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Abstract Acute myeloid leukemia (AML) featuring retinoic acid receptor-gamma (RARG) rearrangements exhibits morphological features resembling those of acute promyelocytic leukemia but is associated with drug resistance and poor clinical outcomes. However, the mechanisms underlying the role of RARG fusions in leukemogenesis remain elusive. Here, we show that RARG fusions disrupt myeloid differentiation and promote proliferation and self-renewal of hematopoietic stem and progenitor cells (HSPCs) by upregulating BCL2 and ATF3. RARG fusions overexpression leads to preleukemic phenotypes but fails to induce oncogenic transformation. However, the co-occurrence of RARG fusions and heterozygous Wt1 loss induce fully penetrant AML by activating MYC and HOXA9/MEIS1 targets. Leveraging Connectivity Map resources and high-throughput screening, we identify venetoclax, homoharringtonine, and daunorubicin as potential therapeutic options for RARG-AML. Overall, our findings provide pivotal insights into the molecular mechanisms governed by RARG fusions and enhanced by WT1 loss in AML development and propose a rational therapeutic strategy for RARG-AML.

Abstract Ovarian function declines significantly as females enter middle-age, but the mechanisms underlying this decline remain unclear. Here, we utilize whole-organ imaging to observe a notable decrease in ovarian blood vessel (oBV) density and angiogenesis intensity of middle-aged mice. This leads to a diminished blood supply to the ovaries, resulting in inadequate development and maturation of ovarian follicles. Utilizing genetic-modified mouse models, we demonstrate that granulosa cell secreted VEGFA governs ovarian angiogenesis, but the physiological decline in oBV is not attributed to VEGFA insufficiency. Instead, through single-cell sequencing, we identify the aging of the ovarian vascular endothelium as the primary factor contributing to oBV decline. Consequently, the administration of salidroside, a natural compound that is functional to reverse oBV aging and promote ovarian angiogenesis, significantly enhances ovarian blood supply and improve fertility in older females. Our findings highlight that enhancing oBV function is a promising strategy to boost fertility in females.

Abstract Disrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, and lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent cell death. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkalization-induced cell death in pancreatic cancer cells. Inducing intracellular alkalization by the small molecule JTC801 leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of cell death. In animal models, including xenografts, syngeneic orthotopic, and patient-derived models, the genetic or pharmacological inhibition of CYP51A1 enhances the effectiveness of JTC801 in suppressing pancreatic tumors. These findings demonstrate a role of the CYP51A1-dependent lysosomal pathway in inhibiting alkalization-induced cell death and highlight its potential as a targetable vulnerability in pancreatic cancer.

Abstract Materials science exploits only properties that are available at ambience. Therefore, although high-pressure changes the physical state of all condensed matter, most of the extraordinary properties discovered vanish after decompression and cannot be utilized. Here, we demonstrate sublattice decoupling in a mixed-anion chalcohalide Rb6Re6S8I8 upon compression, in which the [Rb6I2]4+ framework is soft and plastic, while the [Re6S8I6]4- clusters are hard and elastic. This discrepancy in the rigidity allows the applied pressure to selectively amorphize the framework while maintaining the ordered state in the cluster, leading to intriguing photocurrent generation and enhancement upon compression. These high-pressure properties are retained at ambience, permitting scalable synthesis of the decompressed samples using a large-volume press, followed by further fabrication into self-powered broadband photodetectors with a response time of ~ 102 μs and a specific detectivity of ~ 1011 Jones. This study subverts the stereotype that pressure engineering is hardly to be employed for device applications.

Abstract Electrochemical extraction of uranium from seawater is a promising strategy for the sustainable supply of nuclear fuel, whereas the current progress suffers from the co-deposition of impurities. Herein, we construct a synergistic coordination-reduction interface in CMOS@NSF, achieving electrochemical extraction of black UO2 product from seawater. The internal sulfur of CoMoOS tailors the electron distribution, resulting in the electron accumulation of terminal O sites for strong uranyl binding. Meanwhile, the interfacial connection of CoMoOS with Ni3S2 accelerates the electron transfer and promoted the reductive properties. Such synergistic coordination-reduction interface ensures the formation and preservation of tetravalent uranium, preventing the co-deposition of alkalis in crystalline transformation. From natural seawater, CMOS@NSF exhibits an electrochemical extraction capacity of 2.65 mg g−1 d−1 with black UO2 solid products as final products. This work provides an efficient strategy for the electrochemical uranium extraction from seawater with low impurities.

Abstract Plant peptide hormones play an important role in regulating root development and stress responses. Here, we identify a root-derived CLAVATA3/Endosperm surrounding region-related (CLE) peptide TaCLE24b and its leucine-rich repeat receptor-like kinase CLAVATA1 (CLV1) TaCLV1, which together regulate the formation of lateral root primordium and the outgrowth of lateral root in wheat. Additionally, a loss-of-function mutation of TaSG-D1, encoding a Ser/Thr protein kinase glycogen synthase kinase 3 (STKc_GSK3), also enhances the formation of lateral root primordium and the outgrowth of lateral roots in wheat. Furthermore, TaCLV1 interacts with TaSG-D1, leading to phosphorylation and degradation of TaSG-D1. Whereas the presence of TaCLE24b enhances the binding affinity and phosphorylation ability of TaCLV1 to TaSG-D1, thereby positively fine-tuning lateral root development and contributing to drought tolerance in wheat. Overall, our findings provide new insights into the significance of the peptide signaling pathway in regulating lateral root development and responding to drought stress in wheat.

