The complex roles of m 6 A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases.

N6-methyladenosine (m 6 A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m 6 A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m 6 A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m 6 A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m 6 A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m 6 A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m 6 A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m 6 A's role in neurodegenerative processes. The roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the time-specific nature of m 6 A and its varying effects on distinct brain regions and in different environments.

A small library of copper-based metallenes with superior antibacterial activity.

We report the preparation of a small library of copper-based metallenes, such as copperene, brassene, bronzene, cupronickelene and AlCuZn trimetallene, via a cryo-pretreatment assisted liquid phase exfoliation method. To the best of our knowledge, these nanosheets may represent a new category of metallenes. Benefiting from mixed-valence copper-induced oxidative stress and cleavage effects of layered structures, the obtained metallenes could efficiently eliminate drug-resistant bacteria even at a concentration as low as 1 µg mL-1. Due to the alloy engineering-induced change in the release rate of metal ions, the CuZn metallene exhibited a much better antibacterial ability than the other metallenes and three clinical antibiotics. We believe this work not only expands the category of emerging 2D metallenes, but also proposes a strategy combining 2D and alloy engineering to improve the antibacterial properties of copper-based materials.

Making an inverted Keggin ion lacunary.

The century-old inverted Keggin ion has been revisited in an effort to unleash its potential in the structural engineering and functional development of polyoxomolybdates (POMos). Over the past hundred years, attempts to program the metal-oxo scaffold of inverted Keggins have been conducted continually but without any success. In this work, a structurally inert, inverted Keggin-type POMo could finally be altered by means of a binary heterogroup-templated approach, resulting in the successful isolation of two lacunary species. The local structure and charge distribution of these species are adjustable, and hence they serve as available building blocks for the subsequent controlled assembly of a CeIII-incorporated derivative. From the plenary to the lacunary, the enclosed structure of the inverted Keggin has been opened up significantly, resulting in less steric hindrance, along with a transition from an electron neutral species to a negatively charged species. Owing to these beneficial properties, the emerging defect-containing polyanions demonstrated outstanding Lewis acid-base catalytic activity in the high efficiency production of pyrazoles.

Pancreatic Cancer Cell-derived Migrasomes Promote Cancer Progression by Fostering an Immunosuppressive Tumor Microenvironment.

Pancreatic cancer is distinguished by an immunosuppressive tumor microenvironment (TME) that facilitates cancer progression. The assembly of the TME involves numerous contributing factors. Migrasomes, recently identified as cellular organelles in migrating cells, play a pivotal role in intercellular signaling. However, research into their involvement in cancers remains nascent. Thus far, whether pancreatic cancer cells generate migrasomes and their potential role in TME formation remains unexplored. In this study, it was found that both murine and human pancreatic cancer cells could indeed generate migrasomes, termed pancreatic cancer cell-derived migrasomes (PCDMs), which actively promote cancer progression. Moreover, utilizing chemokine antibody arrays and quantitative mass spectrometry analysis, we observed significant differences between the chemokines, cytokines, and proteins present in PCDMs compared to their originating cell bodies. Notably, PCDMs exhibited an enrichment of immunosuppression-inducing factors. Furthermore, macrophages could directly uptake PCDMs, leading to the expression of high levels of M2-like markers and secretion of tumor-promoting factors. PCDM-induced macrophages played a pivotal role in inhibiting T cell proliferation and activation partially through ARG-1. In summary, this study provides compelling evidence that pancreatic cancer cells generate migrasomes, which play a crucial role in promoting tumor progression by contributing to an immunosuppressive TME. The exploration of migrasomes as a therapeutic target could pave the way for the development of tailored immunotherapies for pancreatic cancer.

Bidirectional Causal Association Between Chronic Obstructive Pulmonary Disease and Cardiovascular Diseases: A Mendelian Randomization Study.

Background: A large number of studies have demonstrated links between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVDs). However, the causal relationship between COPD and CVDs and the reverse causality remains divergent. Methods: Exposure and outcome data from the largest available genome-wide association studies were extracted for Mendelian randomization (MR) studies. Univariate MR analysis was performed using IVW as the primary analysis method, and multiple sensitivity analyses were used to enhance the robustness of the results. Furthermore, this was followed by mediation MR analysis of positive results after excluding confounding factors with multivariable MR analysis. Results: The MR estimation based on IVW method indicated a strong association between genetically determined COPD and heart failure (HF) (OR = 1.117, 95% CI: 1.066-1.170, p <0.001), coronary heart disease (CHD) (OR = 1.004, 95% CI: 1.002-1.006, p <0.001), essential hypertension (EH) (OR = 1.009, 95% CI: 1.005-1.013, p <0.001) as well as Stroke (OR = 1.003, 95% CI: 1.001-1.004, p <0.001). The results of multivariable MR analysis revealed that COPD is not significantly associated with CHD after adjusting for IL-6, LDL, or total cholesterol (p>0.05). Our findings indicated that BMI, smoking initiation, smoking status, obesity, and FEV1 played a role in the causal effect of COPD on HF, EH, and Stroke. Conclusion: We found positive causal relationships between COPD and HF, EH, and Stroke essentially unaffected by other confounding factors. The causal relationship exhibited between COPD and CHD was influenced by confounding factors. BMI, obesity, initiation of smoking, smoking status, and FEV1 were the mediators between COPD and CVDs.

