CDK4 inhibitor with high selectivity over CDK6. ISM6210 demonstrated potent inhibition of the CDK4/Cyclin D1 complex in enzymatic assays with nanomolar IC50 values and good selectivity over CDK6 and other CDKs. Kinome profiling revealed minimal off-target activity, confirming its high selectivity. In cellular assays, ISM6210 selectively targeted CDK4-dependent breast cancer cells over CDK6-dependent cells. Notably, in human hematopoietic stem cell assays, ISM6210 exhibited an IC50 value about 30-fold higher than the dual CDK4/6 inhibitor Palbociclib against human hematopoietic stem cells, suggesting reduced myelosuppressive potential. Mechanistically, ISM6210 effectively blocked Rb phosphorylation and the G1/S cell cycle transition, resulting in growth arrest in HR+ breast cancer cell lines. In vivo, ISM6210 achieved robust anti-tumor activity at 30 mg/kg BID across multiple HR+ breast cancer xenograft models with notable tumor enrichment. In addition to its robust biological potency and high selectivity, ISM6210 exhibited favorable drug-like properties, including desirable in vitro ADMET profiles, excellent in vivo exposure and clearance, and good oral bioavailability across multiple preclinical species. Collectively, these findings establish ISM6210 as a potent and selective CDK4 inhibitor that delivers strong efficacy and a promising hematologic safety margin for HR+/HER2- breast cancer treatment. Citation Format: Yilin Yang, Zhongying Cao, Zhisen Zhang, Fanye Meng, Jinxin Liu, Jiamin Zheng, Zuoxiao Shi, Ling Wang, David Gennert, Suguna Rachakonda, Xiao Ding, Xin Cai, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM6210, a potent and selective CDK4 inhibitor for the treatment of HR+/HER2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4562.

The development of high-performance beta-Ga2O3 electronics is critically hindered by the fundamental limitation of self-compensation in n-type doping, which severely suppresses free carrier concentrations. To explore the microscopic mechanism of this effect, we systematically investigate the four n-type dopants (Si, Sn, Ge, and Zr) in beta-Ga2O3, combining first-principles calculations and experimental investigations. The calculation results show that the lower formation energies of SiGaVGa and SnGaVGa complexes compared to GeGaVGa and ZrGaVGa complexes lead to their higher concentrations and consequently stronger compensation in Si and Sn doping beta-Ga2O3 under O-rich conditions. Oxygen annealing induces a severe compensation effect, as consistently validated by Hall effect and non-contact eddy current measurements. Beyond this universal mechanism, we further identify that the carrier compensation predominantly occurs near the surface, manifesting as a dramatic drop in near-surface carrier concentration and a sharp increase in contact resistivity in Sn-doped beta-Ga2O3. Furthermore, photoluminescence spectra exhibit distinct green emission (similar to 2.5 eV), confirming the formation of the predicted deep-level defects SnGaVGa. This work reveals the microscopic compensation mechanism, providing vital theoretical and experimental insights for optimizing n-type beta-Ga2O3 conductivity.

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Aging is increasingly viewed as a pathological process and a principal driver of diverse age-related diseases (ARDs). Framing aging as a disease offers an opportunity to identify therapeutic targets capable of modifying multiple chronic disorders simultaneously. Here, we developed an artificial intelligence (AI)-driven target discovery framework that integrates large-scale multi-omic datasets to prioritize therapeutic targets shared between aging and 12 ARDs spanning four major disease areas: neurological, inflammatory, metabolic, and fibrotic disorders. We identified 29 high-confidence and 16 previously unrecognized aging-associated targets implicated across the selected disease areas, together with convergent pathway perturbations characterized by robust upregulation of interferon and inflammatory signaling, alongside coordinated downregulation of MYC-driven proliferative programs, consistent with heightened inflammatory activation and reduced anabolic activity during aging. Age-dependent transcriptomic alterations across tissues were observed for all identified target genes. Hallmarks of aging assessment revealed chronic inflammation as the most enriched hallmark across aging and ARDs. Mendelian randomization analyses provided genetic causal support for IL6, IL6R, NLRP3, NOS2, TLR4, and GLP1R in aging-related traits and multiple ARDs, highlighting potential opportunities for drug repurposing. Co-localization analyses suggested that the same genetic variants influencing IL6R expression are also associated with parental survival, a proxy for human lifespan, supporting a role for IL-6 signaling in longevity, and indicated a shared genetic signal at the NOS2 locus associated with rheumatoid arthritis risk. Together, our findings outline a scalable AI-guided multi-omic framework for identifying causal and repurposable therapeutic targets for aging and ARDs.