Abstract The efficacy and safety of induction-immunotherapy followed by surgery for unresectable Stage III non-small cell lung cancer (NSCLC) remain challenging. In this open-label, single-center, phase II clinical umbrella trial (ChiCTR2000035367), 100 unresectable Stage III NSCLC patients are enrolled. Patients with PD-L1 expression ≥ 50% but contraindications to anti-angiogenic therapy receive immuno-monotherapy. Patients with PD-L1 expression ≥ 1% and no contraindications to anti-angiogenic therapy receive immunotherapy plus anti-angiogenesis therapy. Patients with PD-L1 expression between 1% and 49%, contraindications to anti-angiogenic therapy, or negative/unknown PD-L1 expression receive chemoimmunotherapy. The primary endpoint is the major pathological response (MPR) rate. Among 47 surgically-treated patients, the MPR rate is 61.7% (95% confidence interval [CI]: 46.4%-75.5%), achieving the prespecified endpoint. For secondary endpoints, the objective response rate for all patients is 54.0% (95% CI: 43.7-64.0). The median event-free survival is 29.9 months (95% CI: 17.0-42.7). Most common adverse event is anemia (49.0%). Exploratory transcriptomic analyses reveal Bone Marrow Stromal Cell Antigen 1 (BST1) as a promising biomarker for response to chemoimmunotherapy. Generally, for unresectable stage III NSCLC patients, anti-PD1 based induction-therapy according to PD-L1 expression and contraindication to antiangiogenic therapy followed by surgery is a feasible option.

Abstract G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by protecting the integrity of the endothelial barrier without affecting immune cell egress. Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment.

Abstract Chiral metal clusters have promise for circularly polarized luminescent materials; however, the absence of a unified understanding of the emission mechanism causes challenges in designing high-efficiency lighting materials based on these clusters. These challenges primarily arise from their vast structural variability and intricate emissive states. In this study, we show the crucial roles of the exciton binding energy and electron‒phonon interactions in achieving high-efficiency phosphorescence. Through Cu doping in the Au4 clusters and changing ligand substituents, we increase the exciton binding energies and reduce the electron‒phonon interactions; this results in a maximum 1.3-fold increase in the radiative recombination rate, a maximum 241.1-fold decrease in the nonradiative recombination rate, and ultimately a phosphorescence quantum yield of over 96% and circularly polarized luminescence in metal cluster crystals. A solution-processed circularly polarized light-emitting diode prototype exhibits an external quantum efficiency of 15.51% in green and a maximum dissymmetry factor |g EL| of 7.6 × 10−3. Our findings highlight the significance of designing metal clusters with optimized exciton binding energies and electron‒phonon interactions for enhanced optoelectronic performance, including in circularly polarized optoelectronics.

Abstract Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

Abstract During infection and cancer, mTORC1-mediated metabolic regulation impacts CD8+ T cell effector expansion and memory development. However, the mechanisms by which CD8+ T cells regulate mTORC1 to support their unique metabolic requirements remain unknown. Here we show that NKG7, a lysosomal protein whose expression is restricted to cytotoxic lymphocytes, negatively regulates mTORC1 recruitment and activation by inhibiting assembly and function of the lysosomal proton pump, vacuolar ATPase (v-ATPase). Human and mouse CD8+ T cells lacking NKG7 show more acidic lysosomes and increased activation of mTORC1 signaling, which could be reversed by inhibition of v-ATPase activity. In mice responding to LCMV infection, NKG7-deleted effector CD8+ T cells are less durable and generate fewer memory precursors, whereas induced expression of NKG7 in CD8+ T cells results in increased presence of intra-tumoral T cells. Overall, our work identifies NKG7 as a CD8+ T cell-specific regulator of mTORC1 activity, required for optimal immune responses.

Abstract Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid (DHA). An increased level of circulating DHA inhibits PD-L1 expression in tumor cells by binding the PD-L1 promoter and subsequently prevents c-myc-initiated transcription of PD-L1. Colonization of germ-free male mice with gut bacteria from anti-PD-L1 non-responding patients supplemented with DHA enhances the efficacy of anti-PD-L1 therapy compared to controls. Our findings reveal a previously unknown mechanistic impact of PNP on human tumor immunotherapy by modulating gut bacterial metabolic pathways.

Abstract Despite numerous efforts involving surface coating, doping, and alloying, maintaining surface stability of metal at high temperatures without compromising intrinsic properties has remained challenging. Here, we present a pragmatic method to address the accelerated oxidation of Cu, Ni, and Fe at temperatures exceeding 200 °C. Inspired by the concept that oxygen (O) itself can effectively obstruct the pathway of O infiltration, this study proposes the immobilization of O on the metal surface. Through extensive calculations considering various elements (C, Al, Si, Ge, Ga, In, and Sn) to anchor O on Cu surfaces, Si emerges as the optimal element. The theoretical findings are validated through systematic sputtering deposition experiments. The introduction of anchoring elements to reinforce Cu–O bonds enables the formation of an atomically thin barrier on the Cu surface, rendering it impermeable to O even at high temperatures (400 °C) while preserving its intrinsic conductivity. This oxidation resistance, facilitated by the impermeable atomic monolayer, opens promising opportunities for researchers and industries to overcome limitations associated with the use of oxidizable metal films.

Abstract The literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases.