TRß activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA.

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRß fuels cell maturation in lung regeneration. Using a specific TRß agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRß in mice. Cellularly, TRß activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRß activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRß-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

A convenient colorimetric assay for Cr(VI) detection based on homogeneous Cu(II)-GMP system with oxidoreductase-like activity.

Hexavalent chromium (Cr(VI)) is an environmental pollutant and recognized as a human carcinogen. Therefore, it is necessary to develop a simple and sensitive detection technique for Cr(VI). Herein, it is found that Cu2+ interacts with guanosine 5'-monophosphate (GMP) to form a homogeneous Cu(II)-GMP complex (Cu2+·GMP) that efficiently displays the oxidoreductase-like catalytic activity. Cu2+·GMP can catalyze the oxidation between Cr(VI) and substrate 3,3',5,5'- tetramethylbenzidine (TMB), resulting in color change recognized by the naked eyes. Base on this, a convenient colorimetric assay for Cr(VI) detection was developed. The detection limit (3σ/s) of this sensor for Cr(VI) was 23 nM with a linear range of 0.1-25 µM. Moreover, the proposed assay was successfully applied to detect Cr(VI) in different environmental water samples with satisfactory recoveries. Our method is simple, efficient, rapid and cost-effective for Cr(VI) detection without the need for complicated material preparation or special separation, which shows great potential in environmental monitoring.

Unraveling the Role of PCDH9 in Breast Cancer and Identifying Therapeutic Strategies for PCDH9-Deficient Tumors.

Introduction: Protocadherin 9 (PCDH9), a member of the cadherin superfamily of transmembrane proteins, plays a role in cell adhesion and neural development. Recent studies suggest that PCDH9 may function as a tumor suppressor in certain cancers, though its specific role in breast cancer remains unclear. Methods: UALCAN database to retrieve information on PCDH9 expression in breast cancer tissues compared with that in normal tissues. The biological effects of PCDH9 in breast cancer cells were analyzed using the DepMap database. Stable knockdown or overexpression of PCDH9 in breast cancer cell lines and subsequently assessed tumor cell proliferation and migration. Synthetic lethal screening was conducted for breast cancer cells with low PCDH9 expression or deficiency. Results: In this study, we observed significant downregulation of PCDH9 in breast cancer tissues, with its expression negatively correlated with progression-free survival. Further investigations revealed that decreased PCDH9 expression promotes breast cancer cell proliferation and migration, while overexpression of PCDH9 has the opposite effect. Subsequently, we identified the TAS-102, an approved drug for metastatic colorectal cancer, exhibited selective cytotoxicity against breast cancer cells with low PCDH9 expression. Conclusion and discussion: In summary, our study identified PCDH9 as a tumor suppressor in breast cancer and highlighted TAS-102 as a potential therapeutic option for tumors with low PCDH9 expression or deficiency. The specific interaction between TAS-102 and PCDH9 warrants further exploration, providing deeper insights into its mode of action in treating PCDH9-deficient breast cancer.

Reaction-Modulated Surface-Enhanced Raman Scattering Strategy for Stereoselective Differentiation and Identification of Amino Acids.

Surface-enhanced Raman scattering (SERS) sensing of racemates is a remarkably fascinating yet very sophisticated objective because of similar physicochemical features of enantiomers. Inspired by the enantiomeric selectivity of nucleophilic addition reaction (NAR) toward amino acids, we herein propose highly effective, robust SERS discrimination of d- and l-valine by synergizing asymmetric gold nanorods-embedded ZIF-8 nanoparticles (AGNZ) with NAR to engender stereoselective molecular fingerprint. Experimental and chemometric analyses disclose that enantioselectivity lies in dual aspects: (i) abundant interfacial cavities and 3D hot-spots in AGNZ offer necessary confined asymmetrical surroundings to trigger enantiospecific molecular adsorption and interaction affinity, and (ii) the specified NAR drags the racemates adjacent to the interfacial area of AGNZ for maximum analytes-substrate interaction. This strategy is universal and can be utilized for the recognition of different amino acid enantiomers. Importantly, multiple quantifications of the racemic ratio can be realized with superior prognostic performances. This synergizing strategy therefore provides a significant paradigm shift from traditional methods to realize highly effective SERS discrimination of racemates.

