The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8+ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8+ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8+ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8+ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (TTSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-TTSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy.

The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3ß kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2-AKT-GSK3ß axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Regulated Proteolysis of MutSγ Controls Meiotic Crossing Over.

Crossover recombination is essential for accurate chromosome segregation during meiosis. The MutSγ complex, Msh4-Msh5, facilitates crossing over by binding and stabilizing nascent recombination intermediates. We show that these activities are governed by regulated proteolysis. MutSγ is initially inactive for crossing over due to an N-terminal degron on Msh4 that renders it unstable by directly targeting proteasomal degradation. Activation of MutSγ requires the Dbf4-dependent kinase Cdc7 (DDK), which directly phosphorylates and thereby neutralizes the Msh4 degron. Genetic requirements for Msh4 phosphorylation indicate that DDK targets MutSγ only after it has bound to nascent joint molecules (JMs) in the context of synapsing chromosomes. Overexpression studies confirm that the steady-state level of Msh4, not phosphorylation per se, is the critical determinant for crossing over. At the DNA level, Msh4 phosphorylation enables the formation and crossover-biased resolution of double-Holliday Junction intermediates. Our study establishes regulated protein degradation as a fundamental mechanism underlying meiotic crossing over.

The Kinase mTORC1 Promotes the Generation and Suppressive Function of Follicular Regulatory T Cells.

Follicular regulatory T (Tfr) cells differentiate from conventional regulatory T (Treg) cells and suppress excessive germinal center (GC) responses by acting on both GC B cells and T follicular helper (Tfh) cells. Here, we examined the impact of mTOR, a serine/threonine protein kinase that senses and integrates diverse environmental cues, on the differentiation and functional competency of Tfr cells in response to protein immunization or viral infection. By genetically deleting Rptor or Rictor, essential components for mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), respectively, we found that mTORC1 but not mTORC2 is essential for Tfr differentiation. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 induced the expression of the transcription factor TCF-1 by promoting STAT3 binding to the Tcf7 5'-regulatory region. Subsequently, TCF-1 bound to the Bcl6 promoter to induce Bcl6 expression, which launched the Tfr cell differentiation program. Thus, mTORC1 initiates Tfr cell differentiation by activating the TCF-1-Bcl-6 axis during immunization or infection.

Efficient C-N coupling in the direct synthesis of urea from CO2 and N2 by amorphous SbxBi1-xOy clusters.

Although direct generation of high-value complex molecules and feedstock by coupling of ubiquitous small molecules such as CO2 and N2 holds great appeal as a potential alternative to current fossil-fuel technologies, suitable scalable and efficient catalysts to this end are not currently available as yet to be designed and developed. To this end, here we prepare and characterize SbxBi1-xOy clusters for direct urea synthesis from CO2 and N2 via C-N coupling. The introduction of Sb in the amorphous BiOx clusters changes the adsorption geometry of CO2 on the catalyst from O-connected to C-connected, creating the possibility for the formation of complex products such as urea. The modulated Bi(II) sites can effectively inject electrons into N2, promoting C-N coupling by advantageous modification of the symmetry for the frontier orbitals of CO2 and N2 involved in the rate-determining catalytic step. Compared with BiOx, SbxBi1-xOy clusters result in a lower reaction potential of only -0.3 V vs. RHE, an increased production yield of 307.97 µg h-1 mg-1cat, and a higher Faraday efficiency (10.9%), pointing to the present system as one of the best catalysts for urea synthesis in aqueous systems among those reported so far. Beyond the urea synthesis, the present results introduce and demonstrate unique strategies to modulate the electronic states of main group p-metals toward their use as effective catalysts for multistep electroreduction reactions requiring C-N coupling.

Dopamine Receptor 1 Impedes ILC2-Mediated Antitumor Immunity.

Ever-growing evidence has revealed that group 2 innate lymphoid cells (ILC2s) exhibit pleiotropic effects in antihelminth immunity, allergy, tissue protection, and cancer. Currently, the role of ILC2s in cancer is highly controversial regarding the intricate tumor microenvironment (TME), and the tumor-promoting or antitumor immunological mechanisms of ILC2s remain largely unknown. In this study, we report that dopamine receptor 1 (DRD1) restrains ILC2 activity in the TME. DRD1 deficiency promotes ILC2 activation, which irritates eosinophil recruitment and cytotoxic CD8+ T cell expansion during ongoing malignancy. Consequently, DRD1-deficient mice exhibit delayed tumor growth and reduced tumor progression. Furthermore, fenoldopam, a selective DRD1 agonist, restrains the ILC2 response in the TME and aggravates tumor burden in mice. Taken together, our data elaborate that the DRD1 signal acts as an excitatory rheostat in regulating ILC2-dependent antitumor immunity.