Abstract A human hand has 23-degree-of-freedom (DOF) dexterity for managing activities of daily living (ADLs). Current prosthetic hands, primarily driven by motors or pneumatic actuators, fall short in replicating human-level functions, primarily due to limited DOF. Here, we develop a lightweight prosthetic hand that possesses biomimetic 19-DOF dexterity by integrating 38 shape-memory alloy (SMA) actuators to precisely control five fingers and the wrist. The prosthetic hand features real-time sensing of joint angles in each finger, feeding data into a control module for selectively heating or cooling SMA actuators in a closed-loop manner, mimicking the functioning of human muscles. Enabled by the high-power density of SMAs, the hand part (from the wrist to the fingertip) only weighs 0.22 kg, much lower than existing products. We also integrate an onboard power management module that provides electricity for operating the entire system. In addition to 33 standard grasping modes, this prosthetic hand supports 6 advanced grasping modes designed for enhanced dexterity evaluation, expanding the range of achievable ADLs for amputees while facilitating standard prosthesis function tests and validation in real-world scenarios. This innovation offers a significant advancement in prosthetic hand functions, promising improved quality of life for users.

Abstract The high performance of two-dimensional (2D) channel membranes is generally achieved by preparing ultrathin or forming short channels with less tortuous transport through self-assembly of small flakes, demonstrating potential for highly efficient water desalination and purification, gas and ion separation, and organic solvent waste treatment. Here, we report the construction of vertical channels in graphene oxide (GO) membrane based on a substrate template with asymmetric pores. The membranes achieved water permeance of 2647 L m−2 h−1 bar−1 while still maintaining an ultrahigh rejection rate of 99.9% for heavy metal ions, which is superior to the state-of-the-art 2D membranes reported. Furthermore, the membranes exhibited excellent stability during long-term filtration experiments for at least 48 h, as well as resistance to ultrasonic treatment for over 100 minutes. The vertical channels possess very short pathway for almost direct water transport and a highly effective channel area, meanwhile the asymmetric porous template enhances the packing of the inserted GO nanosheets to avoid the swelling effect of membrane. Our work provides a simple way to fabricate vertical channels of 2D nanofiltration membranes with high water purification performance.

Abstract Transition-metal layered double hydroxides are widely utilized as electrocatalysts for the oxygen evolution reaction (OER), undergoing dynamic transformation into active oxyhydroxides during electrochemical operation. Nonetheless, our understanding of the non-equilibrium structural changes that occur during this process remains limited. In this study, utilizing in situ energy-dispersive X-ray absorption spectroscopy and machine learning analysis, we reveal the occurrence of deprotonation and elucidate the role of incorporated iron in facilitating the transition from nickel-iron layered double hydroxide (NiFe LDH) into its active oxyhydroxide. Our findings demonstrate that iron substitution promotes deprotonation process within NiFe LDH, resulting in the preferential removal of protons from the specific bridged hydroxyl group (Ni2+-OH-Fe3+) linked to edge-sharing [NiO6] and [FeO6] octahedron. This deprotonation behavior drives the formation of high-valence Ni3+δ species (0

Abstract While self-assembled material based inverted perovskite solar cells have surpassed power conversion efficiencies of 26%, enhancing their performance in large-area configurations remains a significant challenge. In this work, we report a self-assembled material based hole-selective layer 4-(7H-dibenzo[c,g]carbazol-7-yl)phenyl)phosphonic acid, with a π-expanded conjugation. The enhanced intermolecular π–π interactions facilitate the self-assembly of 4-(7H-dibenzo[c,g]carbazol-7-yl)phenyl)phosphonic acid molecules to form an ordered bilayer with a hydrophilic surface, which passivates the buried perovskite interface defect and enables high-quality and large-area perovskite preparation, while simultaneously enhancing interfacial charge extraction and transport. The certified efficiency of 4-(7H-dibenzo[c,g]carbazol-7-yl)phenyl)phosphonic acid based small-area (0.0715 cm2) device is 26.39% with high stability. Furthermore, a certified efficiency of 25.21% is achieved for a 99.12 mm2 large area device.

Abstract Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that circPETH, a circular RNA (circRNA) transported via extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis in recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in an m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via the MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by increasing HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, through virtual and experimental screening, we find that a small molecule, Norathyriol, is an effective inhibitor that targets the MEG pocket on the circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes by HCC cells, increases anti-PD1 efficacy, and enhances cytotoxic CD8+ T-cell function. Here we show that Norathyriol is a promising anti-HCC agent that contributes to attenuating the resistance of advanced HCC to immune checkpoint blocker (ICB) therapies.

Abstract Aqueous zinc ion batteries exhibit great prospects due to their low cost and high safety, while their lifespan is limited by severe dendritic growth problems. Herein, we develop an anti-dendrite hot-pressing separator interlayer through a mass-producible hot-pressing strategy, by spreading metal-organic framework (MOF) precursor on nonwoven matrix followed by a simple hot-pressing process. The in situ modification of MOF crystals on fiber surface processes abundant nitrogenous functional groups and high specific surface area (190.8 m2 g−1) with a strong attraction to Zn2+. These features contribute to a staged deposition behavior to promote uniform nucleation at high concentrations and two-dimensional grain growth at low concentrations. Consequently, Zn | |Zn symmetrical cells with hot-pressing separator interlayer demonstrate cycle lives of 3000 hours at 2 mA cm−2, 2 mAh cm−2. Moreover, Zn | |I2 pouch batteries with hot-pressing separator interlayer realizes 840 cycles lifespan with a capacity retention of 90.9% and a final discharge capacity of 110.6 mAh at 25 °C.