The damage to Plasma-Faced Materials (PFMs) under helium (He) plasma irradiation includes upward fuzz growth and inward He bubble erosion. While current research on PFMs mainly focuses on fuzz growth, the equally critical issue of inward erosion into materials by high-flux, low-energy He plasma irradiation is often ignored. To fill this gap, we propose He bubble erosion thickness (L) as a quantitative metric to characterize the degree of He bubble erosion in PFMs induced by He plasma, defined as the thickness difference between the pristine sample and the remaining undamaged region after irradiation. Experimental studies on tantalum (Ta) and tungsten (W) films reveal that L follows a square-root dependence on He fluence, closely linked to He diffusion and He bubble formation. Similar to the diffusion coefficient of fuzz (D), the diffusion coefficient of He bubble erosion (D ') is introduced as a new quantitative parameter for evaluating the He bubble erosion rate of PFMs. A parameter, eta, is further introduced to distinguish the dominant damage mode. Notably, designed Ta/W multilayer exhibits significantly reduced D and similar D ' values compared to W, which is attributed to semi-coherent interfaces and the formation of a Ta-W alloy within the fuzz. This study provides not only valuable parameters for PFM evaluation but also a promising strategy for designing future PFMs.

Abstract MTAP deficiency is observed in approximately 15% of human cancers and leads to accumulation of methylthioadenosine (MTA), which competes with the methyl-donor S-adenosylmethionine (SAM) to partially inhibit post-translational methyltransferase activity of PRMT5. This molecular context creates a vulnerability in MTAP-deleted tumors, rendering them particularly susceptible to PRMT5 inhibition. MTA-cooperative PRMT5 inhibitors preferentially bind to PRMT5 when MTA occupies the SAM-binding pocket of PRMT5, thus increasing inhibitory specificity to MTAP-deficient cells. Here, we characterize ISM1745, a novel, orally bioavailable MTA-cooperative inhibitor. ISM1745 potently inhibits formation of symmetric dimethylarginine (SDMA), the PRMT5-catalyzed methylation product, and impairs cell growth in MTAP-deficient HCT116 cancer cells in vitro (IC50 = 1.1 nM), with 272-fold selectivity over MTAP wild-type HCT116 cells. In addition, Safety44 and methyltransferase panel screening indicated minimal off-target activity for ISM1745. Mechanistically, ISM1745 induces apoptosis, cell cycle arrest, and DNA damage specifically in MTAP-deleted cells, as indicated by an increased proportion of annexin V-positive cells, accumulation in the G1 phase, and elevated expression of DNA damage markers such as γH2AX. Once-daily oral administration of ISM1745 results in marked and sustained tumor growth inhibition in MTAP-deleted xenograft models. Moreover, when combined with ISM3412, an inhibitor of MAT2A, which catalyzes formation of SAM, ISM1745 exhibits significant synergistic anti-tumor activity, highlighting its promise as part of a combinatorial strategy for targeting MTAP-deficient cancers. In addition to its robust biological potency and high selectivity, ISM1745 exhibits favorable drug-like properties, including optimal in vitro ADMET profiles, excellent in vivo exposure, low clearance (CL<30% Qh in non-rodent species), and moderate to high oral bioavailability across multiple preclinical species. Taken together, these findings support ISM1745 as a potent and selective MTA-cooperative PRMT5 inhibitor with robust anti-tumor efficacy, providing potential therapy for treatment of MTAP-deleted cancers. Citation Format: Yilin Yang, Zhongying Cao, Meng Zhang, Xiaoyu Ding, Hongfu Lu, Qingchuan Zhao, Xiaoxia Lin, Jiaojiao Yu, David Gennert, Suguna Rachakonda, Xiao Ding, Xin Cai, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM1745, an MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7077.