Anomalous water transport in narrow-diameter carbon nanotubes.

Carbon nanotubes (CNTs) mimicking the structure of aquaporins support fast water transport, making them strong candidates for building next-generation high-performance membranes for water treatment. The diffusion and transport behavior of water through CNTs or nanoporous graphene can be fundamentally different from those of bulk water through a macroscopic tube. To date, the nanotube-length-dependent physical transport behavior of water is still largely unexplored. Herein, on the basis of molecular dynamics simulations, we show that the flow rate of water through 0.83-nm-diameter (6,6) and 0.96-nm-diameter (7,7) CNTs exhibits anomalous transport behavior, whereby the flow rate increases markedly first and then either slowly decreases or changes slightly as the CNT length l increases. The critical range of l for the flow-rate transition is 0.37 to 0.5 nm. This anomalous water transport behavior is attributed to the l-dependent mechanical stability of the transient hydrogen-bonding chain that connects water molecules inside and outside the CNTs and bypasses the CNT orifice. The results unveil a microscopic mechanism governing water transport through subnanometer tubes, which has important implications for nanofluidic manipulation.

Patterned Gold Nanoparticle Superlattice Film for Wearable Sweat Sensors.

Nanoparticle superlattices are beneficial in terms of providing strong and uniform signals in analysis owing to their closely packed uniform structures. However, nanoparticle superlattices are prone to cracking during physical activities because of stress concentrations, which hinders their detection performance and limits their analytical applications. In this work, template printing methods were used in this study to prepare a patterned gold nanoparticle (AuNP) superlattice film. By adjustment of the size of the AuNP superlattice domain below the critical size of fracture, the mechanical stability of the AuNP superlattice domain is improved. Thus, long-term sustainable high-performance signal output is achieved. The patterned AuNP superlattice film was used to construct a wearable sweat sensor based on surface-enhanced Raman scattering (SERS). The designed sensor showed promise for long-term reliable use in actual scenarios in terms of recommending water replenishment, monitoring hydration states, and tracking the intensity of activity.

Metal-Organic Framework-Based Surface-Enhanced Raman Scattering Sensing Platform for Trace Malondialdehyde Detection in Tears.

Disease biomarkers in tears are crucial for clinical diagnosis and health monitoring. However, the limited volume of tear samples, low concentration of tear biomarkers, and complex tear composition present challenges for precise testing. We introduce a spot-on testing platform of metal-organic framework (MOF)-based surface-enhanced Raman scattering (SERS) capillary column, which is capable of target molecules selective separation and enrichment for tear biomarkers in situ detection. It consists of Au nanostars for effective SERS signal and a porous MOF shell for separating impurities through molecular sieving effect. This platform allows for simultaneous collection and detection of tear, capturing the disease biomarker malondialdehyde in tears with a 9.38 × 10-9 mol/L limit of detection. Moreover, we designed a hand-held device based on this tubular SERS sensor, successfully diagnosing patients with dry eye disease. This functional capillary column enables noninvasive and rapid diagnosis of biomarkers in biofluids, providing potential for disease diagnosis and healthcare monitoring.

Radical Replacement Process for Ligated Boryl Radical-Mediated Activation of Unactivated Alkyl Chlorides for C(sp3)-C(sp3) Bond Formation.

The ligated boryl radical (LBR) has emerged as a potent tool for activating alkyl halides in radical transformations through halogen-atom transfer (XAT). However, unactivated alkyl chlorides still present an open challenge for this strategy. We herein describe a new activation mode of the LBR for the activation of unactivated alkyl chlorides to construct a C(sp3)-C(sp3) bond. Mechanistic studies reveal that the success of the protocol relies on a radical replacement process between the LBR and unactivated alkyl chloride, forming an alkyl borane intermediate as the alkyl radical precursor. Aided with the additive K3PO4, the alkyl borane then undergoes one-electron oxidation, generating an alkyl radical. The incorporation of the radical replacement activation model to activate unactivated alkyl chlorides significantly enriches LBR chemistry, which has been applied to activate alkyl iodides, alkyl bromides, and activated alkyl chlorides via XAT.