Abstract The continuous push for high-performance photonic switches is one of the most crucial premises for the sustainable scaling of programmable and reconfigurable photonic circuits for a wide spectrum of applications. Conventional optical switches rely on the perturbative mechanisms of mode coupling or mode interference, resulting in inherent bottlenecks in their switching performance concerning size, power consumption and bandwidth. Here we propose and realize a silicon photonic 2×2 elementary switch based on a split waveguide crossing (SWX) consisting of two halves. The propagation direction of the incident light is manipulated to implement the OFF/ON states by splitting/combining the two halves of the SWX, showing excellent performance with low excess loss and low crosstalk over an ultrawide bandwidth. Both elementary switch and a 64×64 switch array based on Benes topology are fabricated and characterized, demonstrating great potential for practical scenarios such as photonic interconnect/routing, Lidar and spectroscopy, photonic computing, as well as microwave photonics.

Abstract Solar-driven CO2 reduction to value-added C2 chemicals is thermodynamically challenging due to multiple complicated steps. The design of active sites and structures for photocatalysts is necessary to improve solar energy efficiency. In this work, atomically dispersed Ru-O sites in RuxIn2-xO3 are constructed by interior lattice anchoring of Ru. This results in the dynamic reconstruction of Ruδ+-O/Ru0-O sites upon photoexcitation, which facilitates the CO2 activation, *CO intermediates adsorption, and C-C coupling as demonstrated by varied in situ techniques. A SiO2 core in RuxIn2-xO3/SiO2 construction further enhances the solar energy utilization and individual RuxIn2-xO3 nanocrystals dispersion for photocatalytic CO2 reduction reaction. It results in the maximum ethanol production rate up to 31.6 μmol/g/h with over 90% selectivity. DFT simulation reveals that the C2 dimer formation primarily underwent an asymmetric *CO-*CHO coupling route via a low-energy precedence ladder of *CHO. This work provides an insightful understanding of active sites with dynamic reconstruction towards asymmetric C-C coupling for CO2RR at the atomic scale.

Abstract Direct carbonylation of CH4 to CH3COOH provides a promising pathway for upgrading of natural gas to transportable liquid chemicals, in which high-efficiency CH4 activation and controllable C–C coupling are both critical but challenging. Herein, we report that highly efficient photo-driven carbonylation of CH4 with CO and O2 to CH3COOH is achieved over MoS2-confined Rh-Zn atomic-pair in conjunction with TiO2. It delivers a high CH3COOH productivity of 152.0 μmol gcat. −1 h−1 and turnover frequency of 62.0 h−1 with a superior selectivity of 96.5%, outperforming previous photocatalytic CH4 carbonylation processes. Mechanistic investigations disclose the key effect of Rh-Zn synergy in combination with photo-excited electrons from TiO2 for CH3COOH formation. The active OH species produced from O2 photoreduction on the Zn site through proton-coupled electron transfer promotes CH4 dissociation to CH3 species, which then facilely couples with adsorbed CO on the adjacent Rh site forming the key CH3CO intermediate for CH3COOH formation.

Abstract The growing potential of low-dimensional metal-halide perovskites as conversion-type cathode materials is limited by electrochemically inert B-site cations, diminishing the battery capacity and energy density. Here, we design a benzyltriethylammonium tellurium iodide perovskite, (BzTEA)2TeI6, as the cathode material, enabling X- and B-site elements with highly reversible chalcogen- and halogen-related redox reactions, respectively. The engineered perovskite can confine active elements, alleviate the shuttle effect and promote the transfer of Cl- on its surface. This allows for the utilization of inert high-valent tellurium cations, eventually realizing a special eleven-electron transfer mode (Te6+/Te4+/Te2-, I+/I0/I-, and Cl0/Cl-) in suitable electrolytes. The Zn||(BzTEA)2TeI6 battery exhibited a high capacity of up to 473 mAh g-1 Te/I and a large energy density of 577 Wh kg-1 Te/I at 0.5 A g-1, with capacity retention up to 82% after 500 cycles at 3 A g-1. The work sheds light on the design of high-energy batteries utilizing chalcogen-halide perovskite cathodes.

Abstract The capacity to discern and locate positions in three-dimensional space is crucial for human-machine interfaces and robotic perception. However, current soft electronics can only obtain two-dimensional spatial locations through physical contact. In this study, we report a non-contact position targeting concept enabled by transparent and thin soft electronic skin (E-skin) with three-dimensional sensing capabilities. Inspired by the active electrosensation of mormyroidea fish, this E-skin actively ascertains the 3D positions of targeted objects in a contactless manner and can wirelessly convey the corresponding positions to other devices in real-time. Consequently, this E-skin readily enables interaction with machines, i.e., manipulating virtual objects, controlling robotic arms, and drones in either virtual or actual 3D space. Additionally, it can be integrated with robots to provide them with 3D situational awareness for perceiving their surroundings, avoiding obstacles, or tracking targets.

Abstract SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2H34, and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity.