H2 18O vapour labelling reveals evidence of radial Péclet effects, but in not all leaves.

Contradictory evidence exists regarding the relevance of Péclet-like gradients in leaf water isotopes, making it difficult to accurately predict variation in isotope composition. Here, we use H2 18O vapour labelling to directly test whether leaf water isotopes diffuse back into the xylem to be carried forward to more distal leaf portions. Backward diffusion has been assumed, due to observations of increasing enrichment towards the tip and outer edges of some leaves. Further complicating the selection of leaf water isotope models is the observation that some, but not all, leaves demonstrate a radial Péclet effect in bulk leaf water and that the hydraulic design of leaves may influence the development of isotope gradients in leaves. Carry-forward of H2 18O vapour label was detected in the two monocot species assessed (oat and corn), but not in the two dicot species (foxglove and sunflower). Further, bulk leaf water measurements at differing transpiration rates indicated that a bulk leaf water Péclet effect was relevant for foxglove only. We conclude that both leaf hydraulic design and relative velocities of water within transport pathways influence leaf water isotope composition, reconciling seemingly contradictory previous results regarding the relevance of Péclet effects to leaf water isotopes.

Measuring and optimizing the spatial accessibility of primary health care in remote and rural areas: a case study of Liannan Yao Autonomous County in China.

The need for equitable access to primary healthcare services in the current global context has attracted widespread attention, prompting nations to continuously enhance their grassroots medical service levels. In response, China launched the "Healthy China" initiative, which prioritizes the enhancement of national health as a core goal of the healthcare system and uses this opportunity to deepen reforms aimed at strengthening primary care. However, in remote and rural areas, the optimization of medical resource allocation and the achievement of balanced service development remain critical challenges owing to limited resources. This study selected Liannan Yao Autonomous County, which is situated in the northwestern corner of Guangdong Province, as a case study due to its remote mountainous location, underdeveloped economy, and minority region characteristics. Through field research and interviews, this study thoroughly explored the needs of both supply and demand, factoring in elements such as the service capability of healthcare facilities and residents' travel thresholds to enhance the two-step floating catchment area model, thus making it more applicable to remote villages. By integrating electric bikes and cars, which are the primary means of transportation in rural areas, this study conducted a thorough analysis and comparison of the accessibility of medical services in Liannan Yao Autonomous County (Liannan County) . The results reveal significant disparities in healthcare accessibility, an uneven distribution of medical resources, and varying impacts of transportation conditions and facility service capabilities on accessibility. Notably, the study revealed that improving transportation conditions alone has limited effects in rural areas; the key lies in balancing medical service capabilities and the rationality of overall layouts. From the perspectives of equity and efficiency, this study employs the equitable coverage model and the efficiency-driven model to construct two scenarios, comparing accessibility changes in Liannan County under both conditions and proposing strategies to improve the spatial layout of local healthcare facilities. This research not only deepens the understanding of healthcare service accessibility in rural areas but also provides a scientific basis for optimizing resource allocation and enhancing primary medical services, offering valuable guidance and reference for Liannan County and other similar rural regions.

Dual-energy CT: Impact of detecting bone marrow oedema in occult trauma in the Emergency.

Dual-energy computed tomography (DECT) is an advanced imaging technique that acquires data using two distinct X-ray energy spectra, typically at 80 and 140 kVp, to differentiate materials based on their atomic number and electron density. This capability allows for the enhanced visualisation of various pathologies, including bone marrow oedema (BMO), by providing high-resolution images with notable energy spectral separation while maintaining radiation doses comparable to conventional CT. DECT's ability to create colour-coded virtual non-calcium (VNCa) images has proven particularly valuable in detecting traumatic bone marrow lesions (BMLs) and subtle fractures, offering a reliable alternative or complement to MRI. DECT has emerged as a significant tool in the detection and characterisation of bone marrow pathologies, especially in traumatic injuries. Its ability to generate high-resolution images and distinguish between different tissue types makes it a valuable asset in clinical diagnostics. With its comparable diagnostic accuracy to MRI and the added advantage of reduced examination time and increased availability, DECT represents a promising advancement in the imaging of BMO and related conditions.