Achieving Nickel-Catalyzed Reductive C(sp2)-B Coupling of Bromoboranes via Reversing the Activation Sequence.

Transition metal-catalyzed reductive cross-couplings to build C-C/Si bonds have been developed, but the reductive cross-coupling to create the C(sp2)-B bond has not been explored. Herein, we describe a nickel-catalyzed reductive cross-coupling between aryl halides and bromoboranes to construct a C(sp2)-B bond. This protocol offers a convenient approach for the synthesis of a wide range of aryl boronate esters, using readily available starting materials. Mechanistic studies indicate that the key to the success of the reaction is the activation of the B-Br bond of bromoboranes with a Lewis base such as 2-MeO-py. The activation ensures that bromoboranes will react with the active nickel(I) catalyst prior to aryl halides, which is different from the sequence of the general nickel-catalyzed reductive C(sp2)-C/Si cross-coupling, where the oxidative addition of an aryl halide proceeds first. Notably, this approach minimizes the production of undesired homocoupling byproduct without the requirement of excessive quantities of either substrate.

Amorphous Bismuth-Tin Oxide Nanosheets with Optimized C-N Coupling for Efficient Urea Synthesis.

Closing the carbon and nitrogen cycles by electrochemical methods using renewable energy to convert abundant or harmful feedstocks into high-value C- or N-containing chemicals has the potential to transform the global energy landscape. However, efficient conversion avenues have to date been mostly realized for the independent reduction of CO2 or NO3-. The synthesis of more complex C-N compounds still suffers from low conversion efficiency due to the inability to find effective catalysts. To this end, here we present amorphous bismuth-tin oxide nanosheets, which effectively reduce the energy barrier of the catalytic reaction, facilitating efficient and highly selective urea production. With enhanced CO2 adsorption and activation on the catalyst, a C-N coupling pathway based on *CO2 rather than traditional *CO is realized. The optimized orbital symmetry of the C- (*CO2) and N-containing (*NO2) intermediates promotes a significant increase in the Faraday efficiency of urea production to an outstanding value of 78.36% at -0.4 V vs RHE. In parallel, the nitrogen and carbon selectivity for urea formation is also enhanced to 90.41% and 95.39%, respectively. The present results and insights provide a valuable reference for the further development of new catalysts for efficient synthesis of high-value C-N compounds from CO2.

Integrated Electrochemical Aptasensor Array toward Monitoring Anticancer Drugs in Sweat.

In the realm of clinical practice, the concurrent utilization of anticancer medications can enhance their overall therapeutic efficacy. However, it is crucial to acknowledge that the interactions among these anticancer drugs can potentially yield detrimental consequences on their intended outcomes. Consequently, the assessment of both anticancer potency and potential toxic side effects is greatly refined when multiple anticancer drugs are simultaneously detected and evaluated. Here, we designed a wearable electrochemical aptasensor array for monitoring multiple anticancer drugs in sweat. The integrated sensor array consists of three working electrodes modified with three different aptamers (Apt1, Apt2, and Apt3), a Au counter electrode, and a Ag/AgCl reference electrode. Molecular docking simulations were performed to show the binding affinities between three anticancer drugs and their corresponding aptamers. Various eigenvalues were derived from the square-wave voltammetry electrochemical signals, and these data sets were subjected to rigorous analysis through multivariate data analysis techniques. This analytical approach demonstrated exceptional performance by achieving flawless 100% accuracy in the precise identification of nine anticancer drugs consistently at uniform concentrations. Furthermore, the integrated wearable sensor array exhibited impressive capabilities, correctly recognizing all nine anticancer drugs with 100% accuracy and successfully distinguishing between these drugs in artificial sweat samples. The proposed sensor array presents good stability for 15 days. Flexibility tests showed stable device performance after 500 twisting cycles. This innovative wearable sensing array represents a novel approach for achieving real-time monitoring and precise adjustment of drug dosages. It offers invaluable insights for tailoring the treatment of anticancer drugs to individual patients, predicting both drug efficacy and potential adverse reactions within the field of clinical medicine.