Abstract Unlike most other picornaviruses, foot-and-mouth disease (FMD) intact virions (146S) dissociate easily into small pentameric subunits (12S). This causes a dramatically decreased immunogenicity by a mechanism that remains elusive. Here, we present the high-resolution structures of 12S (3.2 Å) and its immune complex of a single-domain antibody (VHH) targeting the particle interior (3.2 Å), as well as two 146S-specific VHHs complexed to distinct sites on the 146S capsid surface (3.6 Å and 2.9 Å). The antigenic landscape of 146S is depicted using 13 known FMD virus-antibody complexes. Comparison of the immunogenicity of 146S and 12S in pigs, focusing on the resulting antigenic sites and incorporating structural analysis, reveals that dissociation of 146S leads to structural alteration and destruction of multiple epitopes, resulting in significant differences in antibody profiles/lineages induced by 12S and 146S. Furthermore, 146S generates higher synergistic neutralizing antibody titers compared to 12S, whereas both particles induce similar total FMD virus specific antibody titers. This study can guide the structure-based rational design of novel multivalent and broad-spectrum recombinant vaccines for protection against FMD.

Abstract Questions of unfairness and inequity pose critical challenges to the successful deployment of artificial intelligence (AI) in healthcare settings. In AI models, unequal performance across protected groups may be partially attributable to the learning of spurious or otherwise undesirable correlations between sensitive attributes and disease-related information. Here, we introduce the Attribute Neutral Framework, designed to disentangle biased attributes from disease-relevant information and subsequently neutralize them to improve representation across diverse subgroups. Within the framework, we develop the Attribute Neutralizer (AttrNzr) to generate neutralized data, for which protected attributes can no longer be easily predicted by humans or by machine learning classifiers. We then utilize these data to train the disease diagnosis model (DDM). Comparative analysis with other unfairness mitigation algorithms demonstrates that AttrNzr outperforms in reducing the unfairness of the DDM while maintaining DDM’s overall disease diagnosis performance. Furthermore, AttrNzr supports the simultaneous neutralization of multiple attributes and demonstrates utility even when applied solely during the training phase, without being used in the test phase. Moreover, instead of introducing additional constraints to the DDM, the AttrNzr directly addresses a root cause of unfairness, providing a model-independent solution. Our results with AttrNzr highlight the potential of data-centered and model-independent solutions for fairness challenges in AI-enabled medical systems.

Abstract Bats are presumed reservoirs of diverse coronaviruses (CoVs) including progenitors of Severe Acute Respiratory Syndrome (SARS)-CoV and SARS-CoV-2, the causative agent of COVID-19. However, the evolution and diversification of these coronaviruses remains poorly understood. Here we use a Bayesian statistical framework and a large sequence data set from bat-CoVs (including 589 novel CoV sequences) in China to study their macroevolution, cross-species transmission and dispersal. We find that host-switching occurs more frequently and across more distantly related host taxa in alpha- than beta-CoVs, and is more highly constrained by phylogenetic distance for beta-CoVs. We show that inter-family and -genus switching is most common in Rhinolophidae and the genus Rhinolophus. Our analyses identify the host taxa and geographic regions that define hotspots of CoV evolutionary diversity in China that could help target bat-CoV discovery for proactive zoonotic disease surveillance. Finally, we present a phylogenetic analysis suggesting a likely origin for SARS-CoV-2 in Rhinolophus spp. bats.

Abstract Iron is a potent biochemical, and accurate homeostatic control is orchestrated by a network of interacting players at multiple levels. Although our understanding of organismal iron homeostasis has advanced, intracellular iron homeostasis is poorly understood, including coordination between organelles and iron export into the ER/Golgi. Here, we show that SLC39A13 (ZIP13), previously identified as a zinc transporter, promotes intracellular iron transport and reduces intracellular iron levels. ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol. ZIP13 overexpression has the opposite effect, increasing iron in organellar compartments. We suggest that ZIP13 gatekeeps an iron trafficking route that shunts iron from the cytosol to the ER/Golgi hub. Zip13-knockout male mice have iron deposition in several tissues. These data demonstrate that mammalian ZIP13 is crucial for iron homeostasis and suggest a potential iron transport function.

Abstract Water oxidation presents a promising avenue for hydrogen peroxide (H2O2) production. However, the reliance on alkaline bicarbonate electrolytes as an intermediate has limitations, such as H2O2 decomposition and a narrow pH effectiveness range (7–9), restricting its utility across wider pH ranges. This study unveils a crystal OH mediating pathway that stabilizes SO4OH* as a crucial intermediate. Basic copper carbonate (Cu2(OH)2CO3) tablets, commonly found on cultural relics, exhibit the capability to generate H2O2 in neutral or acidic non-bicarbonate electrolytes. By leveraging this crystal OH mediating strategy, considerable H2O2 production in Na2SO4 electrolytes is achievable. Notably, the H2O2 production rate can reach 64.35 μmol h−1 at 3.4 V vs. RHE in a 50 mL 0.5 M Na2SO4 electrolyte. This research underscores the importance of crystal part in catalyst in catalyzing the 2e− water oxidation reaction, offering valuable insights for future investigations.

Abstract The antioxidant protein sulfiredoxin-1 (SRX) is an oncogenic factor that promotes tumor progression, but the regulatory mechanism underlying SRX degradation remains to be understood. Herein, we report that Keap1, the substrate-specific adapter of CRL3 complex, specifically binds and promotes the ubiquitin-mediated degradation of SRX at residue K61. Keap1 knockdown accumulates SRX, which in turn facilitates colorectal cancer (CRC) metastasis by activating the activator protein-1/matrix metalloproteinase 9 (AP-1/MMP9) pathway. CRC-associated Keap1 mutants within the BACK domain lose the capability to ubiquitinate SRX and instead promote CRC metastasis. Moreover, inactivation of Keap1 facilitates CRC tumorigenesis and metastasis in mouse models of tumor xenograft due to SRX accumulation. Clinical sample analysis reveals that Keap1 is downregulated while SRX is overexpressed in CRC, which correlates with poor prognosis. Our findings elucidate a mechanism by which CRL3Keap1 ubiquitin ligase degrades SRX to suppress CRC progression, indicating that the Keap1-SRX axis will guide the targeted therapy towards CRC.