Association between the atherogenic index of plasma and early neurological deterioration in mechanical thrombectomy patients.

BACKGROUND AND PURPOSE: Atherogenic index of plasma (AIP) is a newly identified as marker of lipid metabolism and glucose metabolism, showing significant predictive value in individuals with cardiovascular disease. This study aimed to explore the correlation between AIP and early neurological deterioration (END) in ischemic stroke patients after mechanical thrombectomy (MT). METHODS: Patients with anterior circulation large artery occlusive stroke who underwent MT were retrospectively enrolled from 2 stroke center in China. The AIP is a logarithmically transformed ratio of triglycerides to high-density lipoprotein cholesterol. END was defined as an increase of ≥ 4 point in National Institutes of Health Stroke Scale within 24 hours after surgery. Multivariable regression analysis and restricted cubic spline was utilized to determine the association of AIP index with risk of END. RESULTS: Of 601 patients (mean age, 70.2 ± 12.1 years; 62.1 % of male) enrolled, 91 (15.1 %) experienced postoperative END. After adjustment for potential confounders, higher AIP levels were significantly associated with an increased risk of END after MT treatment (Per 1-standard deviation increase; odd ratio, 1.474; 95 % confidence interval, 1.162-1.869, P = 0.001). Similar results were confirmed when the AIP was analyzed as a categorical variable. Restricted cubic spline further demonstrated a linear relationship between AIP and risk of END (P = 0.001 for linearity). CONCLUSIONS: The present study found that a higher AIP index were associated with END in acute ischemic stroke patients following MT treatment for emergent large vessel occlusion.

Discriminative analysis of aroma profiles in diverse cigar products varieties through integrated sensory evaluation, GC-IMS and E-nose.

Cigars, treasured for their rich aromatic profiles, occupy a notable segment in the global consumer market. The objective of this study was to characterize the volatile aroma compounds that shape the flavor profiles of six distinct varieties of Great Wall cigars, contributing to the understanding of cigar aroma analysis. Utilizing HS-GC-IMS and sensory evaluation, the study discerned the aroma profiles of GJ No. 6 (GJ), Animal from the Chinese zodiac (SX), Range Rover No. 3 Classic (JD), Miracle 132 (QJ), Sheng Shi No. 5 (SS), and Red 132 (HS) cigars. The analysis uncovered a spectrum of characteristic aromas, including tobacco, creaminess, cocoa, leather, baking, herbaceous, leathery, woodsy, and fruity notes. A total of 88 compounds were identified, categorized into 11 chemical classes, with their quantities varying among the cigars in a descending order of QJ, JD, GJ, SS, HS, and SX. 24 compounds, such as 2-heptanone, n-butanol, 2,6-dimethylpyrazine and 2-furfuryl methyl sulfide were considered as key differential components. The volatile components were effectively differentiated using principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), and cluster analysis, revealing correlations between sensory attributes, key components, and electronic nose (E-nose). This research introduces a novel method for analyzing volatile aroma components in cigars, offering insights to enhance cigar quality and to foster the development of new products with unique aroma profiles.

Advances in Interventional Radiology Technology for the Treatment of Knee Osteoarthritis.

Minimally invasive interventional radiology procedures play an adjunctive role in treating the symptoms of osteoarthritis (OA) with the hopes of delaying total knee arthroplasty (TKA). However, currently available intra-articular injections offer only short-term benefits. This has led to evolution of new techniques such as genicular artery embolization and genicular nerve ablation, which show benefit in pain control and quality of life, especially for mild-to-moderate OA, positioning these techniques as potential alternatives to intra-articular injections to help delay TKA.

ALDH2 deficiency augments atherosclerosis through the USP14-cGAS-dependent polarization of proinflammatory macrophages.

The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism commonly exists in the East Asian populations and is associated with high risks of cardiovascular disease (CVD). However, the cellular and molecular mechanisms that underlie the ALDH2 rs671 mutant-linked high CVD remain elusive. Here, we show that macrophages derived from human ALDH2 rs671 carriers and ALDH2 knockout mice exhibited an enhanced pro-inflammatory macrophage phenotype and an impaired anti-inflammatory macrophage phenotype. Transplanting bone marrow from ALDH2-/-ApoE-/- to ApoE-/- mice significantly increased atherosclerotic plaque growth and pro-inflammatory macrophage polarization in vivo. Mechanistically, ALDH2 inhibited activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Pharmacological inhibition of cGAS by RU.521 completely neutralized ALDH2-deficiency-induced macrophage polarization. In-depth mechanistic investigation showed that ALDH2 accelerated cGAS K48-linked polyubiquitination degradation at lysine 282 in macrophages by reducing the interaction between ubiquitin-specific protease 14 (USP14) and cGAS, mainly through its enzymatic role in mitigating 4-hydroxy-2-nonenal (4-HNE) accumulation. Consistently, USP14 knockdown in bone marrow cells alleviated proinflammatory responses in macrophages and protected against atherosclerosis. Our findings provide new mechanistic insights of ALDH2 deficiency-associated proinflammation and atherosclerosis and new therapeutic and preventive paradigms for treatment of atherosclerosis-associated CVD.