The development of bifunctional electrocatalysts with outstanding performance is crucial for overall water splitting but remains a major challenge. Interfacial engineering has emerged as a promising strategy for fabricationg low-cost and highly efficient bifunctional catalysts. Herein, we report a Mo-NiSex/CoFe layered double hydroxide (LDH) heterojunction bifunctional electrocatalyst that integrates the high conductivity of NiSex with the abundant active sites of CoFe LDH. The catalyst was synthesized by combining in-situ selenization of nickel‑molybdenum foam (NMF) and electrodeposition growth, resulting in three-dimensional heterostructures composed of Mo-NiSex nanoneedles and CoFe LDH nanosheets grown on NMF. Benefiting from the high specific surface area and excellent electrical conductivity of Mo-NiSex, the strong corrosion resistance of CoFe LDH, and the low reaction energy barrier at their interfaces, the Mo-NiSex/CoFe LDH catalyst simultaneously exhibits outstanding hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performance, with ultra-low overpotentials of 144 and 200 mV at a current density of 100 mA/cm2, respectively, along with excellent stability. Furthermore, the dual-electrode water-splitting system assembled with Mo-NiSex/CoFe LDH achieves a current density of 100 mA/cm2 at 1.732 V and operates continuously for 600 h at industrial-grade current densities of 500 and 1000 mA/cm2. Anion exchange membrane water electrolyzer (AEMWE) constructed from Mo-NiSex/CoFe LDH attains a 1000 mA/cm2 current density at merely 1.990 V at 80 °C. Density functional theory (DFT) calculations reveal that Mo-NiSex/CoFe LDH enables electron redistribution through the heterogeneous interface, thereby optimizing the adsorption energies of hydrogen- and oxygen-containing intermediates. This process brings the Gibbs free energy of H* (ΔGH⁎) for the HER close to the optimal value and reduces the Gibbs free energy (ΔG) of the rate-determining step (RDS) for the OER. Furthermore, this synthesis method is environmentally friendly and easily scalable, and has been successfully applied to other systems, such as Mo-NiSex/NiFe LDH. Future work will focus on scaling up the preparation process and optimizing the parameters to prepare large-area, uniform electrodes, thereby advancing the practical application of this catalyst for efficient overall water electrolysis.

By employing reactive radio-frequency magnetron sputtering technology under various deposition pressures, high c-axis oriented AlN films were fabricated for high-temperature sensing applications. Through controlling the deposition pressure, the structure was optimized, resulting in dense, vertically aligned columnar grains with strong c-axis (002) orientation, enhancing the piezoelectric response and ultrasonic signal intensity. To improve thermal stability, a layer of HEAO protective layer was deposited by arc ion plating, effectively inhibiting oxidation and nitrogen loss during a long-term annealing process at up to 800 degrees C. The AlN film sensor with the HEAO layer maintained the stability of longitudinal wave excitation at high temperatures. Finally, it was integrated onto an alumina ceramic rod, achieving temperature sensing based on guided waves, with a R2 value of 99.999%, an absolute temperature error of less than 0.5 degrees C, and a relative error of less than 0.4%. These results indicate that combining structure optimization and HEAO protection provides an effective method for developing ultrasonic sensors suitable for harsh high-temperature environments.

Exploring efficient bifunctional electrocatalysts for both hydrogen and oxygen evolution reactions is key to water electrolysis. However, the inherently slow reaction kinetics of electrocatalysis are constrained by the mass transfer limitation and unsuitable adsorption/desorption dynamics. Herein, a Fe-doped-Ni3S2/NiFeCoCeIn oxide hydroxide (FNS/HEOXY) crystalline–amorphous heterostructure electro-catalyst with a large work function difference (ΔΦ) and strong built-in electric field (BEF) is successfully designed and synthesized. Benefiting from the electron transfer behavior from FNS to HEOXY, the FNS/HEOXY shows outstanding catalytic activity for both hydrogen and oxygen evolution, along with ultra-high stability in an alkaline medium at an industrial-level current density. Moreover, the anion exchange membrane water electrolyzer (AEMWE) assembled by the FNS/HEOXY requires only a minimal cell voltage of 1.83 V to reach 1 A cm−2 at 80 °C. Both experimental and theoretical results confirm the interfacial charge redistribution induced by the strong BEF, thus finely optimizing the adsorption energy. This work proposes a new design principle toward efficient electrocatalysts for energy conversion.