Abstract Schizophrenia is a severe neuropsychiatric disease, but the initiation mechanisms are unclear. Although antipsychotics are effective against positive symptoms, therapeutic interventions for negative symptoms are limited due to the lack of pathophysiological mechanisms. Here we identify synaptotagmin-11 (Syt11) as a potential genetic risk factor and dopamine over-transmission as a mechanism in the development of schizophrenia. Syt11 expression is reduced in individuals with schizophrenia but restored following the treatment with antipsychotics. Syt11 deficiency in dopamine neurons in early adolescence, but not in adults, leads to persistent social deficits and other schizophrenia-like behaviors by mediating dopamine over-transmission in mice. Accordingly, dopamine neuron over-excitation before late adolescence induces persistent schizophrenia-associated behavioral deficits, along with the structural and functional alternations in the mPFC. Notably, local intervention of D2R with clinical drugs presynaptically or postsynaptically exhibits both acute and long-lasting therapeutic effects on social deficits in schizophrenia mice models. These findings not only define Syt11 as a risk factor and DA over-transmission as a potential risk factor initiating schizophrenia, but also propose two D2R-targeting strategies for the comprehensive and long-term recovery of schizophrenia-associated social withdrawal.

Abstract Optical properties of cholesteric liquid crystal elastomers (CLCEs) can be tuned by an external field, however, it will spontaneously restore to the original state after the field is removed. Here, we introduce diselenide dynamic covalent bonds (DCBs) into CLCEs, whose optical properties can be reversibly and precisely tuned under the combined action of force and light. The tuned optical properties will be written into and remembered by the CLCEs, thus a programming effect is achieved. The prepared dynamical diselenide bonded CLCE films have the typical reversibly mechanochromism property, and high-resolution colourful patterning can be programmed by adjusting exposure time and intensity of masked visible-light under different tensile or compressive strain states. The DCB-CLCEs combine the novel anisotropy of CLCEs and the dynamic chain exchangeable ability of DCBs, which endows the materials with reprogrammable optical properties. We demonstrate a simple strategy of writing naked-eye high-resolution colourful patterning into a film with mechanochromism property by thermal or visible-light, it shows great potential in display devices, anticounterfeiting labels, sensors, optical films and smart materials.

Abstract Embryonic stem cells possess the remarkable ability to self-organize into blastocyst-like structures upon induction. These stem cell-based embryo models serve as invaluable platforms for studying embryogenesis and therapeutic developments. Nevertheless, the specific intrinsic regulators that govern this potential for blastoid formation remain unknown. Here we demonstrate an intrinsic program that plays a crucial role in both blastoids and blastocysts across multiple species. We first establish metrics for grading the resemblance of blastoids to mouse blastocysts, and identify the differential activation of gene regulons involved in lineage specification among various blastoid grades. Notably, abrogation of nuclear receptor subfamily 1, group H, member 2 (Nr1h2) drastically reduces blastoid formation. Nr1h2 activation alone is sufficient to rewire conventional ESC into a distinct pluripotency state, enabling them to form blastoids with enhanced implantation capacity in the uterus and contribute to both embryonic and extraembryonic lineages in vivo. Through integrative multi-omics analyses, we uncover the broad regulatory role of Nr1h2 in the transcriptome, chromatin accessibility and epigenome, targeting genes associated with embryonic lineage and the transposable element SINE-B1. The Nr1h2-centred intrinsic program governs and drives the development of both blastoids and early embryos.

Abstract Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer’s patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

Abstract Oxide ceramic electrolytes (OCEs) have great potential for solid-state lithium metal (Li0) battery applications because, in theory, their high elastic modulus provides better resistance to Li0 dendrite growth. However, in practice, OCEs can hardly survive critical current densities higher than 1 mA/cm2. Key issues that contribute to the breakdown of OCEs include Li0 penetration promoted by grain boundaries (GBs), uncontrolled side reactions at electrode-OCE interfaces, and, equally importantly, defects evolution (e.g., void growth and crack propagation) that leads to local current concentration and mechanical failure inside and on OCEs. Here, taking advantage of a dynamically crosslinked aprotic polymer with non-covalent –CH3⋯CF3 bonds, we developed a plastic ceramic electrolyte (PCE) by hybridizing the polymer framework with ionically conductive ceramics. Using in-situ synchrotron X-ray technique and Cryogenic transmission electron microscopy (Cryo-TEM), we uncover that the PCE exhibits self-healing/repairing capability through a two-step dynamic defects removal mechanism. This significantly suppresses the generation of hotspots for Li0 penetration and chemomechanical degradations, resulting in durability beyond 2000 hours in Li0-Li0 cells at 1 mA/cm2. Furthermore, by introducing a polyacrylate buffer layer between PCE and Li0-anode, long cycle life >3600 cycles was achieved when paired with a 4.2 V zero-strain cathode, all under near-zero stack pressure.

Abstract Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women’s health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, genetic alterations, immune infiltration, and post-translational modification regulations. PRKCB is further identified as a potential radioresponse-related biomarker of CC patients. This study provides a valuable public resource for researchers and clinicians to delve into the molecular basis of CC, to identify potential treatments and to ultimately advance clinical practice.

