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Efficient persistent monitoring in dynamic environments using multiple Unmanned Aerial Vehicles (UAVs) is essential for various applications. The complexity of this task is heightened by factors such as time-varying environmental states, limited energy capacity, and constrained communication ranges. This paper introduces IRADA (Integrated Reward Aggregation for Distributed Allocation), a novel distributed task allocation method for multi-UAV persistent monitoring in dynamic environments aims to maintain up-to-date situational awareness by minimizing information uncertainty across distributed points of interest (POIs). The decision-making of each UAV is guided by real-time reward of POIs computed in a distributed manner. These rewards integrate information collection efficiency, operational range under energy constraints, and communication tendencies with other UAVs. Furthermore, the integrated rewards are spatially aggregated using Gaussian Mixture Model (GMM) to enhance multi-step decision-making capabilities in a computationally efficient way. Extensive simulations demonstrate that our approach achieves superior performance in rapid information collection across various system configurations, including different numbers of UAVs, travel budgets, and communication ranges, under varying numbers of POIs. Ablation studies validate the advantages of GMM-based reward aggregation in both performance and computational efficiency. Additionally, our method exhibits system resilience when facing UAV failures, maintaining effective coverage through autonomous task redistribution.

SIRT1 (Sir2) is an NAD+-dependent deacetylase that plays critical roles in a broad range of biological events, including metabolism, the immune response and ageing1–5. Although there is strong interest in stimulating SIRT1 catalytic activity, the homeostasis of SIRT1 at the protein level is poorly understood. Here we report that macroautophagy (hereafter referred to as autophagy), a catabolic membrane trafficking pathway that degrades cellular components through autophagosomes and lysosomes, mediates the downregulation of mammalian SIRT1 protein during senescence and in vivo ageing. In senescence, nuclear SIRT1 is recognized as an autophagy substrate and is subjected to cytoplasmic autophagosome–lysosome degradation, via the autophagy protein LC3. Importantly, the autophagy–lysosome pathway contributes to the loss of SIRT1 during ageing of several tissues related to the immune and haematopoietic system in mice, including the spleen, thymus, and haematopoietic stem and progenitor cells, as well as in CD8+CD28− T cells from aged human donors. Our study reveals a mechanism in the regulation of the protein homeostasis of SIRT1 and suggests a potential strategy to stabilize SIRT1 to promote productive ageing.Xu et al. report that nuclear SIRT1 is recognized as an autophagy substrate during senescence and also observe ageing of the immune system.

Using a comprehensive library of histone H2A and H2B mutants, we assessed the biological function of each amino acid residue involved in various stress conditions including exposure to different DNA damage-inducing reagents, different growth temperatures, and other chemicals. H2B N- and H2A C-termini were critical for maintaining nucleosome function and mutations in these regions led to pleiotropic phenotypes. Additionally, two screens were performed using this library, monitoring heterochromatin gene silencing and genome stability, to identify residues that could compromise normal function when mutated. Many distinctive regions within the nucleosome were revealed. Furthermore, we used the barcode sequencing (bar-seq) method to profile the mutant composition of many libraries in one high-throughput sequencing experiment, greatly reducing the labor and increasing the capacity. This study not only demonstrates the applications of the versatile histone library, but also reveals many previously unknown functions of histone H2A and H2B.

Prediction of renewable energy consumption structure (RECS) can provide important guidance for energy development planning and energy structure transformation. The RECS refer to the proportion of various renewable energy consumptions and belong to compositional data, which could reflect the structural shapes of a complete system better. The multivariate compositional data’s vector autoregressive model (CDVAR) on the basis of the Simplex space and its algebraic system is proposed in this study aiming at the multi-dimensional small sample size. Firstly, the algebraic system of the Simplex space is introduced and the statistics of the compositional data are defined. Secondly, the novel model with the form of the compositional data is obtained and the least square parameter estimation of the model is derived according to Aitchison geometry. Third, the validation of the novel model is verified by the data on RECS in countries (China, USA, and Canada). The validation presents that the proposed model performs better in fitting, prediction, stability, and applicability compared with other five models under transformation. Last, the proposed model is applied to analyze and forecast the RECS of the above countries in 2021–2025 to provide an important basis for the optimization of the RECS.