A Triboelectric-Electromagnetic Hybrid Nanogenerator with Magnetic Coupling Assisted Waterproof Encapsulation for Long-Lasting Energy Harvesting.

Ocean energy harvesting based on a triboelectric nanogenerator (TENG) has great application potential, while the encapsulation of triboelectric devices in water poses a critical issue. Herein, a triboelectric-electromagnetic hybrid nanogenerator (TE-HNG) consisting of TENGs and electromagnetic generators (EMGs) is proposed to harvest water flow energy. A magnetic coupling transmission component is applied to replace traditional bearing structures, which can realize the fully enclosed packaging of the TENG devices and achieve long-lasting energy harvesting from water flow. Under the intense water impact, magnetic coupling reduces the possibility of internal gear damage due to excessive torque, indicating superior stability and robustness compared to conventional TENG. At the waterwheel rotates speed of 75 rpm, the TE-HNG can generate an output peak power of 114.83 mW, corresponding to a peak power density of 37.105 W m-3. After 5 h of continuous operation, the electrical output attenuation of TENG is less than 3%, demonstrating excellent device durability. Moreover, a self-powered temperature sensing system and a self-powered cathodic protection system based on the TE-HNG are developed and illustrated. This work provides a prospective strategy for improving the output stability of TENGs, which benefits the practical applications of the TENGs in large-scale blue energy harvesting.

Multiple strategies, including 6mA methylation, affecting plant alternative splicing in allopolyploid peanut.

Alternative splicing (AS), an important post-transcriptional regulation mechanism in eukaryotes, can significantly increase transcript diversity and contribute to gene expression regulation and many other complicated developmental processes. While plant gene AS events are well described, few studies have investigated the comprehensive regulation machinery of plant AS. Here, we use multi-omics to analyse peanut AS events. Using long-read isoform sequencing, 146 464 full-length non-chimeric transcripts were obtained, resulting in annotation corrections for 1782 genes and the identification of 4653 new loci. Using Iso-Seq RNA sequences, 271 776 unique splice junctions were identified, 82.49% of which were supported by transcriptome data. We characterized 50 977 polyadenylation sites for 23 262 genes, 12 369 of which had alternative polyadenylation sites. AS allows differential regulation of the same gene by miRNAs at the isoform level coupled with polyadenylation. In addition, we identified many long non-coding RNAs and fusion transcripts. There is a suppressed effect of 6mA on AS and gene expression. By analysis of chromatin structures, the genes located in the boundaries of topologically associated domains, proximal chromosomal telomere regions, inter- or intra-chromosomal loops were found to have more unique splice isoforms, higher expression, lower 6mA and more transposable elements (TEs) in their gene bodies than the other genes, indicating that chromatin interaction, 6mA and TEs play important roles in AS and gene expression. These results greatly refine the peanut genome annotation and contribute to the study of gene expression and regulation in peanuts. This work also showed AS is associated with multiple strategies for gene regulation.

Ultralow thermal conductivity of 2D Dion-Jacobson (PDA)(FA)n - 1PbnI3n + 1 perovskite films.

Two-dimensional (2D) perovskites exhibit enhanced thermal stability compared to three-dimensional perovskites, especially the emerging 2D Dion-Jacobson (DJ) phase perovskite. However, the heat transfer mechanisms in DJ phase perovskites are rarely reported. Herein, we determine thermal conductivities of (PDA)(FA)n - 1PbnI3n + 1 films with n = 1-6 by time-domain thermoreflectance. The measured results indicate that the thermal conductivities of these films are extremely low, showing a trend from decline to rise with increasing n values, and reaching to the lowest when n = 2. We measure the propagation of acoustic phonons in films with n = 1-3 by time-domain Brillouin scattering and find phonon velocity plays a key role in the thermal conductivity, which can be explained by the mismatch of spring constants between the inorganic layer and the organic layer using the bead-spring model. The gradually increasing thermal conductivity for larger n values is attributed to the gradual transformation of the grain orientation from horizontal to vertical, which is demonstrated by the grazing-incidence wide-angle x ray scattering (GIWAXS) results. Our work deepens the understanding of the thermal transport process in 2D DJ phase perovskite films and provides insights into thermal management solutions for their devices.

Bidirectional influence between benign prostatic hyperplasia, prostate cancer, and prostatitis and mental disorders: two-sample and multivariate mendelian randomization analyses.