Abstract Covalent organic frameworks have emerged as a thriving family in the realm of photocatalysis recently, yet with concerns about their high exciton dissociation energy and sluggish charge transfer. Herein, a strategy to enhance the built-in electric field of series β-keto-enamine-based covalent organic frameworks by ionic polarization method is proposed. The ionic polarization is achieved through a distinctive post-synthetic quaternization reaction which can endow the covalent organic frameworks with separated charge centers comprising cationic skeleton and iodide counter-anions. The stronger built-in electric field generated between their cationic framework and iodide anions promotes charge transfer and exciton dissociation efficiency. Moreover, the introduced iodide anions not only serve as reaction centers with lowered H* formation energy barrier, but also act as electron extractant suppressing the recombination of electron-hole pairs. Therefore, the photocatalytic performance of the covalent organic frameworks shows notable improvement, among which the CH3I-TpPa-1 can deliver an high H2 production rate up to 9.21 mmol g−1 h−1 without any co-catalysts, representing a 42-fold increase compared to TpPa-1, being comparable to or possibly exceeding the current covalent organic framework photocatalysts with the addition of Pt co-catalysts.

Abstract Microplastic pollution, an emerging environmental issue, poses significant threats to aquatic ecosystems and human health. In tackling microplastic pollution and advancing green hydrogen production, this study reveals a tandem catalytic microplastic degradation-hydrogen evolution reaction (MPD-HER) process using hierarchical porous carbon nitride-supported single-atom iron catalysts (FeSA-hCN). Through hydrothermal-assisted Fenton-like reactions, we accomplish near-total ultrahigh-molecular-weight-polyethylene degradation into C3-C20 organics with 64% selectivity of carboxylic acid under neutral pH, a leap beyond current capabilities in efficiency, selectivity, eco-friendliness, and stability over six cycles. The system demonstrates versatility by degrading various daily-use plastics across different aquatic settings. The mixture of FeSA-hCN and plastic degradation products further achieves a hydrogen evolution of 42 μmol h‒1 under illumination, outperforming most existing plastic photoreforming methods. This tandem MPD-HER process not only provides a scalable and economically feasible strategy to combat plastic pollution but also contributes to the hydrogen economy, with far-reaching implications for global sustainability initiatives.

Abstract Iron is an essential biomineral in the human body. Here, we describe a subset of iron-loaded cancer-associated fibroblasts, termed as FerroCAFs, that utilize iron to induce immunosuppression in prostate cancer and predict an unfavorable clinical outcome. FerroCAFs secrete myeloid cell-associated proteins, including CCL2, CSF1 and CXCL1, to recruit immunosuppressive myeloid cells. We report the presence of FerroCAFs in prostate cancer from both mice and human, as well as in human lung and ovarian cancers, and identify a conserved cell surface marker, the poliovirus receptor. Mechanistically, the accumulated iron in FerroCAFs is caused by Hmox1-mediated iron release from heme degradation. The intracellular iron activates the Kdm6b, an iron-dependent epigenetic enzyme, to induce an accessible chromatin state and transcription of myeloid cell-associated protein genes. Targeting the FerroCAFs by inhibiting the Hmox1/iron/Kdm6b signaling axis incurs anti-tumor immunity and tumor suppression. Collectively, we report an iron-loaded FerroCAF cluster that drives immunosuppression through an iron-dependent epigenetic reprogramming mechanism and reveal promising therapeutic targets to boost anti-tumor immunity.

Abstract The etiology of primary open angle glaucoma is constituted by both intraocular pressure-dependent and intraocular pressure-independent mechanisms. However, GWASs of traits affecting primary open angle glaucoma through mechanisms independent of intraocular pressure remains limited. Here, we address this gap by subtracting the genetic effects of a GWAS for intraocular pressure from a GWAS for primary open angle glaucoma to reveal the genetic contribution to primary open angle glaucoma via intraocular pressure-independent mechanisms. Seventeen independent genome-wide significant SNPs were associated with the intraocular pressure-independent component of primary open angle glaucoma. Of these, 7 are located outside known normal tension glaucoma loci, 11 are located outside known intraocular pressure loci, and 2 are novel primary open angle glaucoma loci. The intraocular pressure-independent genetic component of primary open angle glaucoma is associated with glaucoma endophenotypes, while the intraocular pressure-dependent component is associated with blood pressure and vascular permeability. A genetic risk score for the intraocular pressure-independent component of primary open angle glaucoma is associated with 26 different retinal micro-vascular features, which contrasts with the genetic risk score for the intraocular pressure-dependent component. Increased understanding of these intraocular pressure-dependent and intraocular pressure-independent components provides insights into the pathogenesis of glaucoma.

Abstract Oral corticosteroids represents the most prevalent treatment for idiopathic granulomatous mastitis. Ductal lavage with triamcinolone acetonide and antibiotics followed by observation (DL-OBS) has emerged as a novel strategy, but a comparison of them remains lacking. Here in this multicenter, open-label, non-inferiority, randomized trial (ClinicalTrials.gov identifier: NCT03724903), we assigned 140 patients to oral corticosteroids (N = 71) and DL-OBS (N = 69), stratified by baseline M-score. The primary outcome is complete Clinical Response rate at 1 year. The non-inferiority margin is −15%. The primary outcome is 85.5% in DL-OBS and 87.3% in oral corticosteroids (difference: −1.8%; 95%CI, 13.2 to 9.5; Pnon-inferiority = .01) in intention-to-treat population, and 92.6% vs 98.2% (difference −5.6%; 95%CI −13.4 to 2.2; Pnon-inferiority = .01) in per-protocol population, respectively. The most common (>15%) adverse events were Cushingoid, epigastric pain and arthralgia in oral corticosteroids, and irregular menstruation in DL-OBS, respectively. Here, we report that DL-OBS shows similar efficacy to oral corticosteroids but with better safety profile.