112-GBaud mode-division-multiplexing IM-DD transmission beyond net 6.4†Tb/s over weakly coupled FMF for optical interconnections.

Weakly coupled mode-division-multiplexing (MDM) systems based on intensity modulation and direct detection (IM-DD) are a good candidate for further improving the capacity of short-reach optical interconnections. However, restrained by the modal crosstalk of the transmission link and the reception of degenerate mode groups (DMGs) utilizing bandwidth-limited multimode photodetectors (PDs), high-speed MDM IM-DD has encountered a capacity bottleneck. In this Letter, we investigate a high-speed weakly coupled MDM IM-DD transmission system utilizing a degenerate mode diversity receiver scheme adopting high-bandwidth single-mode PDs over a multiple-ring-core (MRC) few-mode fiber (FMF) and a low-crosstalk mode multiplexer/demultiplexer (MUX/DMUX). An MDM IM-DD transmission with four DMGs and eight wavelengths is experimentally demonstrated with 112-GBaud four-level pulse-amplitude modulation (PAM4) and probabilistically shaped PAM8 per lane over 200-m weakly coupled MRC-FMF. To the best of our knowledge, this is the first experimental demonstration of the MDM IM-DD transmission system with up to 112-GBaud baud rate and beyond 6.4-Tb/s net rate. Meanwhile, the experimental results show that the proposed MDM IM-DD transmission link has a superior performance only adopting a low-complexity feedforward equalizer, making it a promising candidate for high-speed optical interconnections.

Lactate promotes bone healing by regulating the osteogenesis of bone marrow mesenchymal stem cells through activating Olfr1440.

Bone malunion or nonunion leads to functional and esthetic problems and is a major healthcare burden. Activation of bone marrow mesenchymal stem cells (BMSCs) and subsequent induction of osteogenic differentiation by local metabolites are crucial steps for bone healing, which has not yet been completely investigated. Here, we found that lactate levels are rapidly increased at the local injury site during the early phase of bone defect healing, which facilitates the healing process by enhancing BMSCs regenerative capacity. Mechanistically, lactate serves as a ligand for the Olfr1440 olfactory receptor, to trigger an intracellular calcium influx that in turn activates osteogenic phenotype transition of BMSCs. Conversely, ablation of Olfr1440 delays skeletal repair and remodelling, as evidenced by thinner cortical bone and less woven bone formation in vivo. Administration of lactate in the defect area enhanced bone regeneration. These findings thus revealed the key roles of lactate in the osteogenic differentiation of BMSCs, which deepened our understanding of the bone healing process, as well as provided cues for a potential therapeutic option that might greatly improve bone defect treatment.

The long-term effectiveness and mechanism of oncolytic virotherapy combined with anti-PD-L1 antibody in colorectal cancer patient.

Colorectal cancer (CRC) is known to be resistant to immunotherapy. In our phase-I clinical trial, one patient achieved a 313-day prolonged response during the combined treatment of oncolytic virotherapy and immunotherapy. To gain a deeper understanding of the potential molecular mechanisms, we performed a comprehensive multi-omics analysis on this patient and three non-responders. Our investigation unveiled that, initially, the tumor microenvironment (TME) of this responder presented minimal infiltration of T cells and natural killer cells, along with a relatively higher presence of macrophages compared to non-responders. Remarkably, during treatment, there was a progressive increase in CD4+ T cells, CD8+ T cells, and B cells in the responder's tumor tissue. This was accompanied by a significant upregulation of transcription factors associated with T-cell activation and cytotoxicity, including GATA3, EOMES, and RUNX3. Furthermore, dynamic monitoring of peripheral blood samples from the responder revealed a rapid decrease in circulating tumor DNA (ctDNA), suggesting its potential as an early blood biomarker of treatment efficacy. Collectively, our findings demonstrate the effectiveness of combined oncolytic virotherapy and immunotherapy in certain CRC patients and provide molecular evidence that virotherapy can potentially transform a "cold" TME into a "hot" one, thereby improving sensitivity to immunotherapy.