BACKGROUND: We aimed to use Mendelian randomization (MR) to determine the causality between fifteen major mental disorders (MDs) and benign prostatic hyperplasia (BPH), prostate cancer (PCa), and prostatitis. METHODS: The main MR analysis was performed using the inverse variance-weighted (IVW) method. RESULTS: The study found that insomnia (odds ratio [OR], 1.6190; p = .0017) was significantly associated with an increased risk of BPH, and mood disorders (OR, 1.1590; p = .0221) was nominally associated with an increased risk of BPH. Conversely, BPH was suggestively associated with a low epilepsy risk (OR, 0.9988; p = .0043), and was nominally associated with an increased risk of insomnia (OR, 1.0061; p = .0291). Furthermore, attention deficit hyperactivity disorder (ADHD) was suggestively associated with a low PCa risk (OR = 0.9474; p = .0058). However, no causal relationship was observed between PCa and MDs. Finally, anorexia nervosa (OR, 1.1686; p = .0248) and depression (OR, 336.5383; p = .0308) were nominally positively correlated with prostatitis. Prostatitis was suggestively associated with increased risk of ADHD (OR, 1.0868; p = .0413). CONCLUSION: Our findings provide clinicians with a basis for developing programs to prevent or treat MDs and prostatic diseases.

Mn(II)-Based Metal Halide with Near-Unity Quantum Yield for White LEDs and High-Resolution X-ray Imaging.

Metal halides have drawn great interest as luminescent materials and scintillators due to their outstanding optical properties. Exploring new types of phosphors with easy production processes, excellent photophysical properties, high light yields, and environmentally friendly compositions is crucial and quite challenging. Herein, a novel Mn(II)-based metal halide (4-BTP)2MnBr4 was produced using a facile solvent evaporation method, which exhibited a strong green emission peaking at 524 nm from the d-d transition of tetrahedral-coordinated Mn2+ ion and a near-unity quantum yield. The prepared white light-emitting diode device has a wide color gamut of 100.7% NTSC with CIE chromaticity coordinates of (0.32, 0.32). In addition, (4-BTP)2MnBr4 demonstrates excellent characteristics in X-ray scintillation, including a high light yield of 98 000 photons/MeV, a sensitive detection limit of 37.4 nGy/s, excellent resistance to radiation damage, and successful demonstration of X-ray imaging with high resolution at 21.3 lp/mm, revealing the potential for application in diagnostic X-ray medical imaging and industry radiation detection.

Contact Electrification at the Liquid-Solid Interface.

Interfaces between a liquid and a solid (L-S) are the most important surface science in chemistry, catalysis, energy, and even biology. Formation of an electric double layer (EDL) at the L-S interface has been attributed due to the adsorption of a layer of ions at the solid surface, which causes the ions in the liquid to redistribute. Although the existence of a layer of charges on a solid surface is always assumed, the origin of the charges is not extensively explored. Recent studies of contact electrification (CE) between a liquid and a solid suggest that electron transfer plays a dominant role at the initial stage for forming the charge layer at the L-S interface. Here, we review the recent works about electron transfer in liquid-solid CE, including scenerios such as liquid-insulator, liquid-semiconductor, and liquid-metal. Formation of the EDL is revisited considering the existence of electron transfer at the L-S interface. Furthermore, the triboelectric nanogenerator (TENG) technique based on the liquid-solid CE is introduced, which can be used not only for harvesting mechanical energy from a liquid but also as a probe for probing the charge transfer at liquid-solid interfaces.

Wearable biosensors for human sweat glucose detection based on carbon black nanoparticles.

Wearable glucose biosensors enable noninvasive glucose monitoring, thereby enhancing blood glucose management. In this work, we present a wearable biosensor based on carbon black nanoparticles (CBNPs) for glucose detection in human sweat. The biosensor consists of CBNPs, Prussian blue (PB), glucose oxidase, chitosan, and Nafion. The fabricated biosensor has a linear range of 5 µM to 1250 µM, sensitivity of 14.64 µA mM-1 cm-2, and a low detection potential (-0.05 V, vs. Ag/AgCl). The detection limit for glucose was calculated as 4.83 µM. This reusable biosensor has good selectivity and stability and exhibits a good response to glucose in real sweat. These results demonstrate the potential of our CBNP-based biosensor for monitoring blood glucose in human sweat.