Abstract Direct photocatalytic conversion of methane to value-added C1 oxygenate with O2 is of great interest but presents a significant challenge in achieving highly selective product formation. Herein, a general strategy for the construction of copper single-atom catalysts with a well-defined coordination microenvironment is developed on the basis of metal-organic framework for selective photo-oxidation of CH4 to HCHO. We propose the directional activation of O2 on the mono-copper site breaks the original equilibrium and tilts the balance of radical formation almost completely toward •OOH. The synchronously generated •OOH and •CH3 radicals rapidly combine to form HCHO while inhibiting competing reactions, thus resulting in ultra-highly selective HCHO production (nearly 100%) with a time yield of 2.75 mmol gcat −1 h−1. This work highlights the potential of rationally designing reaction sites to manipulate reaction pathways and achieve selective CH4 photo-oxidation, and could guide the further design of high-performance single-atom catalysts to meet future demand.

Abstract Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy, the leading cause of blindness in the working-age population. However, the molecular mechanisms by which disturbed metabolic homeostasis causes vascular dysfunction in diabetic retinopathy remain unclear. O-GlcNAcylation modification acts as a nutrient sensor particularly sensitive to ambient glucose. Here, we observe pronounced O-GlcNAc elevation in retina endothelial cells of diabetic retinopathy patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase effectively mitigates vascular dysfunction. Mechanistically, we find that Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are O-GlcNAcylated in diabetic retinopathy. We identify threonine 383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at serine 397, leading to its stabilization and activation, thereby promoting vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. This work emphasizes the critical role of the O-GlcNAc-Hippo axis in the pathogenesis of diabetic retinopathy and suggests its potential as a therapeutic target.

Abstract Dynamic tracking of spinal instrumentation could facilitate real-time evaluation of hardware integrity and in so doing alert patients/clinicians of potential failure(s). Critically, no method yet exists to continually monitor the integrity of spinal hardware and by proxy the process of spinal arthrodesis; as such hardware failures are often not appreciated until clinical symptoms manifest. Accordingly, herein, we report on the development and engineering of a bio-adhesive metal detector array (BioMDA), a potential wearable solution for real-time, non-invasive positional analyses of osseous implants within the spine. The electromagnetic coupling mechanism and intimate interfacial adhesion enable the precise sensing of the metallic implants position without the use of radiation. The customized decoupling models developed facilitate the precise determination of the horizontal and vertical positions of the implants with incredible levels of accuracy (e.g.,

Abstract The SARS-CoV-2 Omicron variant sparked the largest wave of infections worldwide. Mainland China eased its strict COVID-19 measures in late 2022 and experienced two nationwide Omicron waves in 2023. Here, we investigated lineage distribution and virus evolution in Guangdong, China, 2022-2023 by comparing 5813 local viral genomes with the datasets from other regions of China and worldwide. Additionally, we conducted three large-scale serological surveys involving 1696 participants to measure their immune response to the BA.5 and XBB.1.9 before and after the corresponding waves. Our findings revealed the Omicron variants, mainly the BA.5.2.48 lineage, causing infections in over 90% of individuals across different age groups within a month. This rapid spread led to the establishment of widespread immunity, limiting the virus’s ability to further adaptive mutation and dissemination. While similar immune responses to BA.5 were observed across all age groups after the initial wave, children aged 3 to 11 developed a stronger cross immune response to the XBB.1.9 strain, possibly explaining their lower infection rates in the following XBB.1 wave. Reinfection with Omicron XBB.1 variant triggered a more potent neutralizing immune response among older adults. These findings highlight the impact of age-specific immune responses on viral spread in potential future waves.

Abstract Chloroaluminate ionic liquids selectively transform (waste) polyolefins into gasoline-range alkanes through tandem cracking-alkylation at temperatures below 100 °C. Further improvement of this process necessitates a deep understanding of the nature of the catalytically active species and the correlated performance in the catalyzing critical reactions for the tandem polyolefin deconstruction with isoalkanes at low temperatures. Here, we address this requirement by determining the nuclearity of the chloroaluminate ions and their interactions with reaction intermediates, combining in situ 27Al magic-angle spinning nuclear magnetic resonance spectroscopy, in situ Raman spectroscopy, Al K-edge X-ray absorption near edge structure spectroscopy, and catalytic activity measurement. Cracking and alkylation are facilitated by carbenium ions initiated by AlCl3-tert-butyl chloride (TBC) adducts, which are formed by the dissociation of Al2Cl7 − in the presence of TBC. The carbenium ions activate the alkane polymer strands and advance the alkylation cycle through multiple hydride transfer reactions. In situ 1H NMR and operando infrared spectroscopy demonstrate that the cracking and alkylation processes occur synchronously; alkenes formed during cracking are rapidly incorporated into the carbenium ion-mediated alkylation cycle. The conclusions are further supported by ab initio molecular dynamics simulations coupled with an enhanced sampling method, and model experiments using n-hexadecane as a feed.

Abstract The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.