BackgroundDespite the success of immune checkpoint blockade (ICB), many patients still fail to achieve durable clinical benefit. Previous studies have shown that CD8 T cells are reinvigorated by ICB. However, not all patients with this immunological response experience an effective clinical response, suggesting additional parameters may be relevant.DNA damage and repair (DDR) has been extensively studied in the context of inducing cell death of highly-proliferating tumor cells. However, whether T cell-intrinsic DDR impacts T cell differentiation and function, and how the coordination of DDR affects immunological and clinical response to proliferation-inducing ICBs have been largely unexplored. We hypothesized that the T celI-intrinsic DDR responses to proliferative and genotoxic stress might contribute to the disparity between immunological and clinical response.MethodsTo understand the impact of cell-intrinsic DDR on T cell differentiation and responses to cancer therapies, we developed a novel high-dimensional cytometry platform. This DDR-Immune platform enables simultaneous analysis of T cell differentiation state and multiple DDR pathways at single cell resolution. We then investigated immune reinvigoration and its association with DDR, in a cohort of chemotherapy-resistant hypermutated or microsatellite instability-high (MSI-H) uterine cancer patients treated with nivolumab. Peripheral blood samples were examined every 2–4 weeks after initiating anti-PD-1 treatment (N = 21).ResultsThe DDR-Immune platform revealed consistent T cell subset specific patterns of DDR, as well as specific DDR pathways induced by different types of DNA damage, such as γ-irradiation (IR), UV irradiation (UV) or proliferative stress (i.e. anti-CD3/CD28 stimulation). For example, terminally differentiated effector cells had higher DNA damage accumulation and cell death. In contrast, stem cell memory (TSCM) and regulatory T cells (Treg) displayed high DDR with less cell death, suggesting better cell-intrinsic DDR against genotoxic stress for survival advantage. In hypermutated MSI-H uterine cancer patients, CD8 T cells underwent rapid pharmacodynamic proliferation 2–4 weeks after starting PD-1 blockade, which did not correlate with clinical response. Application of the DDR-Immune platform to this cohort revealed, however, that in clinical responders but not clinical non-responders, Ki67+ CD8 T cells responding to PD-1 blockade had rapid induction of DDR represented as a spike increase of phosphorylated-ATM, presumably adapting T cell ‘fitness’ in response to proliferative stress induced by PD-1 blockade.ConclusionsCollectively, the new platform reveals previously unrecognized roles for T cell-intrinsic DDR as a novel determinant of immune responsiveness and clinical outcome to ICB and have potential application to other cancer therapies including chemotherapy and radiotherapy.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 (NCT03241745).

Cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. Tumours feel the sting from chromatin It has been observed that cells undergoing senescence—meaning that they can no longer divide and grow—contain cytoplasmic chromatin fragments. Shelley Berger and colleagues now show that these fragments are sensed by the cGAS–STING pathway, which senses foreign DNA during infection with pathogens. Activation of this pathway leads to an inflammatory phenotype and, in mice, allows the immune system to restrain tumour growth. These findings hint at the possibility that other endogenous sources of DNA may also elicit an inflammatory phenotype and influence various biological processes. Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing 1 , 2 , 3 . However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence 4 , 5 , a form of terminal cell-cycle arrest associated with pro-inflammatory responses 6 . The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING (cyclic GMP–AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin–cGAS–STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

In response to cancer-associated stress, autophagy machinery mediates degradation of nuclear lamina components in mammals, suggesting that cells might degrade nuclear components to prevent tumorigenesis. Autophagy in action in the nucleus Much is known about degradation of the cytoplasmic content by the process of autophagy. Shelly Berger and colleagues provide evidence that the nuclear content is also subject to such cellular clearance. The authors show that, in response to cancer-associated stress such as the activated oncogene RAS, the autophagy protein LC3 interacts with the nuclear lamina protein lamin B1 and binds to lamin-associated domains on chromatin. Lamin B1 is then shuttled to the cytoplasm for degradation within lysosomes. Inhibiting this process led to delay in oncogene-induced senescence, hinting that cells might degrade nuclear components to prevent tumorigenesis. Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases 1 , 2 , 3 . Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery 4 , 5 , 6 , is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3–lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3–lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.