Drugs for aging-related diseases may modulate aging itself, but standard clinical trial designs cannot detect such effects. Aging clocks could close this gap, but epigenetic models often yield inconsistent, hard-to-interpret results. In contrast, proteomic clocks, by tracking the immediate effectors of biological change, may excel in providing aging biomarkers or mechanistic insight. Here we compare six proteomic clocks (ProtAge, OrganAgemortality, OrganAgechrono, PAC, ipfP3GPT and PAOPAC) on serum proteomes from a published 12-week phase 2a trial of the candidate anti-fibrotic drug rentosertib in idiopathic pulmonary fibrosis. We measure the variance between the clocks and find that all six clocks consistently predicted lower biological age in treated arms. However, proteomic clocks alone cannot deconvolute aging- and disease-specific effects. We addressed this issue indirectly through pathway analyses that identified potential anti-aging shifts in senescence and metabolic processes alongside the anti-fibrotic activity of rentosertib. This work supports the goal of dual-purpose clinical trial designs that integrate aging endpoints into studies for specific disease indications.

Developing high performance plasma facing materials (PFMs) is one of the greatest challenges for fusion reactors because PFMs face unprecedented harsh environments. In this work, the radiation resistance of tungstencontaining amorphous refractory multi-component alloy film was studied by He plasma irradiation. The amorphous TiZrHfTaW film was evaluated by 50 eV helium plasma irradiation at 1275 K. The invaded helium atoms quickly diffuse inside the film delaying the formation of large He bubbles near surface and its break to form fuzz. Instead, He migrates and merges to form large number of relatively small helium bubbles, leading to the formation of nanoporous structures, which blocks the diffusion of He. This new "migration-blocking" strategy in the amorphous TiZrHfTaW film greatly slowing down the growth of fuzz. The threshold fluence for forming fuzz structure in TiZrHfTaW film is increased greatly to 20 times higher and the length of fuzz irradiated to the fluence of 3 x 1026 ions/m2 is 28 times shorter than those of bulk W. The presented results provide an idea for development of amorphous refractory multi-component alloys as a new kind of radiation resistant PFMs and trigger further study on it.

Fibroblast growth factor receptors (FGFRs) are established oncogenic drivers in various solid tumors. However, the approved FGFR inhibitors face challenges with acquired resistance and dose-limiting adverse effects associated with FGFR1/4 inhibition, limiting therapeutic efficacy. Herein, we systematically explored linker and electrophile moieties based on the pyrrolopyrazine carboxamide core and identified aniline α-fluoroacrylamide as an effective covalent warhead. Compound 10 potently inhibited FGFR2 and FGFR3, even in the context of common inhibitor-resistance mutations, including in the gatekeeper, molecular brake, and activation loop regions. Compound 10 spared FGFR1/4 and other kinases without causing diarrhea and serum phosphate elevation in vivo. Oral administration of compound 10 induced tumor stasis or regression in the SNU-16 gastric cancer model with favorable pharmacokinetics and robust pharmacodynamic suppression.

Photocatalytic reduction of carbon dioxide (CO2) to carbon monoxide (CO) is the first step in reducing CO2 levels and synthesis of more complex carbon-containing compounds. The primary problem of the low efficiency of photocatalytic CO2 reduction reaction (CO2RR) is the difficulty of CO2 adsorption due to the weak dipole formed on CO2 and the surface of the catalyst, which prevents CO2RR. In this work, through S and single atom Co codoping into graphitic carbon nitride (g-C3N4) nanosheets, the greatly enhanced photocatalytic activity for CO2 reduction is triggered. The vacancies formed in-situ in the defect-containing g-C3N4 nanosheets become fast channels for S-atom doping. Compared with the defect-free g-C3N4, free S atoms are more likely to enter into gC3N4 nanosheets and be captured by single atom Co to form dopant atoms. The strong synergistic effect between S and single atom Co is found in S and single atom Co co-doped high crystallinity defective g-C3N4 (S-Co-hCN), which achieves a high CO conversion efficiency of 15.1 mu mol g- 1h- 1 (151 times of hCN), high CO selectivity of 95 %, and the highest reported apparent quantum yield (AQY) of 3.31 % at 420 nm. The mechanism for the triggered photocatalytic activity was studied by in-situ FTIR measurements and DFT calculations, it was recognized that S and Co co-doping formed larger and more stable CO2 adsorbed dipole moments on the catalyst surface which were beneficial to the CO2 adsorbing and the process of CO2RR to CO. This new strategy of modulating dipole by metal and non-metal element co-doping is a new route to solve the week absorption of CO2 on catalyst, and therefore, enhancing the catalytic activity for CO2RR.