Burnout among intensive care unit (ICU) nurses threatens patient safety and healthcare quality. We aimed to develop and internally validate a machine learning model to identify current burnout and its key correlates in this population. We surveyed 318 ICU nurses across four tertiary hospitals in three provinces of China (October 2024-November 2024), measuring 34 potential predictor variables. Data were partitioned into training (70%) and testing (30%) sets with downsampling addressing class imbalance. LASSO regression identified 12 significant predictors, which were evaluated using 10 machine learning algorithms. The final model was assessed using AUC, calibration, and SHAP analysis. The random forest algorithm showed optimal performance, with the final nine-predictor model achieving an AUC of 0.983, with good calibration (Brier score 0.054). SHAP analysis revealed psychological resilience (0.197) and job satisfaction (0.152) as primary protective factors, while nursing stress (0.059), night shift frequency (0.016), and poor sleep quality (0.015) emerged as key risk factors. Marital status, commuting mode, children, and residential area contributed additionally to predictions. The internally validated classification model developed in this study suggests that psychological resilience, job satisfaction, and nursing stress may play important roles in ICU nurse burnout. These findings can help nurse managers target organizational interventions-such as adequate staffing, recovery-protective scheduling, and support for resilience and job satisfaction-to prevent burnout, rather than placing responsibility on individual nurses. Further validation of this tool in diverse healthcare settings would be beneficial.

Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi.

Autophagy is an evolutionally conserved membrane trafficking process that degrades unwanted proteins, organelles and exogenous pathogens through autophagosomes and lysosomes. In mammals, dysfunction of autophagy machinery is associated with a number of diseases and pathologies. While the majority of autophagy studies focus on its function in maintaining protein homeostasis in the cytoplasm, the role of autophagy in the nucleus is less known. In the first part of my dissertation research, I have explored the mechanism of autophagy in degrading nuclear lamina. We show that a key autophagy protein, LC3, associates with nuclear lamina protein Lamin B1 and chromatin, and mediates the translocation of Lamin B1 and associated chromatin fragments to the cytoplasm for degradation during cellular senescence. This study provides new insight into the nuclear function of mammalian autophagy pathway. With the initial understanding of the nuclear autophagy pathway, in the second part of my dissertation, I have investigated the mechanism underlying the loss of SIRT1, a critical nuclear regulator of cell metabolism and aging, in the context of cellular senescence and in vivo aging. We demonstrate that nuclear SIRT1 is degraded through autophagy machinery in senescent human fibroblasts and certain tissues of aged mice. During senescence, SIRT1 is recognized as an autophagy substrate and undergoes nucleus-to-cytoplasm transportation. The autophagy protein LC3 interacts with SIRT1 to facilitate its degradation process, while disruption of LC3-SIRT1 association rescues SIRT1 downregulation. Moreover, SIRT1 is downregulated in aged mouse spleen, testis and hematopoietic stem and progenitor cells through lysosomal degradation. Given the important roles of SIRT1 in metabolism and aging, this study sheds light on a potential strategy to maintain SIRT1 protein levels to improve SIRT1 function and promote healthy lifespan. Overall, my dissertation studies characterize two major nuclear substrates of the autophagy pathway, contribute to our knowledge in the nuclear aspect of mammalian autophagy machinery and sirtuin biology, and suggest a new perspective in pharmaceutical design of anti-aging compounds.